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Treatment of the scorpion envenoming syndrome: 12-years experience with serotherapy
International Journal of Antimicrobial Agents 21 (2003) 170 /174 www.isochem.org
Treatment of the scorpion envenoming syndrome: 12-years experience with serotherapy Mohammad Ismail Hamed * October 6 University, 6th of October City, Main Center 111, Egypt
Abstract 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. # 2002 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Scorpion envenomation; Serotherapy; Saudi Arabia
1. Introduction Different approaches to the treatment of scorpion envenoming have been advocated by different investigators. Some investigators recommend treatment of mild cases of envenoming with symptomatic measures and/or antivenin and severe cases with symptomatic measures, support of vital functions and i.v. injection of antivenin [1,2]. Others [3,4] recommend close monitoring in ICU for pulmonary or CNS complications, especially for children. Intravenous hydralazine may be beneficial in the presence of systemic hypertension in such cases. A treatment protocol based mainly on serotherapy using antivenin in high doses was reported to be unsurpassed in reducing the morbidity and mortality from dangerous scorpion stings [5 /7]. Scorpion venoms are known to stimulate both branches of the autonomic nervous system simultaneously with predominance of sympathetic stimulation * Tel.: /20-2-337-1058; fax: /20-2-337-1058 E-mail address: [email protected] (M.I. Hamed).
and release of tissue and medullary catecholamines [8 / 12]. It would seem logical, therefore, that blockers of the sympathetic and parasympathetic nervous systems can abolish or diminish the actions of the venoms. However, opinions differ in this kind of approach. Antivenom therapy, despite its success in saving the lives of millions of scorpion sting victims, has also caused controversy between different investigators. The majority of investigators consider antivenom the only specific treatment for scorpion stings [13 /17,1,2]. Few others, however, questioned its value in preventing cardiovascular manifestations in human scorpionism.
2. Treatment strategy of scorpion envenoming The extensive studies on the pathophysiology of scorpion envenoming and the understanding of the molecular mechanism of action of scorpion toxins had little impact on the development or selection of drugs used in therapy. Also, the understanding of the absorption, distribution and elimination of scorpion venom and the determination of its site of action in the tissue
0924-8579/02/$30 # 2002 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 2 ) 0 0 2 8 9 - 3
M.I. Hamed / International Journal of Antimicrobial Agents 21 (2003) 170 /174
compartment were not applied [18 /21]. It is clear that in the absence of clear medical agreement, treatment of scorpion envenoming would be symptomatic. No argument can be made against treatment of symptomatic patients presenting with hypertension and heart failure, hypotension with or without pulmonary oedema, CNS manifestations in infants and young children or main system instability following scorpion stings in an intensive care unit. Two approaches, mainly antivenin therapy and alternative/adjunctive therapy are used.
3. Antivenin therapy and Saudi experience Serotherapy of the scorpion envenoming syndrome has been the subject of much debate and controversy in the last few years. The majority of opinions supports serotherapy and considers antivenin the only specific treatment of scorpion stings. Few others, however, questioned the effectiveness of antivenin in the abolition or prevention of the cardiovascular manifestations of envenoming. The crucial factors in the success of serotherapy are the potency of the antivenin and its dose and route of administration. The i.m. injection of antivenin is useless in the treatment of scorpion envenoming because of the slow absorption and distribution of the immunoglobulins compared with the rapid absorption and distribution of scorpion venom. Except for the work of Freire-Maia and his group [2,3] who collected data over a period of 16 years and that of Ismail [5 /7] based on serotherapy of several thousands victims using a preset treatment protocol applied nationwide, other studies are individualized. A treatment protocol for scorpion envenoming based mainly on the intravascular administration of high doses of polyvalent antivenin was applied nationwide. The protocol in turn was based on the results of pharmacokinetic studies showing very rapid absorption and distribution of venom and slow to very slow absorption and distribution of antivenins. This necessitated the intravascular administration of doses of antivenin higher than the calculated in vitro neutralizing dose to compensate for the slow rate of transfer of antivenin and speed up the neutralization of venom effect. The summary of the treatment protocols is shown in Appendix A. The results of applying the treatment protocol were very impressive. The overall mortality was reduced from an average of 4.6 /8% to less than 0.05%. There was only a very low incidence of the major manifestations of envenomation such as pulmonary oedema, hypertension, hypotension, cardiac dysrhythmias and neurological symptoms requiring drug therapy following antivenin administration. The period of stay in hospital was much reduced. The details of the outcome of
171
treatment of 2028 scorpion sting cases at Al-Qassim and Al-Baha regions have been previously published [6,7]. Table 1 shows the analysis of 2010 additional scorpion sting cases in the Central Province, Saudi Arabia of which 1600 cases (80%) were treated with antivenin. The remaining victims were not given antivenin either because of unavailability (19.4%) or sensitivity to antivenin (1%). Early reactions to antivenin administration developed in 13.9% of the patients with low severity, consisting mainly of skin rashes, urticaria, wheezing and bronchial secretions but no anaphylaxis. None of the patients have died over the last 6 years of using this treatment protocol (Ismail, unpublished).
Table 1 Analysis of 2010 cases of scorpion sting cases treated principally with antivenin Parameter (I) Causative scorpion L. quinquestriatus A. crassicauda Unidentified (II) Previous scorpion stings Yes No (III) Previous treatment with antivenin Yes No (IV) Sensitivity to antivenin (/ve skin test) Yes No (V) Antivenin treatmenta Receiveda Not receivedb (VI) Early reaction to antiveninc Present Absent (VII) Outcome of therapy Cured Transferredd Dischargede Died
Number of patients %
985 600 400
49.0 29.9 21.1
288 1722
14.3 85.7
148 1862
7.4 92.6
20 1990
1.0 99.0
1600 410
79.6 20.4
223 1377
13.9 86.1
1176 649 185 /
58.5 32.3 9.2 0.0
a 5 /1 ml ampoules polyvalent antivenin diluted in 50 ml saline and injected slowly i.v. b Patients did not receive antivenin because of either unavailability or sensitivity. c Consisted mainly of skin rashes, urticaria, wheezing and/or bronchial secretion but no anaphylaxis. d Patients either have sensitivity to antivenin or transferred to a central hospital for better facilities. e Discharged against medical advice before the 24 h observation period.
172
M.I. Hamed / International Journal of Antimicrobial Agents 21 (2003) 170 /174
4. Alternative and adjunctive therapy 4.1. Vasodilators 4.1.1. Hydralazine Causes direct relaxation of arteriolar smooth muscles through NO generation. It also causes hyperpolarization of arteries and interferes with mobilization of Ca2 in vascular smooth muscles. The induced vasodilatation is associated with sympathetic stimulation and increased heart rate. It also elevates plasma renin and stimulates norepinephrine release directly. Hydralazine, therefore, can physiologically antagonize the vasoconstrictor effects of scorpion venom but its stimulant action on the sympathetic nervous system constitutes an important side effect. Furthermore, the hypotensive response to i.v or i.m. hydralazine is very unpredictable, and prolonged hypotension occurred with i.v. doses as low as 10 mg.
cular manifestations of scorpion envenoming, although in one report it was used to correct hypotension caused by diuretics in patients with pulmonary oedema due to scorpion stings. Ismail [5] cautioned against its use, since the drug inhibits the kininase II enzyme leading to accumulation of bradykinin, the neurohumoral agent, incriminated experimentally for the pulmonary oedema of the scorpion envenoming syndrome. 4.1.5. Other potentially useful vasodilator drugs The central stimulant action of clonidine on a2adrenergic receptors. The rapid onset and the titrable hypotension of sodium nitroprusside especially in case of pulmonary oedema. Phentolamine (or prazosin) in case of hypertension with tachycardia. The bradykinin receptor blockers (e.g. the experimental drug Hoe 148) to prevent development of pulmonary oedema. 4.2. Atropine and other parasympatholytic drugs
4.1.2. Prazosin This is a selective a1-adrenergic receptor blocker and is also a potent inhibitor of phosphodiesterase. It blocks the a1-receptors in arterioles and veins causing a decreased peripheral resistance and venous return with no increase in heart rate. It does not block the a2receptors and does not cause norepinephrine release from sympathetic nerve terminals. It has an action on CNS suppressing the sympathetic outflow. Prazosin, therefore, possesses pharmacological properties that render it most suitable in antagonizing the toxicological effects of scorpion venom. It appears superior to hydralazine, and except for the first dose phenomenon (syncope), other side effects seem minimal. 4.1.3. Nifedipine Is a Ca2 channel blocker that causes a selective vasodilatation to the arteriolar resistance vessels and greatly enhances coronary blood flow. Reflex sympathetic stimulation occurs with increased heart rate and force of contraction. The cardiac output increases as a result of the decreased peripheral resistance and the positive inotropism. It appears that nifedipine, although capable of antagonizing the hypertensive effect of the venom, suffers from a serious side effect. The reflex sympathetic stimulation may add to the effect of the venom and cause dangerous cardiac stimulation. Different types of arrhythmias have been observed following administration of nifedipine to scorpion sting victims (Ismail, unpublished; Bawaskar, personal communication). 4.1.4. Captopril and other ACE inhibitors Inhibit the conversion of the relatively inactive angiotensin I to active angiotensin II and inhibit the degradation of bradykinin and potentiate its hypotensive action. Are not commonly used in the cardiovas-
Atropine is very effective experimentally in prolonging the survival time and protecting mice, rats and rabbits from the lethal and several pharmacological actions of the venom. When combined with an aadrenergic receptor blocker such as phentolamine, the protective effects increase greatly. This is because atropine blocks the initial cardiac depressant and hypotensive actions and phentolamine blocks the hypertensive effect of the venom. Clinically, the use of atropine is not recommended because of the frequent heavy perspiration, vomiting and salivation in scorpion envenoming and the effect of atropine in potentiating the hypertensive effect and the severity of pulmonary oedema induced by scorpion toxin. It can be used, however, in emergency states where scorpion venom causes severe bradycardia. 4.3. Anticonvulsants Scorpion venom induces its pharmacological effects at the molecular level through activation of the voltagesensitive Na channels and blocking the Ca2 activated K channels and small conductance Cl channels. Phenobarbitone potentiates GABA-induced increase in Cl conductance and reduces glutamateinduced depolarization. It causes prolongation of the periods during which bursts of channel openings occur. Diazepam and other benzodiazepines enhance GABAinduced increase in conductance of Cl and thus augment the inhibitory effect produced by stimulating various GABAergic pathways in the CNS. The effect is associated with increased frequency of bursts of openings of the Cl channels. Both phenobarbitone and diazepam, thus, can antagonize the scorpion venominduced seizures by antagonizing the effect of scorpion toxin on the specific ionic channels concerned. Because
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of the risk of respiratory depression by phenobarbitone, diazepam, is preferred as an anticonvulsant. 4.4. Antiemetics Vomiting is frequently encountered in scorpion sting victims. The mechanism of action is not yet studied. It is likely due to the release of dopamine in the chemoreceptor trigger zone. Dopaminergic agonists are emetic, while dopaminergic, muscarinic and H1 antagonists have antiemetic properties to varying degrees. Scorpion venom releases dopamine, other catecholamines, acetylcholine and histamine in various tissues. Metoclopramide is a selective D2-dopaminergic antagonist which is effective both by i.v. and oral administration in controlling vomiting associated with Tityus serrulatus envenoming. Chlorpromazine is a non-selective dopaminergic antagonist which possesses in addition potent a-adrenergic, serotonergic and cholinergic blocking activities. It is used successfully in scorpion sting victims to check vomiting, especially in children, and to induce sedation. 4.5. Acetaminophen and other antipyretics Hyperthermia is a frequent symptom in victims stung by various scorpions. Possible mechanisms of action include release of norepinephrine in the anterior hypothalamus, shift in the balance of sodium and calcium in favour of sodium in the posterior hypothalamus and enhancing the synthesis and release of prostaglandins. Acetaminophen and water sponges were effective in lowering the markedly elevated temperature of victims stung by Leiurus quinquestriatus and Androctonus crassicauda (Fig. 1). The effect is likely due to inhibition of prostaglandin synthesis and the effectiveness of acetaminophen against enzymes in CNS [20,22,7]. Dipyrone by intravascular injection was recommended for hyperthermia induced by T. serrulatus venom [3]. 4.6. Preventive control of scorpion sting Scorpion stings always occur under accidental circumstances, more often at night, and when the weather is stormy, the temperature elevated and the wind hot. Stings occur in houses, tents, palm, cane or banana plantations or gardens during agricultural work, or on trips. The parts of the body most frequently stung are the limbs or occasionally the head and neck of sleeping persons. The latter case is more frequent in infants and young children. Scorpions have their ‘domiciles’ in infested areas under stones, rocks, logs, loose bark of trees and around human habitations in gardens, old lumber, boxes, garages, washhouses, sacks, porches, chicken houses, under wash clothes and in old shoes, mattresses, clothes or piles of newspapers stored in dark
Fig. 1. Leiurus quinquestriatus and Androctonus crassicauda are two of the five most venemous scorpions in the world.
places. In infested areas, scorpions may be eradicated or their numbers much reduced by the use of insecticides. The following precautions may be of value for travellers or residents in areas harbouring dangerous scorpions: 1) Do not walk with bare feet during the night Always wear a shoe or better a half-boot covering your ankle 2) Do not keep old clothes, mattresses, newspapers and other rubbish in your house as they provide a good domicile for scorpions 3) When camping outdoors, keep your garbage in closed bags as garbage attract cockroaches and other insects which in turn attract scorpions preying on them 4) Always check your shoes before putting your feet in 5) Houses in infested areas should have a step of at least 20 cm high made of glazed bricks or paint all around to prevent scorpions climbing from outside 6) Use insecticides in suspected areas when a scorpion is seen or caught.
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174
Appendix A: Summary of the treatment protocol Stage I All patients with confirmed stings or suspected stings with systemic manifestations: (1) 5 /1 ml ampoules antivenin in 20 /50 ml saline i.v slowly in ER. Repeat up to 20 /1 ml ampoules (2) Appropriate treatment for: High fever: water sponges plus acetaminophen suppositories Vomiting: chlorpromazine 0.5 /1 mg/kg i.m., or Promethazine 0.5 /1 mg/kg i.m Convulsions: Diazepam i.v. slowly Local pain: 1% zylocaine infiltration at the site of the sting (0.5 ml. maximum) Stage II Children below 12 years and debilitated patients with systemic manifestations: Transfer to ICU Hypertension: hydralazine or nifedipine Pulmonary oedema: oxygen, frusemide and fluid restriction Convulsions: diazepam (NOT Barbiturates) Dyspnoea: I.P.P.V. (start at ER) C.V.P. line with 0.5 N saline to keep value at 8 /12 cmH2O Correct for blood gases and electrolytes N.B. Do not use barbiturates, morphine, pethidine or b-blockers.
References [1] Freire-Maia L, Campos JA. Response to the letter to the Editor by Gueron an Ovsyshcher on the treatment of the cardiovascular manifestations of scorpion envenomation. Toxicon 1987;25:125 / 30. [2] Freire-Maia, L, Campos, JA, 1989. Pathophysiology and treatment of scorpion poisoning. In: Ownby, CL, Odell, GV, editors. Natural Toxins, Characterization, Pharmacology and Therapeutics, Proceedings of the Ninth World Congress on Animal, Plant and Microbial Toxins, Stillwater, Oklahoma, Oxford: Pergamon Press; August 1988. [3] Freire-Maia L, Campos JA, Amaral CFS. Approaches to the treatment of scorpion envenoming. Toxicon 1994;32:1009 /14. [4] Gueron M, Ilia R, Sofer S. The cardiovascular system after scorpion envenomation. A review. J Toxic-Clin Toxic 1992;30:245 /58.
[5] Ismail M. Serotherapy of the scorpion envenoming syndrome is irrationally convicted without trial. Toxicon 1993;31:1077 /83. [6] Ismail M. The treatment of the scorpion envenoming syndrome: the Saudi experience with serotherapy. Toxicon 1994;32:1019 /26. [7] Ismail M. Review article. The scorpion envenoming syndrome. Toxicon 1995;33:825 /58. [8] Patterson RA. Physiological action of scorpion venom. Am J Trop Med Hyg 1960;9:410 /4. [9] Stahnke HL. Some pharmacological and biochemical characteristics of Centruroides sculpturatus (Ewing) scorpion venom. In: Roudonat HW, editor. Recent advances in pharmacology of toxins, vol. 9. Prague: Pergamon and Czechslovak Medical Press, 1965:63 /70. [10] Ismail M, Osman OH, Ibrahim SA, El-Asmar MF. Cardiovascular and respiratory responses to the venom from the scorpion Leiurus quinquestriatus . E Afr Med J 1972;49:275 /81. [11] Ismail M, Osman OH, El-Asmar MF. Pharmacological studies of the venom from the scorpion Buthus minax (L. Koch). Toxicon 1973;11:15 /20. [12] Ismail M, Osman OH, Gumaa KA, Karrar MA. Some pharmacological studies with scorpion (Pandinus exitialis ) venom. Toxicon 1974;12:75 /82. [13] Rohayem. Scorpion toxin and antagonistic drugs. J trop Med Hyg 1953;56:150 /8. [14] Shulov A, Levy C. Venoms of Buthinae. In: Bettini S, editor. Handbook of experimental pharmacology, arthropod venoms, vol. 48. Berlin: Springer, 1978:309 /17. [15] Goyffon M, Vachon M, Broglion N. Epidemiology and clinical characteristics of the scorpion envenomation in Tunisia. Toxicon 1982;20:337 /44. [16] Hassan F. Production of scorpion antivenin. In: Tu A, editor. Handbook of toxins, insect poisons, allergens and other invertebrate venoms, vol. 2. New York: Marcel Dekker, 1984:577 /605. [17] Kankonkar, RC, Murthy, KR, Zare, A, Malathi, A, Balasubramaniam, P, Yeolekar, ME. Reversal of cardiovascular and haemodynamic disturbances by scorpion antivenom administration in myocarditis due to envenomation by Indian red scorpion Buthus tamulus (Buthidae family) venom. Abstracts of the Tenth World Congress on Animal, Plant and Microbial Toxins. Toxicon. 1992;30:523. [18] Ismail M, Abdullah ME, Morad AM, Ageel AM. Pharmacokinetics of 125I-labelled venom from the scorpion Androctonus amoreuxi (Aud. & Sav.). Toxicon 1980;18:301 /8. [19] Ismail M, Shibl AM, Morad AM, Abdullah ME. Pharmacokinetics of 125I-labelled antivenin to the venom from the scorpion Androctonus amoreuxi . Toxicon 1983;21:47 /56. [20] Ismail M, Abd-Elsalam MA, Morad AM. Do changes in body temperature following envenomation by the scorpion Leiurus quinquestriatus influence the course of toxicity? Toxicon 1990;28:1265 /84. [21] Ismail M, Fatani AJY, Dabees TT. Experimental treatment protocols for scorpion envenomation: a review of common therapies and an effect of kallikrein /kinin inhibitors. Toxicon 1992;30:1257 /79. [22] Ismail M, Abd-Elsalam MA, Al-Ahaidib MS. Androctonus crassicauda (Olivier), a dangerous and unduly neglected scorpion. I- Pharmacological and clinical studies. Toxicon 1994;32:1599 / 618.
Treatment of the scorpion envenoming syndrome: 12-years experience with serotherapy Mohammad Ismail Hamed * October 6 University, 6th of October City, Main Center 111, Egypt
Abstract 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. # 2002 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Scorpion envenomation; Serotherapy; Saudi Arabia
1. Introduction Different approaches to the treatment of scorpion envenoming have been advocated by different investigators. Some investigators recommend treatment of mild cases of envenoming with symptomatic measures and/or antivenin and severe cases with symptomatic measures, support of vital functions and i.v. injection of antivenin [1,2]. Others [3,4] recommend close monitoring in ICU for pulmonary or CNS complications, especially for children. Intravenous hydralazine may be beneficial in the presence of systemic hypertension in such cases. A treatment protocol based mainly on serotherapy using antivenin in high doses was reported to be unsurpassed in reducing the morbidity and mortality from dangerous scorpion stings [5 /7]. Scorpion venoms are known to stimulate both branches of the autonomic nervous system simultaneously with predominance of sympathetic stimulation * Tel.: /20-2-337-1058; fax: /20-2-337-1058 E-mail address: [email protected] (M.I. Hamed).
and release of tissue and medullary catecholamines [8 / 12]. It would seem logical, therefore, that blockers of the sympathetic and parasympathetic nervous systems can abolish or diminish the actions of the venoms. However, opinions differ in this kind of approach. Antivenom therapy, despite its success in saving the lives of millions of scorpion sting victims, has also caused controversy between different investigators. The majority of investigators consider antivenom the only specific treatment for scorpion stings [13 /17,1,2]. Few others, however, questioned its value in preventing cardiovascular manifestations in human scorpionism.
2. Treatment strategy of scorpion envenoming The extensive studies on the pathophysiology of scorpion envenoming and the understanding of the molecular mechanism of action of scorpion toxins had little impact on the development or selection of drugs used in therapy. Also, the understanding of the absorption, distribution and elimination of scorpion venom and the determination of its site of action in the tissue
0924-8579/02/$30 # 2002 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 2 ) 0 0 2 8 9 - 3
M.I. Hamed / International Journal of Antimicrobial Agents 21 (2003) 170 /174
compartment were not applied [18 /21]. It is clear that in the absence of clear medical agreement, treatment of scorpion envenoming would be symptomatic. No argument can be made against treatment of symptomatic patients presenting with hypertension and heart failure, hypotension with or without pulmonary oedema, CNS manifestations in infants and young children or main system instability following scorpion stings in an intensive care unit. Two approaches, mainly antivenin therapy and alternative/adjunctive therapy are used.
3. Antivenin therapy and Saudi experience Serotherapy of the scorpion envenoming syndrome has been the subject of much debate and controversy in the last few years. The majority of opinions supports serotherapy and considers antivenin the only specific treatment of scorpion stings. Few others, however, questioned the effectiveness of antivenin in the abolition or prevention of the cardiovascular manifestations of envenoming. The crucial factors in the success of serotherapy are the potency of the antivenin and its dose and route of administration. The i.m. injection of antivenin is useless in the treatment of scorpion envenoming because of the slow absorption and distribution of the immunoglobulins compared with the rapid absorption and distribution of scorpion venom. Except for the work of Freire-Maia and his group [2,3] who collected data over a period of 16 years and that of Ismail [5 /7] based on serotherapy of several thousands victims using a preset treatment protocol applied nationwide, other studies are individualized. A treatment protocol for scorpion envenoming based mainly on the intravascular administration of high doses of polyvalent antivenin was applied nationwide. The protocol in turn was based on the results of pharmacokinetic studies showing very rapid absorption and distribution of venom and slow to very slow absorption and distribution of antivenins. This necessitated the intravascular administration of doses of antivenin higher than the calculated in vitro neutralizing dose to compensate for the slow rate of transfer of antivenin and speed up the neutralization of venom effect. The summary of the treatment protocols is shown in Appendix A. The results of applying the treatment protocol were very impressive. The overall mortality was reduced from an average of 4.6 /8% to less than 0.05%. There was only a very low incidence of the major manifestations of envenomation such as pulmonary oedema, hypertension, hypotension, cardiac dysrhythmias and neurological symptoms requiring drug therapy following antivenin administration. The period of stay in hospital was much reduced. The details of the outcome of
171
treatment of 2028 scorpion sting cases at Al-Qassim and Al-Baha regions have been previously published [6,7]. Table 1 shows the analysis of 2010 additional scorpion sting cases in the Central Province, Saudi Arabia of which 1600 cases (80%) were treated with antivenin. The remaining victims were not given antivenin either because of unavailability (19.4%) or sensitivity to antivenin (1%). Early reactions to antivenin administration developed in 13.9% of the patients with low severity, consisting mainly of skin rashes, urticaria, wheezing and bronchial secretions but no anaphylaxis. None of the patients have died over the last 6 years of using this treatment protocol (Ismail, unpublished).
Table 1 Analysis of 2010 cases of scorpion sting cases treated principally with antivenin Parameter (I) Causative scorpion L. quinquestriatus A. crassicauda Unidentified (II) Previous scorpion stings Yes No (III) Previous treatment with antivenin Yes No (IV) Sensitivity to antivenin (/ve skin test) Yes No (V) Antivenin treatmenta Receiveda Not receivedb (VI) Early reaction to antiveninc Present Absent (VII) Outcome of therapy Cured Transferredd Dischargede Died
Number of patients %
985 600 400
49.0 29.9 21.1
288 1722
14.3 85.7
148 1862
7.4 92.6
20 1990
1.0 99.0
1600 410
79.6 20.4
223 1377
13.9 86.1
1176 649 185 /
58.5 32.3 9.2 0.0
a 5 /1 ml ampoules polyvalent antivenin diluted in 50 ml saline and injected slowly i.v. b Patients did not receive antivenin because of either unavailability or sensitivity. c Consisted mainly of skin rashes, urticaria, wheezing and/or bronchial secretion but no anaphylaxis. d Patients either have sensitivity to antivenin or transferred to a central hospital for better facilities. e Discharged against medical advice before the 24 h observation period.
172
M.I. Hamed / International Journal of Antimicrobial Agents 21 (2003) 170 /174
4. Alternative and adjunctive therapy 4.1. Vasodilators 4.1.1. Hydralazine Causes direct relaxation of arteriolar smooth muscles through NO generation. It also causes hyperpolarization of arteries and interferes with mobilization of Ca2 in vascular smooth muscles. The induced vasodilatation is associated with sympathetic stimulation and increased heart rate. It also elevates plasma renin and stimulates norepinephrine release directly. Hydralazine, therefore, can physiologically antagonize the vasoconstrictor effects of scorpion venom but its stimulant action on the sympathetic nervous system constitutes an important side effect. Furthermore, the hypotensive response to i.v or i.m. hydralazine is very unpredictable, and prolonged hypotension occurred with i.v. doses as low as 10 mg.
cular manifestations of scorpion envenoming, although in one report it was used to correct hypotension caused by diuretics in patients with pulmonary oedema due to scorpion stings. Ismail [5] cautioned against its use, since the drug inhibits the kininase II enzyme leading to accumulation of bradykinin, the neurohumoral agent, incriminated experimentally for the pulmonary oedema of the scorpion envenoming syndrome. 4.1.5. Other potentially useful vasodilator drugs The central stimulant action of clonidine on a2adrenergic receptors. The rapid onset and the titrable hypotension of sodium nitroprusside especially in case of pulmonary oedema. Phentolamine (or prazosin) in case of hypertension with tachycardia. The bradykinin receptor blockers (e.g. the experimental drug Hoe 148) to prevent development of pulmonary oedema. 4.2. Atropine and other parasympatholytic drugs
4.1.2. Prazosin This is a selective a1-adrenergic receptor blocker and is also a potent inhibitor of phosphodiesterase. It blocks the a1-receptors in arterioles and veins causing a decreased peripheral resistance and venous return with no increase in heart rate. It does not block the a2receptors and does not cause norepinephrine release from sympathetic nerve terminals. It has an action on CNS suppressing the sympathetic outflow. Prazosin, therefore, possesses pharmacological properties that render it most suitable in antagonizing the toxicological effects of scorpion venom. It appears superior to hydralazine, and except for the first dose phenomenon (syncope), other side effects seem minimal. 4.1.3. Nifedipine Is a Ca2 channel blocker that causes a selective vasodilatation to the arteriolar resistance vessels and greatly enhances coronary blood flow. Reflex sympathetic stimulation occurs with increased heart rate and force of contraction. The cardiac output increases as a result of the decreased peripheral resistance and the positive inotropism. It appears that nifedipine, although capable of antagonizing the hypertensive effect of the venom, suffers from a serious side effect. The reflex sympathetic stimulation may add to the effect of the venom and cause dangerous cardiac stimulation. Different types of arrhythmias have been observed following administration of nifedipine to scorpion sting victims (Ismail, unpublished; Bawaskar, personal communication). 4.1.4. Captopril and other ACE inhibitors Inhibit the conversion of the relatively inactive angiotensin I to active angiotensin II and inhibit the degradation of bradykinin and potentiate its hypotensive action. Are not commonly used in the cardiovas-
Atropine is very effective experimentally in prolonging the survival time and protecting mice, rats and rabbits from the lethal and several pharmacological actions of the venom. When combined with an aadrenergic receptor blocker such as phentolamine, the protective effects increase greatly. This is because atropine blocks the initial cardiac depressant and hypotensive actions and phentolamine blocks the hypertensive effect of the venom. Clinically, the use of atropine is not recommended because of the frequent heavy perspiration, vomiting and salivation in scorpion envenoming and the effect of atropine in potentiating the hypertensive effect and the severity of pulmonary oedema induced by scorpion toxin. It can be used, however, in emergency states where scorpion venom causes severe bradycardia. 4.3. Anticonvulsants Scorpion venom induces its pharmacological effects at the molecular level through activation of the voltagesensitive Na channels and blocking the Ca2 activated K channels and small conductance Cl channels. Phenobarbitone potentiates GABA-induced increase in Cl conductance and reduces glutamateinduced depolarization. It causes prolongation of the periods during which bursts of channel openings occur. Diazepam and other benzodiazepines enhance GABAinduced increase in conductance of Cl and thus augment the inhibitory effect produced by stimulating various GABAergic pathways in the CNS. The effect is associated with increased frequency of bursts of openings of the Cl channels. Both phenobarbitone and diazepam, thus, can antagonize the scorpion venominduced seizures by antagonizing the effect of scorpion toxin on the specific ionic channels concerned. Because
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of the risk of respiratory depression by phenobarbitone, diazepam, is preferred as an anticonvulsant. 4.4. Antiemetics Vomiting is frequently encountered in scorpion sting victims. The mechanism of action is not yet studied. It is likely due to the release of dopamine in the chemoreceptor trigger zone. Dopaminergic agonists are emetic, while dopaminergic, muscarinic and H1 antagonists have antiemetic properties to varying degrees. Scorpion venom releases dopamine, other catecholamines, acetylcholine and histamine in various tissues. Metoclopramide is a selective D2-dopaminergic antagonist which is effective both by i.v. and oral administration in controlling vomiting associated with Tityus serrulatus envenoming. Chlorpromazine is a non-selective dopaminergic antagonist which possesses in addition potent a-adrenergic, serotonergic and cholinergic blocking activities. It is used successfully in scorpion sting victims to check vomiting, especially in children, and to induce sedation. 4.5. Acetaminophen and other antipyretics Hyperthermia is a frequent symptom in victims stung by various scorpions. Possible mechanisms of action include release of norepinephrine in the anterior hypothalamus, shift in the balance of sodium and calcium in favour of sodium in the posterior hypothalamus and enhancing the synthesis and release of prostaglandins. Acetaminophen and water sponges were effective in lowering the markedly elevated temperature of victims stung by Leiurus quinquestriatus and Androctonus crassicauda (Fig. 1). The effect is likely due to inhibition of prostaglandin synthesis and the effectiveness of acetaminophen against enzymes in CNS [20,22,7]. Dipyrone by intravascular injection was recommended for hyperthermia induced by T. serrulatus venom [3]. 4.6. Preventive control of scorpion sting Scorpion stings always occur under accidental circumstances, more often at night, and when the weather is stormy, the temperature elevated and the wind hot. Stings occur in houses, tents, palm, cane or banana plantations or gardens during agricultural work, or on trips. The parts of the body most frequently stung are the limbs or occasionally the head and neck of sleeping persons. The latter case is more frequent in infants and young children. Scorpions have their ‘domiciles’ in infested areas under stones, rocks, logs, loose bark of trees and around human habitations in gardens, old lumber, boxes, garages, washhouses, sacks, porches, chicken houses, under wash clothes and in old shoes, mattresses, clothes or piles of newspapers stored in dark
Fig. 1. Leiurus quinquestriatus and Androctonus crassicauda are two of the five most venemous scorpions in the world.
places. In infested areas, scorpions may be eradicated or their numbers much reduced by the use of insecticides. The following precautions may be of value for travellers or residents in areas harbouring dangerous scorpions: 1) Do not walk with bare feet during the night Always wear a shoe or better a half-boot covering your ankle 2) Do not keep old clothes, mattresses, newspapers and other rubbish in your house as they provide a good domicile for scorpions 3) When camping outdoors, keep your garbage in closed bags as garbage attract cockroaches and other insects which in turn attract scorpions preying on them 4) Always check your shoes before putting your feet in 5) Houses in infested areas should have a step of at least 20 cm high made of glazed bricks or paint all around to prevent scorpions climbing from outside 6) Use insecticides in suspected areas when a scorpion is seen or caught.
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Appendix A: Summary of the treatment protocol Stage I All patients with confirmed stings or suspected stings with systemic manifestations: (1) 5 /1 ml ampoules antivenin in 20 /50 ml saline i.v slowly in ER. Repeat up to 20 /1 ml ampoules (2) Appropriate treatment for: High fever: water sponges plus acetaminophen suppositories Vomiting: chlorpromazine 0.5 /1 mg/kg i.m., or Promethazine 0.5 /1 mg/kg i.m Convulsions: Diazepam i.v. slowly Local pain: 1% zylocaine infiltration at the site of the sting (0.5 ml. maximum) Stage II Children below 12 years and debilitated patients with systemic manifestations: Transfer to ICU Hypertension: hydralazine or nifedipine Pulmonary oedema: oxygen, frusemide and fluid restriction Convulsions: diazepam (NOT Barbiturates) Dyspnoea: I.P.P.V. (start at ER) C.V.P. line with 0.5 N saline to keep value at 8 /12 cmH2O Correct for blood gases and electrolytes N.B. Do not use barbiturates, morphine, pethidine or b-blockers.
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