versão On-line ISSN 1678-4936
J. Venom. Anim. Toxins v.8 n.1 Botucatu 2002
SCORPION ANTIVENOM REVERSES METABOLIC, ELECTROCARDIOGRAPHIC, AND HORMONAL DISTURBANCES CAUSED BY THE INDIAN RED SCORPION Mesobuthus tamulus concanesis, Pocock ENVENOMATION
1 Department of Physiology, Seth G. S. Medical College & K. E. M. Hospital, Parel, Mumbai 400 012, India.
ABSTRACT: Electrocardiographic (ECG) changes were induced in dogs by injection of scorpion venom from Mesobuthus tamulus concanesis, Pocock. Venom (3 mg/kg body weight) was given subcutaneously (SQ) while 10 ml of scorpion antivenom (SAV) was administered intravenously (IV) to experimental dogs. Group 1 received only the venom; Groups 2, 3, and 4 received SAV at 0, 30, and 60 min, respectively, following envenoming. Thick, ropy and profuse salivation; muscle fasciculation; clonus and tetany-like contractions; frequent urination; and bowel emptying sometimes stained with bile and occasionally blood and bile were observed 20-25 minutes after envenoming.
Following envenoming, hyperglycemia, increase in free fatty acid (FFA) levels, and reduction in triglyceride levels were observed in Groups 1, 3, and 4. There was an initial rise in insulin levels at 30 min followed by a reduction at 60 min. SAV caused a subsequent rise in insulin levels but there was a reduction in blood sugar to euglycemia levels and lipogenesis (reduction in FFA and increase in triglycerides levels) in Groups 3 and 4. Abnormal ECG changes and arrhythmias were not observed after SAV. Normal sinus rhythm was restored in Group 4.
Scorpion envenoming with multi-system-organ failure (MSOF), characterized by a massive release of counter-regulatory hormones (catecholamines, glucagon, cortisol), angiotensin-II, and changes in insulin secretion, is a condition of fuel-energy deficits and an inability to utilize the existing metabolic substrates. These disturbances are reversed by SAV possibly through insulin release. It is concluded that SAV, under the laboratory conditions, effectively neutralizes, prevents, and reverses scorpion venom toxicity.
KEY WORDS: antivenom, scorpion venom, Mesobuthus tamulus concanesis, hyperglycemia, free fatty acids, triglycerides, insulin, hyperinsulinemia, insulin resistance, electrocardiographic changes.
Deaths due to scorpion stings are common in developed and developing countries including India (1,2,4,6,8,10,11,13,15-19,23-35,37-40). Scorpion sting victims in India have been given less recognition as patients who need medical care and attention by the responsible Health Authorities at local, state, and central government. As a result, fatalities due to scorpion stings are underestimated. Additionally, all standard medical textbooks carry very little information about the pathophysiological mechanism/s responsible for death due to venomous scorpion stings.
Treatment of scorpion envenoming in humans is a difficult problem (8,10-13,16,17). It requires extensive knowledge of clinical manifestations and an understanding of the mechanisms behind clinical symptomatology (13,16,17). Current pathophysiological and biochemical knowledge of scorpion envenoming is inadequate, and consequently, the current therapeutic approach remains highly unsatisfactory. Prof. Ismail has recently published many excellent review articles, but he did not consider the changes in hormonal environment due to scorpion envenoming, and consequently, the therapeutic role of insulin. Metabolic and ECG changes induced by experimental envenoming had been reversed by the administration of either insulin (33) or insulin + alpha-blocker + sodium bicarbonate (31). We have reported the reversal of haemodynamic changes and non-cardiogenic pulmonary oedema in children (34) and adults (25,28,44) stung by scorpions of the Buthidae family in Western Maharashtra and Rayalaseema region in Southern India.
In India, there is no effective species-specific scorpion antivenom (SAV). While the value of antivenom was never questioned following snakebites, opinions differ in the case of scorpion stings (16). Most investigators consider antivenom the only specific treatment for scorpion stings (1,4,8,15-19,37,39). Others, however, question the effectiveness of antivenom in preventing and abolishing cardiovascular manifestations in human scorpion envenoming (2,10-13,38).
SAV is effective to treat the victims of scorpion envenoming. But statements like, Antivenom has no effect whatsoever. What are the goals in the management of human envenomation: to treat the venom or the clinical symptomatology of envenomation? (10,13) Is serotherapy essential? (2) and the strong response from Prof. Ismail (16-19) have raised several important issues that need clarification.
We have demonstrated here SAV effectiveness under laboratory conditions in reversing metabolic and ECG changes in experimental envenoming by the Indian red scorpion venom (Buthidae family).
MATERIALS AND METHODS
Venom from the scorpion Mesobuthus tamulus concanesis, Pocock, was obtained from the Haffkine Institute, Mumbai. The species-specific scorpion antivenom (SAV) was produced at the Haffkine Biopharmaceutical Corporation Ltd., Mumbai. The entire content present in a single SAV vial was dissolved in 10 ml of water for injection; this was administered slowly IV in all experiments. According to the Haffkine Biopharmaceutical Corporation Ltd., Mumbai, SAV present in one vial is capable of neutralizing 13 to 17 mg of crude venom obtained from the scorpion Mesobuthus tamulus concanesis, Pocock. Crude, lyophilized venom (3 mg/kg body weight) was given subcutaneously (SQ). After overnight fast, Mongrel dogs of either sex, weighing 8 ± 3 kg were anaesthetized. These animals were divided randomly into four groups: Group 1, (n=6) envenomed animals did not receive SAV. Groups 2 (n=9), 3 (n=7), and 4 (n=8) animals received IV injection of SAV at 0, 30, and 60 min after SQ injection of venom.
Limb Lead II ECG was recorded continuously in Group 4 before venom, after venom, and up to 120 minutes after SAV.
Blood was collected before venom injection, and thereafter for every 30 minutes and up to 2 hours following SAV. Blood was processed for glucose (3), free fatty acids (FFA), (42) and triglycerides (procedure No. 405, Sigma Chemical Company, USA). Insulin was assayed by radioimmunoassay (Bhabha Atomic Research Centre Kits, Mumbai). The results were analyzed statistically using Students paired t test.
|S.E.D. = Standard error of mean difference
p* < 0.05, p** < 0.02, p*** < 0.01, p**** < 0.001
Comparison of results for biostatistical analysis: before venom with all other values
|Figure 1. Group 1. Effect of venom injection (SQ) on blood sugar, free fatty acids, insulin, and triglycerides (Mean ± S.E.D.) (n = 6).|
S.E.D. = Standard error of mean difference
|Figure 2. Group 2. Effect of simultaneous administration of venom (SQ) and antivenom (IV) on blood sugar, free fatty acids, insulin, and triglycerides (Mean ± S.E.D.) (n = 9).|
|S.E.D. = Standard error of mean difference
p* < 0.05, p** < 0.02, p*** < 0.01, p**** < 0.001
Comparison of results for biostatistical analysis: before venom with 30 min after venom, and 30
min after venom with all other values after antivenom.
|Figure 3. Group 3. Effect of antivenom administration 30 min after venom injection on blood glucose, free fatty acids, insulin, and triglycerides (Mean ± S.E.D.) (n = 7).|
| S.E.D. = Standard error of mean difference
p* < 0.05, p** < 0.02, p*** < 0.01, p**** < 0.001
Comparison of results for biostatistical analysis: before venom with 30 min and 60 min after venom, and 60 min after venom with all other values after antivenom.
|Figure 4. Group 4. Effect of antivenom administration 60 min after venom injection on blood glucose, free fatty acids, insulin, and triglycerides (Mean ± S.E.D.) (n = 8).|
Scorpion envenoming resulted in skeletal muscle fasciculation; clonus and tetany-like contractions; thick, ropy saliva dribbling from the mouth; lacrimation and nasal secretions; frequent micturition and defecation. All Group 1 animals died between 120 to 150 minutes following venom injection. There were no deaths in Groups 2, 3, and 4 prior to sacrifice.
The following ECG changes were observed after envenoming in Group 4: change in axis and RR intervals, extra systoles (ventricular and supra ventricular), and appearance of Q waves, and many other abnormal ECG patterns. All these post-SAV ECG changes initially reduced in frequency and finally disappeared. At the end of 120 minutes of SAV, normal sinus rhythm was sustained (Figure 5).
|Figure 5. ECG changes after scorpion envenoming and after administration of scorpion antivenom (SAV). All ECG tracings from Limb Lead II, Paper Speed 50 mm/Sec in Group 4. Group 4 animals were injected with scorpion venom (SQ). SAV (IV) was given 60 min after venom injection.|
There were significant increases in blood glucose levels from a basal value of 120 mg/100 ml to 402 mg/100 ml within 90 minutes following venom injection in Group 1. Similar increases were seen at 30 and 60 minutes following venom injection in Groups 3 and 4. Blood glucose levels showed a declining trend following SAV in Groups 3 and 4. Glucose levels were normal at 60, 90, and 120 minutes after SAV in Group 4.
Insulin levels were increased (hyperinsulinemia) in Groups 1, 3, and 4 at 30 minutes following venom injection. A further increase was observed at 90 minutes after venom injection in Group 1. A reduction in insulin levels took place in Groups 1 and 4 at 30 minutes followed by an increase at 60, 90, and 120 minutes after SAV. Increased insulin levels were observed at 60 and 90 minutes following SAV in Group 3. Similar increases in insulin levels were observed in Group 4 at 30 and 120 minutes following SAV.
FFA levels were increased immediately following venom injection (30 min in Groups 1, 3, and 4). SAV administration reversed these values back to normal (Groups 2 and 3) or even to less than the control (before venom injection) levels (Group 4).
Triglyceride levels were reduced after envenoming in Groups 1, 3, and 4. SAV administration resulted in an increase in these levels in Groups 2, 3, and 4.
A high incidence of scorpion stings leading to a very high mortality in children and adults is reported (2,4,6,8-13,15-19,23-35,37-41,44). All venomous scorpion species are reported to cause death in humans all over the world belong to the Buthidae family. Forty-five species of these venomous scorpions are distributed throughout the length and breadth of India (40).
Signs and symptoms following stings by dangerous scorpions from different parts of the world are remarkably similar (2,4,6,8-13,15-19,23-35,37-41,44). Scorpion envenoming results in initial transient hypertension followed by hypotension in experimental animals and scorpion sting victims.
Scorpion envenoming results in a severe autonomic storm, which leads to a massive release of catecholamines and angiotensin II (8-13,15-19,38). Increased sympathetic activity causes increased renin release by direct stimulation of juxtaglomerular cells. Subsequent increase in angiotensin secretion enhances ongoing sympathetic nerve output by direct action on the brainstem and by blunting of baroreceptor mechanisms (2). Thus, the renin-angiotensin system is an important facilitator of ongoing sympatho-adrenal traffic (12,29) in scorpion envenoming.
Scorpion Envenoming and Metabolic Changes
Changes in hormonal environment (increased levels of counter-regulatory hormones and either insulinopenia or hyperinsulinemia), hyperglycemia and FFA are demonstrated in scorpion envenoming (29,31-33).
The maintenance of normal glucose homeostasis depends on three simultaneously ongoing processes that must occur in a coordinated fashion. An increase in blood glucose level stimulates the endocrine pancreas to secrete insulin. The resulting combination of hyperinsulinemia plus hyperglycemia must effectively promote glucose uptake by splanchanic (liver and gut) and peripheral muscle and suppress hepatic glucose production. The defects either at the Langerhans islet beta cell level (suppression of insulin secretion by counter regulatory hormones), muscle, or liver might lead to insulin resistance.
The knowledge of the relationship between hyperglycemia, increased FFA levels, hypoinsulinemia, hyperinsulinemia, and insulin resistance in human disease is relevant in understanding the possible mechanism/s of death from scorpion envenoming and the therapeutic role of SAV in scorpion envenoming.
Scorpion Envenoming and Hyperglycemia
Blood glucose levels were increased resulting in hyperglycemia in Groups 1, 2, 3, and 4 after envenoming. These results are in agreement with our previous results (31,32) and literature (16-19). Hyperglycemia could be due to a massive release of catecholamines (1,9-13,15-19,38), glucagon, cortisol, changes in thyroid hormone levels and in insulin secretion (25-28,31-33,35).
Effects of an Acute Increase in Epinephrine and Cortisol on Carbohydrate Metabolism During Insulin Deficiency
Elevations in plasma epinephrine and cortisol levels are associated with physiological stress. In diabetic patients, plasma epinephrine and cortisol levels increase during diabetic ketoacidosis. An acute physiological rise in the plasma epinephrine level is associated with a transient increase in hepatic glucose production and a sustained fall in glucose clearance, and results in persistent hyperglycemia (9).
Cortisone may be synergistic with other stress hormones (9). Small increases in the plasma epinephrine level during insulin deficiency can significantly worsen the resulting hyperglycemia. This might occur as a result of an additive effect on hepatic glucose production (9).
Scorpion Envenoming and Glucose Toxicity
In virtually all tissues except the brain, glucose, at a fixed insulin concentration, promotes its own utilization in a concentration-dependent manner. Insulin stimulates glucose oxidation by its anti-lipolytic effect. Even a small increment in the serum insulin concentration promptly suppresses lipolysis, and consequently, the use of FFA for energy production, which in turn, enhances glucose oxidation. In contrast, glucose is unable to suppress lipolysis in man (14). Glucose per se may be a cellular toxin. Hyperglycemia may cause a generalized desensitization of all cells in the body by downregulation of the glucose metabolism through the glucose transport system. In muscles and adipocytes, this would be reflected by a defect in insulin action, whereas at the Langerhans islet beta cell level, this would be manifested by an impairment in insulin secretion (5,14,36).
Haemodynamic Abnormalities in Short-Term Insulin Deficiency
In diabetic ketoacidosis, the simultaneous relative insulin deficiency and excessive secretion of counter-regulatory hormones lead to magnified lipolysis and FFA beta oxidation with a parallel overproduction and peripheral underutilization of ketone bodies. There are clinical characteristics of drowsiness and over-breathing. In addition, signs of circulatory collapse, such as tachycardia, weak pulse, and low blood pressure are normally present (5,14,36).Similar clinical manifestations are usually observed in scorpion sting victims.
Scorpion Envenoming and Insulin Levels
Insulin levels were elevated after venom injection in Groups 1, 2, and 4. The observation of hyperinsulinemia is in concurrence with Ismail (16-19).
Scorpion Envenoming and FFA Levels
Scorpion envenoming resulted in an increase in FFA along with a simultaneous reduction in triglyceride levels in Groups 1, 3, and 4. These results are also in support of our earlier work (31-33). Increased catecholamines, cortisol, and changes in insulin secretion might be responsible for increased FFA levels in scorpion envenoming.
Effect of Increased FFA on the Heart in Scorpion Envenoming
The use of increased amounts of circulating FFA results in increased oxygen consumption. This could aggravate ischemic injury to the myocardium, predisposing to arrhythmias and heart failure. The elevated FFA also increase the susceptibility of the ventricles to the disorganized electrical behavior and produce ectopic beats in the vulnerable period of cardiac cycle (43). Under pathological conditions, high FFA levels produce inhibition of Na+-K+ stimulated ATPase activity (43) and cardiac sarcolemmal defects (24). The increased FFA, by altering the function of platelets, may increase the tendency for intravascular thrombus and result in disseminated intravascular coagulation (DIC) (6,32).
What is Hyperinsulinemia ?
Hyperinsulinemia is said to exist when plasma insulin levels are inappropriate for the blood glucose estimated simultaneously. True hyperinsulinemia is said to exist when insulin levels are elevated with normal glucose level (22). Insulin resistance is said to exist when high insulin levels occur with elevated blood glucose levels (14). Elevated insulin levels were observed 30 min after venom injection in Groups 1, 2, and 4. It should be stressed here that all Group 1 animals died between 120 to 150 min following envenoming. Short-term hyperglycemia can induce insulin resistance.
The relationship between insulin resistance, plasma insulin levels, and glucose intolerance is mediated to a significant degree by changes in ambient plasma FFA levels (5,7,20,21,36). Plasma FFA levels can be suppressed by relatively small increments in insulin concentration. Increase in circulating FFA levels can be prevented if large amounts of insulin are secreted. If hyperinsulinemia can not be maintained, plasma FFA concentration will result in increased hepatic glucose production. These events are taking place in individuals who are quite resistant to insulin stimulated glucose uptake. Therefore, even small increases in hepatic glucose production are likely to lead to significant hyperglycemia under these conditions (5,36). The observation of hyperglycemia or euglycemia in the face of concomitant hyperinsulinemia suggests an insulin-resistant state in scorpion envenoming.
Scorpion Antivenom (SAV) Administration
Scorpion antivenom (SAV) administration reversed venom-induced ECG, cardiovascular, hemodynamic, metabolic, and hormonal changes in Group 2, 3, and 4. An increase in insulin levels following SAV was observed. Blood sugar (hyperglycemia) and increased FFA levels came back to normal or to less than the values observed before venom injection (control values) following SAV.
SAV administration prevented venom toxic effects in Group 2. SAV administered at 30 and 60 min following envenoming neutralized venom-induced hyperglycemia and lipolysis in Groups 3 and 4. SAV stopped further rises in blood sugar and FFA levels, returning them to normal.
If SAV did not inhibit the catecholamine-mediated toxicity, which in turn, suppressed insulin secretion, we would have observed only the arrest of a further rise in blood sugar and FFA levels. Normal blood glucose level (euglycemia) and lipogenesis (reduction in FFA levels and a simultaneous increase in triglyceride levels) following SAV indicated that it effectively neutralized the inhibitory action of catecholamines on insulin secretion.This might have resulted in physiologically active insulin secretion.
An increase in circulating lactic dehydrogenase (LDH), serum glutamic oxalaceetic transaminase (SGOT), creatine kinase-MB isoenzyme (CK-MB), serum glutamate pyruvic transaminase (SGPT), and alpha hydroxybutyrate dehydrogenase (alpha HBDH) enzyme levels at 60 min and a further rise at 120 min following envenoming was observed in the experimental dogs. SAV administration resulted in reversal of ECG changes and reduction of these cardiac enzymes levels (35). An increase in osmotic fragility of erythrocytes in vitro and in vivo was observed following experimental scorpion envenoming. SAV administration reversed the osmotic fragility changes in vivo (our unpublished results).
All Group 1 animals died within 120-150 minutes after subcutaneous scorpion venom injection. All animals in Groups 3 and 4 showed an initial transient hypertension following envenoming (results observed but not presented). SAV caused blood pressure to return to normal from the initial transient hypertensive level in Group 3. SAV prevented blood pressure from falling to low levels and the occurrence of hypotension in Groups 3 and 4 following SAV administration (results observed but not presented). This indicated that serotherapy (SAV) within 60 minutes is as rapid and effective as administering of insulin + alpha-blocker + sodium bicarbonate or insulin alone at 30 minutes in the experimental animals (28,31,33-34). (Experimental animals usually died 90-150 minutes following subcutaneous envenoming or 45-60 minutes following IV venom injection (28,31,33-34).
We have successfully achieved the labeling of Mesobuthus tamulus concanesis, Pocock venom with Tc 99m using direct tin reduction procedure. Biodistribution studies were carried out in Wistar rats at different time intervals after IV administration of the labeled venom (23). Scintiimages were obtained after envenoming using a large field of view gamma camera to ascertain the pharmacological action of venom in the body. Within 5 min of administration, the labeled venom was found in the blood (27%), muscle (30%), bone (13%), kidney (12%), liver (10%), and other organs. The level of venom in the kidneys was higher than in the liver. The labeled venom was excreted through renal and hepatobiliary pathways. An immunoreactivity study was carried out in rabbits after IV injection of labeled scorpion venom followed by the injection of the species-specific antivenom. A threefold increase in uptake by the kidneys was observed compared with that seen with scorpion venom alone. Venom neutralization in the kidney was higher than in the liver (23).
Ismail and his co-investigators (16-19) showed that low doses of antivenom are unable to neutralize completely the electrocardiographic effects of the venom in experimental animals. The ineffectiveness of antivenom in preventing or abolishing cardiovascular manifestations of scorpion envenoming had been ascribed to the low titers of commercial antivenoms used (16-19). In Israel, 5-15 ml of antivenom (1 ml neutralizes at least 80 % of 50% lethal dose in 20 g mice) was given IV to scorpion sting victims according to age. In Saudi Arabia, 0.5-1.0 ml of a commercial preparation neutralizing 50 mouse LD50/ml (activity was found equivalent to 20-40% of that stated on the label) was given intramuscularly to scorpion sting victims. According to Ismail (16-19), the doses of antivenom shown in all these studies were very low. At least 25-50 times the Israeli and 10-20 times the Saudi doses were required to neutralize the effects of an average L. quinquestriatus sting (1-2 mg dry venom).
We fully agree with Ismails (17) conclusions that antivenom ineffectiveness in preventing or abolishing cardiovascular manifestations in scorpion envenoming (2,13) are strongly questionable.
If the stimulation of sympathetic nerves to the pancreas inhibits insulin secretion via the release of catecholamines, then it is logical to convert the inhibitory response to an excitatory response by alpha blocking drugs (25). This could be the mechanism by which treatment of systemic effects of scorpion venom with blocking agents of the autopharmacologic type is effective. Administration of SAV also works, as discussed, by blocking the release of catecholamines and the consequent release of physiologically active insulin. Serotherapy, in our hands, was able to reverse the metabolic disturbances by changes in the hormonal environment.
In this study, no other intervention except for SAV administration was given to the animals following envenoming in Groups 2, 3, and 4. We fully agree with Ismail (25) that if a sufficient dose of antivenom were used, adjunctive therapy is seldom required. However, we advocate the maintenance of the acid-base-fluid-electrolyte balance in scorpion sting victims. We emphasize that it is essential to correct the acid-base balance, abnormal gaseous exchange, fluids and electrolytes, and maintenance of vital functions in all scorpion sting victims besides SAV administration.
Antivenom is found to be effective in preventing or abolishing the various clinical manifestations of human scorpion envenoming in clinically controlled trials (39).
This work was financed by the Indian Council of Medical Research (I C M R), New Delhi. M. Abbas Zare was the recipient of a Senior Research Fellowship from ICMR. We thank the Haffkine Biopharmaceutical Corporation Ltd., Mumbai, for giving us scorpion antivenom (SAV). This work was conducted in the department of Physiology, L.T.M. Medical College, Sion, Mumbai 400 022, India. We thank Dr. Annavarapu Srinivas for his help in drawing the graphs.
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Received May 29, 2000
Accepted September 4, 2000
K. Radha Krishna Murthy, D. Sc., D., M.N.A.M.S., Professor & Head, Department of Physiology, Seth G. S. Medical College & K. E. M. Hospital, Parel, Mumbai 400 012, India.