Envenomation Syndrome Research Articles

Cytokine and nitric oxide production following severe envenomation.

Venom is a complex mixture of many substances such as toxins, enzymes, growth factor activators, and inhibitors are particularly responsible for the deleterious effects of cells. These constituents interact in the body with a large number of proteins and receptors, and this interaction determines the eventual inflammatory effect of the compounds. Envenomation by bees, scorpions, snakes, spiders and wasps involves the activation of the inflammatory response with the release and activation of pro-inflammatory cytokines and other mediators, such as nitric oxide. Recently, a battery of cytokines produced by activated T cells or macrophages have been added to in envenomations. Cytokines are important for the interactions between cells in the immune and inflammatory responses. Although the pathophysiology of envenomation is not fully understood, venom and immune responses are known to trigger the release of cytokines and nitric oxide. The cytokines initiate a cascade of events that lead to illness behaviors such as fever, anorexia, and, as well as a host of physiologic events such as activation of vasodilation, hypotension and increased nitric oxide production. Accumulating evidence indicates that these cytokines play important roles in mediating cell recruitment and activation necessary for inflammation and the repair of tissue damage. A better understanding of the involvement of the inflammatory system in different envenoming syndromes may have future therapeutic benefits.

Lung compliance, plasma electrolyte levels and acid–base balance are affected by scorpion envenomation in anesthetized rats under mechanical ventilation

To determine the effects of Tityus serrulatus scorpion toxin on lung compliance and resistance, ionic equilibrium and acid–base balance over time in anesthetized and mechanically ventilated rats, we measured air flow, tracheal and esophageal pressure. Lung volume was obtained by electronic integration of airflow signal. Arterial blood samples were collected through a catheter at baseline (before) and 5, 15, 30 and 60 min after scorpion toxin injection for arterial blood gases, bicarbonate, and alkali reserve levels as well as for, sodium, potassium, magnesium, glucose, lactate, hematocrit, and osmolality analysis. Injection of the gamma fraction of the T. serrulatus scorpion venom in rats under mechanical ventilatory support leads to a continuous decrease in lung compliance secondary to pulmonary edema, but no change in airway resistance. The changes in arterial blood gases characterizing metabolic acidosis were accompanied by an increase in arterial lactate and glucose values, suggesting a scorpion toxin-induced lactic acidosis, in association with poor tissue perfusion (hypotension and low cardiac output). Moreover, scorpion toxin injection resulted in hyperosmolality, hyperkalemia, hypermagnesemia and an increase in hematocrit. The experiments have shown a clinically relevant animal model to study severe scorpion envenoming and may help to better understand the scorpion envenoming syndrome.

The Clinical Management of Scorpion Stings in Children

Management of scorpion envenomation in children is a difficult problem. The envenomation syndrome is not very well understood in humans although there has been extensive work on animal envenomation. This is an attempt to bring together the two experiences in order to produce an acceptable management protocol for envenomation in children. This protocol is based on the management of more than 2,500 cases over a period of seven years in Saudi Arabia where the mortality was about five per cent at the start and zero at the end. The management protocol adopted there in 1992 was a result of serious work on clinical data from Ministry of Health hospitals and laboratory work in the pharmacology department of the faculty of Pharmacy, King Saud University

Jellyfish envenoming syndromes: unknown toxic mechanisms and unproven therapies.

Interest in envenoming syndromes caused by Australian jellyfish has been intense since the deaths in early 2002 of two tourists in Queensland, attributed to the Irukandji syndrome. We review current knowledge of these envenoming syndromes, mechanisms of venom action and therapy, focusing on the deadly box jellyfish, Chironex fleckeri, and the array of jellyfish thought to cause the Irukandji syndrome. Current understanding of jellyfish venom activity is very limited, and many treatments are unproven and based on anecdote.

Investigations on the role of insulin and scorpion antivenom in scorpion envenoming syndrome

Acute myocardiopathy in alloxan treated experimental dogs and rabbits was induced by subcutaneous (SQ) injection of scorpion venom from Mesobuthus tamulus concanesis, Pocock. Envenoming resulted in an initial transient hypertension (180-320 mm Hg.) followed by hypotension. Simultaneous administration of venom and species-specific scorpion antivenom (SAV) prevented hypertension and hypotension. Hypotension did not occur when SAV was given 60 min after envenoming. Blood glucose, triglycerides, cholesterol, amylase, insulin, glucagon, cortisol, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count, red blood cell (RBC) count, hemoglobin (Hb), 2,3-diphosphoglycerate (2,3-DPG), and glutathione levels were increased 60 and 90 min after envenoming. Total white blood cell (WBC) count was reduced 60 min and increased 90 min after envenoming. Simultaneous administration of venom and SAV did not alter Hb, MCHC, and packed cell volume (PCV) levels, or ECG, and cardiovascular, biochemical, metabolic, and hormonal changes. Hematological parameters were reversed when SAV was given 30 and 60 min after envenoming. PCV, Hb, and MCHC values returned to normal 120 min after SAV. Alloxan-treated dogs showed increased blood glucose, cholesterol, glucagon, cortisol levels; reduced glycogen content of liver, cardiac and skeletal muscles; and reduced insulin levels and insulin/ glucagon ratio (I/G ratio). Envenoming in the alloxan pre-treated dogs further increased these levels and reduced tissue glycogen content, insulin levels, and I/G ratio. Administration of 4 U of insulin to alloxan pre-treated envenomed rabbits caused a biochemical and clinical improvement and increased glycogen content of all tissues in comparison with the values from those administered with SAV to alloxan pre-treated envenomed animals. SAV administration to envenomed alloxan pre-treated rabbits did not cause clinical or biochemical improvement. Severe scorpion envenoming causes an autonomic storm with a massive release of catecholamines and other counter-regulatory hormones; changes in insulin secretion resulting in fuel energy deficits producing multi-system-organ-failure (MSOF); and death. Administration of either insulin or SAV (through the release of insulin) appears to be the physiological basis for the control of the metabolic support to control the adverse effects triggered by counter-regulatory hormones.

Treatment of the scorpion envenoming syndrome: 12-years experience with serotherapy

The pathophysiology of the scorpion envenoming syndrome is described with emphasis on the body systems commonly affected. Concepts of the mechanisms underlying venom action, as can be explained by the recently discovered effects on ionic channels, are discussed. A protocol for the treatment of scorpion stings based mainly on antivenom therapy was applied nationwide in Saudi Arabia. A list of drugs with alternatives was specified to be used in adjunctive therapy, when required. Analysis of the outcome from 1033 cases at Al-Baha region, 791 cases at Al-Qassim region and more than 2000 cases from 12 central and specialist hospitals in the Central Province, Saudi Arabia gave impressive results. The incidence of severe venom toxicity following antivenom administration was almost negligible. The period of stay in the hospital was reduced. The early reaction to antivenom administration was lower than expected the severity of the reaction consisting mainly of skin rashes, urticaria, wheezing and bronchial hypersensitivity, but no anaphylaxis. About 13.8% of the victims had been previously treated with antivenom but only 1.7% of the patients showed positive skin tests. This might be due to the low protein content of the antivenom and the action of the venom in releasing massive amounts of catecholamines.

Spiders of medical importance in the Asia-Pacific: atracotoxin, latrotoxin and related spider neurotoxins.

1. The spiders of medical importance in the Asia-Pacific region include widow (family Theridiidae) and Australian funnel-web spiders (subfamily Atracinae). In addition, cupboard (family Theridiidae) and Australian mouse spiders (family Actinopodidae) may contain neurotoxins responsible for serious systemic envenomation. Fortunately, there appears to be extensive cross-reactivity of species-specific widow spider antivenom within the family Theridiidae. Moreover, Sydney funnel-web antivenom has been shown to be effective in the treatment of mouse spider envenomation. 2. alpha-Latrotoxin (alpha-LTx) appears to be the main neurotoxin responsible for the envenomation syndrome known as "latrodectism" following bites from widow spiders. This 120 kDa protein binds to distinct receptors (latrophilin 1 and neurexins) to induce neurotransmitter vesicle exocytosis via both Ca2+-dependent and -independent mechanisms, resulting in vesicle depletion. This appears to involve disruption to a process that normally inhibits vesicle fusion in the absence of Ca2+. Precise elucidation of the mechanism of action of alpha-LTx will lead to a major advancement in our understanding of vesicle exocytosis. 3. delta-Atracotoxins (delta-ACTX) are responsible for the primate-specific envenomation syndrome seen following funnel-web spider envenomation. These peptides induce spontaneous repetitive firing and prolongation of action potentials in excitable cells. This results from a hyperpolarizing shift of the voltage-dependence of activation and a slowing of voltage-gated Na+ channel inactivation. This action is due to voltage-dependent binding to neurotoxin receptor site-3 on insect and mammalian voltage-gated Na+ channels in a manner similar, but not identical, to scorpion alpha-toxins and sea anemone toxins. delta-Atracotoxins provide us with highly specific tools to study Na+ channel structure and function 4. omega- and Janus-faced ACTX, from funnel-web spider venom, are novel neurotoxins that show selective toxicity to insects. In particular omega-ACTX define a new insecticide target due to a specific action to block insect voltage-gated Ca2+ channels. Both these ACTX show promise for the development of baculoviral recombinant biopesticides expressing these toxins for the control of insecticide-resistant agricultural pests. In addition, they should provide valuable tools for the pharmacological and structural characterization of insecticide targets.

Cnidarians and human skin

Cnidarians are aquatic animals including the jellyfish, the Portuguese man-of-war, fire coral, hydroids, sea anemones, and coral. Many of these can harm human skin and rarely some envenomations can lead to a serious or even fatal outcome. This article discusses the varied creatures in this group that can harm man and potentially lead to serious envenomation syndromes. Treatment of cnidarian injuries and stings is discussed.

Venom as a source of useful biologically active molecules.

In the specialty area of venomology, emergency physicians traditionally have been most interested in the description of a variety of envenomation syndromes and, subsequent to this, the most appropriate investigative and therapeutic strategies to employ when envenomation is present. Taking an alternative viewpoint, in this paper we have reviewed a selection of interesting areas of biomedical research in which venom components are being investigated for their potential as novel therapeutic agents, pesticides and ion-channel probes. In addition, we describe the molecular imaging tools of X-ray crystallography and nuclear magnetic resonance spectroscopy, key techniques in the development of rationally designed therapeutic agents.

Out-of-hospital and interhospital management of crotaline snakebite

Despite insufficient data for the development of evidence-based guidelines for the out-of-hospital treatment of crotaline snake envenomation, practical concerns dictate a rational approach based on existing information. Out-of-hospital care should focus on stabilization and rapid transport of the victim to a health care facility with the capability of antivenom administration. However, the out-of-hospital interval provides for the evaluation and management of the patients with snakebite. Out-of-hospital providers must be familiar with common first-aid techniques and be aware of their potential complications. Proven measures to slow systemic absorption are limited but should include immobilization of the bitten extremity in a neutral position in every case, and the patient should maintain strict bed rest. Constriction bands or pressure wraps placed on the wound at the scene and without vascular compromise should be left in place until arrival at a health care facility. Placement of a constriction band or pressure wrap (to delay systemic absorption of venom) can be considered for prolonged transport times or when the patient’s condition is deteriorating. A suction device, if applied and functioning, should be left in place. Vital signs should be closely monitored to assess for hypotension as a sign of systemic toxicity. The extent of local swelling should be documented, and information regarding extent and progression of the envenomation syndrome should be relayed to the receiving hospital to expedite antivenom administration, if indicated. During interhospital transport of patients who have received or continue to receive antivenom, the patient should be monitored for allergic reactions to treatment and treated appropriately. Routine stocking of the existing horse serum antivenom product on ambulances is not recommended because of the extended length of time required to prepare the infusion and potential allergic complications. Antivenoms with improved side effect profiles may be better suited to use in the out-of-hospital setting in well-defined cases. [McKinney PE. Out-of-hospital and interhospital management of crotaline snakebite. Ann Emerg Med. February 2001;37:168-174.]

Red-back spider (Latrodectus hasselti) antivenom prevents the toxicity of widow spider venoms

Study Objectives: Widow spiders of the genus Latrodectus are found worldwide and produce similar clinical envenomation syndromes. In Australia, red-back spider antivenom (RBS-AV) is effective therapy for Latrodectus hasselti envenomation and it has been reported to reverse envenomation by other widow spiders. This study assessed the efficacy of RBS-AV in preventing in vitro and in vivo toxicity of widow spider venoms of North America and Europe. Methods: The binding of RBS-AV to α-latrotoxin and Latrodectus venoms (Latrodectus spp mactans, hesperus, lugubris, tredecimguttatus, hasselti ) was assayed using Western blotting. Prevention of in vitro toxicity to α-latrotoxin and the same venoms was tested by pretreating an isolated chick biventer cervicis nerve-muscle preparation with RBS-AV. Prevention of in vivo toxicity was determined by a lethality study in male Balb/c mice (2.5 to 5× median lethal dose [LD50]) or α-latrotoxin (10× LD50) preincubated with antivenom or without RBS-AV (control). Results: In Western blots, RBS-AV bound to α-latrotoxin and similar widow spider proteins in all venoms tested, indicating antigenic similarity with proteins found in RBS venom. Antivenom prevented the typical in vitro muscle contracture and loss of twitch tension seen with α-latrotoxin and the venoms tested. Control mice rapidly developed signs of envenomation, but mice treated with RBS-AV remained free of signs of envenomation. Conclusion: RBS-AV prevented both in vitro and in vivo toxicity from Latrodectus venoms and α-latrotoxin in mice. These data suggest that RBS-AV may be clinically effective in the treatment of envenomation resulting from the bite of other widow spiders. [Graudins A, Padula M, Broady K, Nicholson GM. Red-back spider (Latrodectus hasselti) antivenom prevents the toxicity of widow spider venoms. Ann Emerg Med. February 2001;37:154-160.]

The envenomation syndrome caused by the Australian Red-bellied Black Snake Pseudechis porphyriacus

The Australian elapids inject venom which is characteristic of each species; and which cause characteristic and specific envenomation syndromes in human victims of snakebite. Because many of the medically significant Australian elapids look similar, when glimpsed in the field by snakebite victims, defining human envenomation syndromes with secure species identification has been a slow process. Correlations between securely identified species and the human envenomation syndromes which they produce are still evolving. The genus Pseudechis is the most widespread in Australia of the dangerous Australian elapid genera; and P. porphyriacus, the Red-bellied Black Snake, was the first terrestrial Australian elapid to be described and illustrated and the first to be the subject of experimental study. We present here five previously unreported cases of human envenomation in which the species diagnosis is secure. From these and with the perspective of a selected literature review, we describe the full envenomation syndrome of this species. Until the development of the Commonwealth Serum Laboratories’ Venom Detection Kit in 1979 and the occasional case report of victims of securely identified species, envenomation syndromes for most Australian snake species have remained indeterminate, because of the lack of professional expertise in the identification of the species involved. Symptoms of the P. porphyriacus envenomation syndrome include those of bite-site pain, nausea and vomiting, generalised pruritis, chest pain, prostration and abnormalities of taste and smell. Signs include local necrosis and scarring of tissue at the bite-site, gross inflammation of surrounding tissues and, at least in one case, epilepsy. Although envenomation by the Red-bellied Black Snake is not lethal in adults, the correct therapy is Tiger Snake antivenom, administered with judgement, taking into account knowledge of the specific envenomation syndrome of this species and the clinical status of the victim.

The scorpion envenoming syndrome: a different perspective. The physiological basis of the role of insulin in scorpion envenoming

Death caused by scorpion envenoming (Buthidae family) is a common event in tropical and subtropical countries. Severe scorpion envenoming causes an autonomic storm resulting in a massive release of catecholamines, angiotensin II, glucagon, cortisol, and changes in insulin secretion. As a consequence of these changes in the hormonal milieu, scorpion envenoming results in a syndrome of fuel energy deficits and an inability of the vital organs to utilize the existing metabolic substrates, which causes myocardial damage, cardiovascular disturbances, peripheral circulatory failure, pulmonary oedema, and many other clinical manifestations alone or in combination, producing multi-system-organ-failure (MSOF) and death. Insulin-glucose infusion or antivenom administration through the release of insulin seems to be the physiological basis for the control of the metabolic response when that has become a determinant to survival of scorpion sting victims.

Clinical features and management of Hadronyche envenomation in man

Using case reports and a review of the literature, the clinical features of envenomation by the genus of Australian funnel web spiders known as Hadronyche are characterised. Five cases are reported here, including the first life-threatening envenomation by Hadronyche species 14 (the Port Macquarie funnel web). Two severe envenomations by Hadronyche cerberea (the Southern Tree funnel web) and one each by Hadronyche formidabilis (the Northern Tree funnel web) and Hadronyche infensa (the Darling Downs funnel web) are also described. The clinical experience of the authors’ provided the five cases described in detail one of which has previously been reported in brief. Eight cases of Hadronyche envenomation from the literature (Medline 1966–1998 and Embase 1980–1998) were analysed in order to draw comparisons between this syndrome and the well described envenomation syndrome of Atrax robustus (the Sydney funnel web). Reports of funnel web spider antivenom use to Commonwealth Serum Laboratories (CSL) between 1995 and June 1998 were also examined. The biology of these dangerous spiders, their geographic distribution, venom characteristics and management issues are addressed. It is concluded that bites from at least six Hadronyche species have produced a life-threatening envenomation syndrome clinically indistinguishable from that of Atrax robustus. Atrax robustus derived antivenom is effective although antivenom requirements may be greater than for Atrax envenomation. Antivenom supplies are limited and sufficient stocks to treat a severe envenomation are unlikely to be found in any one institution. Pressure-immobilisation first aid is effective in delaying onset of envenomation, may enhance local inactivation of venom and early removal can result in rapid clinical deterioration.

Scorpion Envenomation in Children: Should All Stings Be Given Antivenom?

Scorpion Envenomation in Children: Should All Stings Be Given Antivenom?

THE SYSTEMIC INFLAMMATORY RESPONSE SYNDROME RELATED TO THE RELEASE OF CYTOKINES FOLLOWING SEVERE ENVENOMATION

Envenomation by insects, snakes, scorpions, and spiders involves the activation of the inflammatory system with the release and activation of pro-inflammatory cytokines, chemotactic mediators, cellular infiltration, and other vasoactive mediators. Activation of the inflammatory system and its cascade of events play a major role in the pathogenesis of envenomation, its clinical picture, and outcome. Additional clinical and laboratory studies are required to characterize the exact mechanisms by which the inflammatory system affects the pathophysiology, clinical course, and complications following envenomations. A better understanding of the involvement of the inflammatory cascade in different envenoming syndromes may have future therapeutic benefits.

Acute myocarditis following Tityus trinitatis envenoming: morphological and pathophysiological characteristics

The clinicopathological features of four cases of scorpion envenoming by Tityus trinitatis are presented. The cardiac histopathology is recorded in the two fatal cases. The pathology of the acute myocarditis was a mixed picture of a toxic myocarditis and coagulative myocytolysis. These cardiac lesions are also seen in catecholamine induced cardiotoxicity and lend support to the theory that an adrenergic surge follows scorpion envenoming. A brief review of scorpion envenoming syndrome is undertaken in the light of these findings.

INSULIN ADMINISTRATION IN SEVERE SCORPION ENVENOMING

The efficacy of insulin-glucose infusion in reversing myocardial damage, haemodynamic changes, peripheral circulatory failure, and pulmonary oedema was evaluated in 25 victims of venomous scorpion stings from the Rayalaseema region in the south of India. Myocardial damage with peripheral circulatory failure was seen in all scorpion sting victims. Ten of these victims also had pulmonary oedema. All the patients received continuous infusion of regular crystalline insulin at the rate of 0.3 U/g of glucose and glucose at the rate of 0.1 g/kg/h with supplementary potassium as needed, inotropic agents, oxygen, as well as maintenance of fluid, electrolytes and acid-base balance. Insulin-glucose infusion was associated with reversal of cardiovascular and haemodynamic changes, and pulmonary oedema in 24 of the 25 victims. One severely envenomed victim admitted 72 hours after the sting died. The scorpion envenoming syndrome with myocardial damage, cardiovascular disturbances, peripheral circulatory failure, pulmonary oedema, and many other clinical manifestations may cause multi-system organ failure (MSOF). It is characterised by a massive release of catecholamines, angiotensin II, glucagon, cortisol, and inhibition of insulin secretion. Under these altered conditions in the hormonal milieu, scorpion envenoming essentially results in a syndrome of fuel-energy deficits and an inability to use the existing metabolic substrates by vital organs, causing MSOF and death. Administration of insulin-glucose infusion to scorpion sting victims appears to be the physiological basis for the control of the metabolic response when that has become a determinant to survival.

THE USE OF SEROTHERAPHY TO REVERSE ECG and CARDIAC ENZYME CHANGES CAUSED BY SCORPION Mesobuthus tamulus concanesis, Pocock ENVENOMING

Acute myocardiopathy in experimental dogs and rabbits was induced by subcutaneous (SQ) injection of 3.5 mg/kg of scorpion venom from Mesobuthus tamulus concanesis, Pocock. An increase in circulating lactic dehydrogenase (LDH), serum glutamic oxalacetic transaminase (SGOT), creatine kinase-MB isoenzyme (CK-MB), serum glutamine pyrovate transaminase (SGPT) and alpha hydroxy butyrate dehydrogenase (HBDH) enzyme levels was observed in dogs 60 min after venom injection, and a further rise was observed 120 min after venom injection. The administration of the species-specific scorpion antivenom (SAV) at different time intervals after venom injection resulted in reversal of electrocardiographic changes and a reduction in cardiac enzyme levels. The administration of SAV to scorpion envenomed alloxan-pretreated animals did not cause clinical or biochemical improvement. On the other hand, administering insulin to envenomed only animals or envenomed alloxan-pretreated animals resulted in a biochemical and clinical improvement, as well as in a reduction of the cardiac enzyme levels. Insulin administration in scorpion envenoming syndrome is essentially a metabolic support to control the adverse effects triggered by catecholamines and other counter-regulatory hormones.

Validation of a Severity Score for the Assessment of Crotalid Snakebite

Study objective: No research tool exists for the clinical evaluation of crotalid snakebite. We sought to determine the correlation of the snakebite severity score (SSS) with the clinical assessment of physicians experienced in the management of crotalid snakebite. Methods: We retrospectively used the SSS to quantify the severity of envenomation in 108 patients with crotalid snakebite. Two physicians experienced in the management of venomous snakebite independently and blindly assessed the severity of envenomation as detailed in medical records with the use of accepted clinical criteria. The correlation of the SSS and the physicians’ consensus was determined with pointbiserial correlation. Results: The SSS correlated well with the physicians’ consensus at presentation (r=+.63, z score=6.52, P<.000001) and at the point at which the patient’s condition was worst (r=+.70, z score=7.24, P<.000001). The SSS also correlated highly with the physicians’ assessment of change in the patient’s condition (r=+.51, z score= 6.10, P<.000001). With the physicians’ consensus as the gold standard, the sensitivity of a change in the SSS of 1 point in detecting clinically significant worsening of the envenomation syndrome was .97; specificity was .81. Conclusion: The SSS correlated well with the clinical condition of patients bitten by crotalid snakes as represented by the medical record. It provides a more objective instrument for the evaluation of severity and progression of envenomation in patients with crotalid snakebite. [Dart RC, Hurlbut KM, Garcia R, Boren J: Validation of a severity score for the assessment of crotalid snakebite. Ann Emerg Med March 1996;27:321-326.]