Scorpion envenomation and antivenom therapy

PEDIATRIC PHARMACOLOGY AND THERAPEUTICS

Scorpion envenomation and antivenom therapy Shaul Sofer, MD, Eliezer S h a h a k , MD, a n d M o s h e G u e r o n , MD From the Pediatric Intensive Care Unit and Department of Cardiology, Soroka University Medical Center, and t h e Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel

The clinical course and o u t c o m e of scorpion envenomation in 52 children treated in a pediatric intensive care unit without specific antivenom were retrospectively e v a l u a t e d and c o m p a r e d with those of scorpion envenomation in the 52 preceding cases treated with specific scorpion antivenom. The d e m o graphic, clinical, and laboratory features on hospital arrival were similar in the two groups. The lengths of stay in the pediatric intensive care unit and in the pediatric wards were c o m p a r a b l e . Hypotension with pulmonary e d e m a develo p e d in four of the children who did not receive antivenom and in one child who did receive antivenom as a complication of the envenomation; all c o m p l e t e l y recovered. Cardiogenic shock occurred in one child who did not receive antivenom, but who recovered completely, and in three children who received antivenom, of whom two died and one survived with a major deficit. Our study did not demonstrate any beneficial effect of therapy with a n t i v e n o m for scorpion envenomation in children. However, our "control" group (i.e:, the treated group) was a historical one; thus a prospective, randomized study appears to be warranted. Such a study m a y define specific subgroups that m a y benefit from treatment with antivenom. (J PEDIATR1994;124:973-8)

Scorpion envenomation is not an uncommon event in various parts of the world.l"5 Severe autonomic and central nervous system symptoms and cardiac, respiratory, and pancreatic dysfunction may Occur, leading to multisystem organ failure and death, especially among children. 61~ The mortality rate after envenomation has declined markedly in some centers during the last few decades. 4,5, 8, 11-19 This improvement has been attributed to treatment in an intensive care setting, 4, 5, 8, 11, !3, 15-17 treatment of symptoms with drugs,4,5,11,! 4 and specific antivenom administration.4,,5, 11, 13 However, there is no convincing evidence of the value of serotherapy in human beings envenomated by scorpions. 1,2~ MoreOver, AV may cause acute allergic

Submitted for publication July 16, 1993; accepted Dec. 20, 1993. Reprint requests: Shaul Sofer, MD, Division of Pediatrics, Soroka Medical Center, PO Box 151, Beer-Sheva 84101, Israel. Copyright | 1994 by Mosby-Year Book, Inc. 0022-3476/94/$3.00 + 0 9/25/53824

reactions, including anaphylaxis 4, 6 and the delayed onset of rash and symptoms of serum sickness, 18 and it is expensive. In the United States, AV has not been subjected to U.S. Food and Drug Administration testing, and its use is not federally approved. At present, AV is available only within the state of Arizona by special action of the Arizona State Board of Pharmacy, 1618 and its use is controversial. For AV ED NAV PICU

Antivenom Emergency department No antivenom Pediatric intensive care unit

these reasons and on the basis of our experience, we have discontinued the use of AV in children with scorpion envenomation since 1989. In this study, we compared the outcome of scorpion envenomation in children treated in a pediatric intensive care unit with specific AV before 1989, with that in children admitted to the P I C U after 1989, who were similarly treated but did not receive AV.

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METHODS The Soroka University Hospital is located in the city of Beer-Sheva and serves a population of about 350,000, including 80,000 Bedouin, seminomadic Moslem inhabitants of the Negev desert. The Soroka PICU is the only one in the region, and practically all children who have been stung by scorpions are initially admitted to this unit. The medical records of all children admitted with signs of intoxication after scorpion sting between July 1, 1989, and Dec. 31, 1992, were retrospectively evaluated. Fifty-two such children who received no AV were identified and were compared with a group consisting of the 52 preceding patients with scorpion envenomation who were treated with AV and admitted to the PICU before July 1, 1989 (from July 10, 1985, to July 1, 1989). Demographic, clinical, and laboratory data were collected from the files, as well as duration of stay in the PICU, duration of hospitalization, rate and type of complications, number of deaths, and long-term morbidity. Specific AV against the venom of the yellow scorpion, Leiurus quinquestriatus (the most prevalent and most toxic scorpion in the Negev desert), was prepared in donkeys by the Hebrew University Department of Entomology and Venomous Animals, in Jerusalem. According to the patient's age, 5 to 15 ml AV diluted in 5% dextrose and 0.33% sodium chloride solution was administered intravenously shortly after arrival. According to the manufacturer, in 20 gm mice, 1 ml AV neutralizes at least 80% of a 50% lethal dose of the venom. Therapy to relieve symptoms included intravenous fluid replacement in all cases. Analgesics, sedatives, or both were given to agitated children. Antihypertensive drugs (hydralazine, 0.2 m g / k g per dose administered intravenously, or sublingually administered nifedipine, 0.5 mg/kg per dose, or both) were given to children with severe or significant hypertension who did not respond to administration of analgesics and sedatives. 23 Treatment with nifedipine was introduced in our PICU in 1988. Supportive therapy did not change substantially between the two study periods with a few minor exceptions. Since 1987, we have become less reluctant to use more potent analgesics such as meperidine, despite some experimental data suggesting that use of narcotics may enhance venom toxicity. 24 In the same year we also started to use antihypertensive drugs more frequently on the basis of our experience with hypertensive encephalopathy. 23 In addition, we replaced diazepam with midazolam for sedation in 1989. RESULTS The groups were similar regarding ethnic origin, sex, and" time interval between envenomation and arrival in the emergency department (Table I). Children in the NAV group were slightly older than those in the AV group and

The Journal of Pediatrics June 1994

consequently somewhat heavier (average weight, 15.1 kg vs 13.4 kg, respectively). The site of the sting could not be identified in 14 (27%) of the children in the AV group and in 20 (38%) of children in the NAV group. Of the children in the AV group, 34 (65%) were stung on a limb, in comparison with 27 (52%) of the N A V children. Head or neck sting occurred in one child in the AV group and in two children in the N A V group. The clinical presentation and laboratory results on arrival were similar and, if anything, to the disadvantage of the NAV group (Table I). Clinical findings such as hypothermia (rectal temperature of 34.1 ~ C to 35.0 ~ C), restlessness, excessive secretions and salivation, and priapism in male patients were similar. Tachycardia was slightly more prevalent in the AV group; bradycardia was slightly more common in the N A V group. Decreased level of consciousness, miosis or mydriasis, and vomiting were more frequent in the NAV group. Hypertension, an important sign of scorpion envenomation,23, 25 is not included in Table I because meticulous, serial measurements of blood pressure with an electronic device were introduced to our PICU in 1987, thus making comparison of this measurement impossible. However, significant or severe hypertension was similar in the two groups; hypertension occurred in 79% of the entire AV group and in 77% of N A V children admitted between 1987 and June 1989. Fifteen children had severe respiratory failure on arrival, including two patients who had tracheal tubes inserted before arrival. Indications for intubation were severe inspiratory stridor as a result of subglottic edema in 2 children and gasping type of breathing with coma in the 13 other patients. Duration of intubation ranged from 1 to 8 hours. Rapid extubation was possible because the respiratory failure was a result of severe central nervous system depression and muscle spasm and not of primary lung abnormalities, and because the central nervous system and neuromuscular dysfunction resolved quickly after endotracheal intubation and initiation of treatment with fluids, sedatives, and analgesics. Of the 13 children with coma and gasping respirations, nine had severe hypertension with blood pressure measurements that ranged between 150/100 and 170/120 mm Hg. The level of consciousness and respiratory functions of these children markedly improved when normal blood pressure was achieved with administration of antihypertensive agents (usually one or two doses of hydralazine or nifedipine, or both). Three of the thirteen cases have been previously reported. 23 All 15 children with respiratory failure eventually recovered completely, and neither heart failure nor any other significant complications developed; all patients left the PICU after 16 to 67 hours of hospitalization. There were no significant differences regarding out-

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Table

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I. Demographic, clinical, and laboratory features of children with envenomation on admission A V g r o u p (n = 52)

Male subjects Bedouins/Jews Age Range Median Time interval from sting to ED arrival (hr) Range Mean Hypothermia (<36 ~ C) Restlessness Excessive secretions and sweating Tachycardia Bradycardia Decreased level of consciousness Miosis or mydriasis Vomiting Priapism~: Respiratory failure Coma with gasping Obstructive subglottic edema Laboratory findings Electrocardiographic changes Arterial pH (units) Range Mean Blood glucose (mmol/L [mg/dl]) Range Mean

N A V g r o u p (n = 52)

30 (58) 49/3

29 (56) 51/ 1

22 days-14 yr 3 yr

30 days-15 yr 4 yr

0.25-4 1.56 16 (31) 45 (86) 50 (96) 38 (73) 4 (8) 15 (29) 13 (25)* 32 (61)t 25/30 (83)

0.3-4 1.53 17 (33) 48 (92) 49 (94) 31 (60) 10 (19) 22 (42) 24 (46)* 42 (81)t 28/29 (96)

5 (10) 1 (2)

8 (15) 1 (2)

24 (46)

23 (44)

6.9-7.4 7.29

7.0-7.4 7.28

4.7-27.8 (85-500) 10.4 (188)

4.7-33.3 (84-600) 12.4 (224)

Values in parentheses (except bloodglucosevalues)are percentages. *p <0.05. tP = 0.05. 1:Inmate subjects.

come, duration of intubation, and duration of PICU stay between the six children in the AV group and the nine children in the NAV group. However, the median age of the 15 children with respiratory failure was lower than that of all children in both groups: 2 versus 3 years, respectively. The site of sting was not identified in nine of the children with respiratory failure and involved the limbs in the six other children. Arterial pH was slightly lower in children in the NAV group, and the blood glucose level was slightly higher in the NAV group. The frequency of electrocardiographic changes, including ST elevations and high T waves, was similar in both groups. Major complications of envenomation that were manifested after arrival consisted mainly of cardiovascular dysfunction (Table II). Abnormalities were noted in five children in the NAV group, including one with cardiogenic shock, and in four of the children in the AV group, including three who had cardiogenic shock. All children in the NAV group survived without sequelae; two of the children in the AV group died. A 3-year-old girl died of shock, se-

vere metabolic acidosis, right and left heart failure, and pulmonary edema. An 8-year-old boy remained brain dead after resuscitation from shock and severe ventricular arrhythmias including ventricular fibrillation. A 13-year-old boy in the AV group survived but remained handicapped by aphasia and leg amputation; he had cardiogenic shock, left heart failure with pulmonary edema and ventricular arrhythmias, and multiple brain infarcts, as shown by computed tomography. On the seventh day of hospitalization the patient had signs of right popliteal artery occlusion that eventually led to amputation. This patient and the first of the two patients who died have been reported elsewhere. 8 All four children in the AV group who had severe cardiovascular complications received the maximum dose of antivenom (15 ml intravenously) promptly on arrival, several hours before the onset of complications. The median age of the children with cardiovascular dysfunction, in both the treated and the nontreated groups, was significantly higher than the median age of all children (12 years vs 3 years, respectively; range, 3 to 15 years). Eight of the nine children

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T a b l e II. Severe complications of envenomation during hospitalization and outcome Complications and outcome

Pulmonary edema with hypotension Cardiogenic shock Death Full recovery 9Noncardiovascular complications*

AV group NAV group (n = 52) (n = 52)

1 (2) 3 (5.8) 2 (3.8) 49 (94) 1 (2)

4 (7.7) 1 (2) 0 0 (0) 52 (100) 0 (0)

Values in parentheses are percentages. *Limb amputation and aphasia in one patient.

with cardiovascular dysfunction, in both groups, were stung on a limb; the site of the sting was not detected in the ninth child. All nine children arrived in the ED between 1 and 3 hours after envenomation. When all children in the AV group were compared with the NAV group, there were no significant differences for either PICU or total hospital stay (Table III). Hundreds of children and adults who were seen in the ED after a scorpion sting without signs of general intoxication were not included in this study. Most of them had local pain, were treated with analgesics, and were discharged. A few children were admitted for observation. All these patients, as well as other sting victims treated at local clinics, were not given specific AV. We are not aware of any complications among these victims. DISCUSSION General intoxication does not develop in most human victims of scorpion sting, but victims do experience local pain or a mild burning sensation at the site of the sting. Those with signs of general intoxication have impressive but usually transient and self-limited manifestations. However, in some victims, especially children, respiratory failure and death may occur as a result of upper airway obstruction, severe hypertensive encephalopathy, or heart failure. 8, 23 Although our study deals with an Israeli population, the situation is not unique to Israel. Hundreds of victims are reported to be stung annually by the American scorpion Centruroides sculpturatus, particularly in Arizona and in parts of California, Texas, Nevada, and New Mexico. 17, 19 The in vitro effects of the venom of the American scorpion are similar to those of the venom of the Israeli and North African scorpion L. quinquestriatus, which is the subject of our study. Both species cause activation of neuronal sodium channels, resulting in excessive firing of neurons,26, 27 and both induce similar increases i n blood pressure and in plasma renin levels in rats. 2s However, the clinical manifestations of envenomation in U.S. patients are dissimilar. American patients with severe envenomation, mostly infants and young children, seem to manifest central nervous

T a b l e III. Duration of stay in PICU and duration of hospitalization Duration of stay

AV group

PICU (hr) Range 4-108 Mean 20.9 Hospitalization (days) Range 1-4t Mean 2.75

NAV group

p*

3-88 21. I

-0.89

1-6 2.83

0.89

*The p values were determined by the multiresponse permutation procedure. 43 ]'One patient hospitalized for 88 days was excluded.

system and neuromuscular dysfunction comparable to that in the Israeli victims. However, cardiovascular dysfunction, the main hazard of the Israeli-North African scorpion, as well as of the Indian scorpion (Buthus tamulus) and the Brazilian scorpion (Tityus serrulatus), has not been reported after envenomation by the American scorpion, at least in the past decade. Severe cardiovascular dysfunction, including shock and pulmonary edema, occurred in 9% of our patients, primarily in "older" children. We have no explanation for the higher incidence of cardiac abnormalities among older children, but our observation is in accord with those of others who reported a single patient younger than 1 year among 34 sting victims with cardiovascular dysfunction (aged 9 months to 60 years). 3' 7, 29, 30 In addition, only 2 patients younger than 1 year of age were among 32 patients aged 8 months to 34 years who died of scorpion sting.3, ~, 7, 29, 30 The death rate from scorpion envenomation dropped significantly in the United States between 1940 and 1970. 31 (The last mortality figures available to us are for 1968.19) The decrease in the mortality rate was attributed to good scorpion control and eradication, and to improved therapeutic practices including immediate airway control and intensive care. 15-19 Specific AV against many toxic scorpion species is now commercially available. This therapeutic modality has been advocated since 1953 as the only specific treatment of scorpion sting. 3234 Uncontrolled studies have shown that children treated with AV shortly after E D arrival recover faster than those who are not treated. 16-18Bond 18 was able to discharge from the ED some children with envenomation after AV administration, thus saving money and use of PICU facilities. However, allergic reactions (rash or serum sickness) developed in 58% of his patients. Bond's approach may be appropriate for Arizona, but we believe that it should not be adopted in other regions where envenomation is associated with severe cardiovascular dysfunction and death. Cardiovascular dysfunction may develop hours after en-

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venomation, and its occurrence is unpredictable; all victims arriving in the ED with signs of systemic intoxication should be admitted to the hospital, preferably to an intensive care unit. The pathogenesis of cardiac dysfunction is not clear. It has been suggested that hypokinesia and diminished myocardial performance are the result of increased catecholamine production, causing increased myocardial oxygen demand in excess of oxygen supply. 7, 35-39 Antivenom given before intoxication may prevent catecholamine excretion but cannot abolish its effect once excreted; this might explain its apparent ineffectiveness in human victims, as shown in our study. Animal studies have shown that it is possible to prevent intoxication and death when AV is administered before, or concomitantly with, the venom. 3234 This situation obviously does not apply to human victims. Cardiac dysfunction develops hours after ED arrival and thus seems to be potentially preventable. However, our study shows that the frequency of significant cardiovascular abnormalities was similar in children treated with A V and in untreated children, and children treated with AV had a more difficult course. Although we do not believe that the apparently higher mortality rate in the AV group is causally related to AV administration, our data demonstrate the ineffectiveness of the AV. In addition, 15% of our patients were already in a state of severe respiratory failure on arrival at the hospital; AV therapy could not be preventive in such cases. In fact, the postintubation course of the children in our study who were treated with specific A V did not differ from the course of the children who did not receive AV. Thus, despite almost 40 years of use, there is no convincing evidence that AV is effective in the treatment of human envenomation. Moreover, no quantitative studies have compared A V dosage, route of administration, time-effectiveness relation, and titer of the A V used. 29, 40 We believe that the marked decrease in the mortality rate in our institution is the result of the introduction of intensive care and treatment of symptoms 8'41, 42 rather than therapy with AV. Similar results have been reported for the Mahad region of India, where the mortality rate decreased from 30% in the 1970s to 2% to 3% in the 1980s without the use of AV but with intensive care and treatment of symptoms.4,14 These data emphasize the need to reconsider therapy with AV in human victims of scorpion stings and the need for a control study regarding its efficacy. Such a study may define specific subgroups that may benefit from therapy with AV. REFERENCES

1. Efrati P. Epidemiology, symptomatology and treatment of Buthidae scorpion. In: Bettini S, ed. Handbook of experimental pharmacology-arthropod venoms; vol 48. Berlin: Springer Verlag, 1978:312-7.

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2. Sutherland SK. Management of venomous bites and stings. Medicine International 1981;1:415-22. 3. Amaral CFS, Rezende NA de, Freire-Maia L. Acute pulmonary edema after Tityus serrulatus scorpion sting in children. Am J Cardiol 1992;71:242-5. 4. Bawaskar HS, Bawaskar PH. Management of the cardiovascular manifestations of poisoning by the Indian red scorpion (Mesobuthus tamulus). Br Heart J 1992;68:478-80. 5. Goyffon M, Vachon M, Broglio N. Epidemiological and clinical characteristics of the scorpion envenomation in Tunisia. Toxicon 1982;20:337-44. 6. Hershkovits Y, Elizur Y, Margolis CZ, Barak N, Sofer S, Moses SW. Criteria map audit of scorpion envenomation in Negev children 1974-1980: clinical picture and quality of care. Toxicon 1985;5:845-54. 7. Gueron M, Yarom R. Cardiovascular manifestations of severe scorpion sting. Chest 1970;57:156-62. 8. Sofer S, Gueron M. Respiratory failure in children following envenomation by the scorpion Leiurus quinquestriatus, herondynamics and neurological aspects. Toxicon 1988;26:931-9. 9. Sorer S, Shachak E, Slonin A, Gueron M. Myocardial injury without heart failure following envenomation by the scorpion Leiurus quinquestriatus in children. Toxicon 1991;29:382-5. 10. Sofer S, Shalev H, Weizman Z, Shachak E, Gueron M. Acute pancreatitis in children following envenomation by the yellow scorpion Leiurus quinquestriatus. Toxicon 1991;29:125-8. 11. Freire-Maia L, Campos MA. Pathophysiology and treatment of scorpion poisoning. In: Ownby CL, Odell GV, eds. Natural toxins, characterization, pharmacology and therapeutics. Oxford: Pergamon Press, 1989;24:139-59. 12. Amitai Y, Mines Y, Aker M, Goiten K. Scorpion sting in children. Clin Pediatr 1985;24:136-40. 13. Freire-Maia L, Campos JA. Response to Letter to the Editor. Toxicon 1987;25:125-30. (Gueron M, Ovsyshcher I. What is the treatment for the cardiovascular manifestations of scorpion envenornation? [Letter]. Toxicon 1987;25:121-4). 14. Bawaskar HS, Bawaskar PH. Prazosin in management of cardiovascular manifestations of scorpion sting [Letter]. Lancet 1986;1:510-1. 15. Rimsza ME, Zimmerman DR, Bergeson PS. Scorpion envenomation. Pediatrics 1980;66:298-30Z 16. Rachesky IJ, Banner W, Dansky J, Tong T. Treatment for Centruroides exilicanda envenomation. Am J Dis Child 1984; 138:1136-9. 17. Curry SC, Vance MV, Ryan PJ, Kunkel DB, Northey WT. Envenomation by the scorpion Centruroides sculpturatus. J Toxicol Clin Toxicol 1984;21:417-49. 18. Bond GR. Antivenin administration for Centruroides scorpion sting: risks and benefits. Ann Emerg Med 1992;21:788-91. 19. Berg RA, Tarantino MD. Envenomation by the scorpion Centruroides exilicanda (C. sculpturatus): severe and unusual manifestations. Pediatrics 1991 ;87:930-3. 20. Ismail M, ABD-Elsalam MH. Are the toxicological effects of scorpion envenomation related to tissue venom concentration? Toxicon 1988;26:233-56. 21. Gueron M, Ovsyshcher I. What is the treatment for the cardiovascular manifestations of scorpion envenomation? [Letter]. Toxicon 1987;25:121-4. 22. Sofer S, Gueron M. Cardiovascular aspects of scorpion envenomation. In: Gopalakrishnakone P, Tan CK, eds. Recent advances in toxinology research; vol 2. Venom and toxin research group. Singapore: National University of Singapore, 1992:40-9.

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23. Sofer S, Gueron M. Vasodilators and hypertensive encephalopathy following scorpion envenomation in children. Chest 1990;97:118-20. 24. Stahnke HL, Dengler AH. The effect of morphine and related substances on the toxicity of venoms. I. Centruroides sculpturatus Ewing scorpion venoms. Am J Trop Med Hyg 1964; 13:346-51. 25. Gueron M, Ilia R, Shachak E, Sofer S. Renin and aldosterone levels and hypertension following envenomation in humans by the yellow scorpion Leiurus quinquestriatus. Toxicon 1992; 30:765-7. 26. Wang GK, Strichartz GR. Purification and physiological characterization of neurotoxins from venoms of the scorpions Centruroides sculpturatus and Leiurus quinquestriatus. Mol Pharmacol 1983;23:519-3. 27. Zlotkin E, Shulov AS. Recent studies on the mode of action of scorpion neurotoxins: a review. Toxicon 1969;7:217-21. 28. La Grange RG. Elevation of blood pressure and plasma renin levels by venoms from scorpions Centruroides sculpturatus and Leiurus quinquestriatus. Toxicon 1977;15:429-33. 29. Ismail M, Fatani FJY, Debess TT. Experimental treatment protocols from scorpion envenomation: a review of common therapies and an effect of kallikrein-kinin inhibitors. Toxicon 1992;30:1257-79. 30. Albroug F, Boujdaria R, Belghith M, Nouiza S, Bouchoucha S. Cardiac dysfunction and pulmonary edema following scorpion envenomation. Chest 1991;100:1057-9. 31. Stahnke HL. Arizona lethal scorpion. Ariz Med 1972;29:490-3. 32. Rohayem H. Scorpion toxin and antagonistic drugs. J Trop Med Hyg 1953;56:150-8. 33. Balozet L. Scorpion venoms and antiscorpion serum. In: Venoms. American Association for the Advancement of Science 1956;141-4.

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34. Shulov A, Levy C. Venoms of Buthidae. In: Bettini S, ed. Handbook of experimental pharmacology-arthropod venoms; vol 48. Berlin: Springer-Verlag, 1978;309-17. 35. Gueron M, Adolph RG, Grupp IL, Gabel M, Grupp G, Fowler NO. Hemodynamic and myocardial consequences of scorpion venom. Am J Cardiol 1980;45:979-86. 36. Gueron M, Margulis G, Sorer S. Echocardiographic and radionuclide angiographic observations following scorpion envenomation by Leiurus quinquestriatus. Toxicon 1990;28: 1005-9. 37. Braun K, Stern S, Werkson S. Sympathomimefic effects of scorpion venom on the cardiovascular system. Isr J Med Sci 1969;5:853-4. 38. Moss J, Kasic T, Henry DP, Kopin IJ. Scorpion venominduced discharge of cateeholamines accompanied by hypertension. Brain Res 1973;54:381-5. 39. Freire-Maia L, Azevedo AD, Cunha-Melo JR, Almeida AP, Silva AB, Alpiom NC. Arterial hypertension, cardiac arrhythmias and pulmonary edema induced by scorpion toxin in unanesthetized rats. Toxicon 1979;17:51. 40. E1-Ayeb ME, Delori P. Immunology and immunochemistry of scorpion neurotoxins. In: Tu A, ed. Insect poisons, allergens and other invertebrate venoms, handbook of natural toxins; vol 2. New York: Marcel Dekker, 1984:607-38. 41. Gueron M, Sorer S. Scorpion envenomation and the heart [Editorial]. J Wilderness Med 1991;2:175-7. 42. Gueron M, Ilia R, Sofer S. The cardiovascular system after scorpion envenomation: a review. J Toxicol Clin Toxicol 1992;30:235-58. 43. Mielke PW. Nonmetric statistical analyses: some metric alternatives. J Statist Plan Inference 1986;13:377-87.

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