- Email: [email protected]
High-Dose Hydrocortisone Hemisuccinate in Scorpion Envenomation
TOXICOLOGY/ORIGINAL CONTRIBUTION
High-DoseHydrocortisone Hemisuccinate in Scorpion Envenomation From the Intensive Care Unit, Centre Hospitalo-Universitaire Fattouma Bourguiba, Monastir;* and the Intensive Care Unit* and the Emergency Department, ~ HOpital Regonal, Tozeur, Tunisia. Receivedfor publication June 26, 1996. Revision received November 12, 1996. Accepted for publication December I8, 1996.
Fekri Abroug, MD* Semir Nouira, MD* Habib Haguiga, MD*§ Souheil Elatrous,MD* Makhlouf Belghith, MD* Rafik Boujdaria, MD* Naceur Touzi, MD*~ Slah Bouchoucha,MD*
Copyright © by the American College of Emergency Physicians.
Study objective: Scorpion envenomation is a common lifethreatening hazard in tropical and subtropical countries. Standard treatment is not clearly defined. Many therapies, such as steroids, are prescribed without experimental justification. We sought to assess the efficacy of systematic administration of intravenous hydrocortisone hemisuccinate (50 mg/kg)in scorpion envenomation. Methods: Six hundred consecutive envenomated patients older than 10 years who presented to the ED of a nonteaching secondary hospital in an area of Tunisia endemic for scorpion envenomation were randomly assigned to receive hydrocortisone hemisuccinate 50 mg/kg (n=305) or placebo (n=295)in addition to standard medical care. Patients in the two groups had similar clinical characteristics on initial clinical evaluation. Each was categorized as grade 1 (absence of systemic symptoms) or grade 2 (systemic symptoms of scorpion envenomatien). Patients were treated in the ED for up to 4 hours or in the ICU, depending on clinical severity. Steroid and placebo groups were compared according to mortality rate, change of severity grade 4 hours after presentation and treatment, and duration of hospital stay. Results: Distribution of patients with respect to severity grade was similar in the two groups at the 4-hour clinical evaluation. We detected no significant difference at the time of discharge between steroid- and placebo-treated patients with respect to mortality (one patient in each group) or duration of hospital stay. Extra costs incurred through steroid administration totaled US$989,000. Conclusion: Our findings do not support the use of intravenous high-dose steroids in scorpion-envenomated patients. The discontinuation of this practice would reduce costs substantially. [Abroug E Nouira S, Haguiga H, Elatrous S, Belghith M, Boujdaria R, Touzi N, Bouchoucha S: High-dose hydrocortisone hemisuccinate in scorpion envenomation. Ann EmergMedJuly1997;30:23-27.]
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1997
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SCORPION
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INTRODUCTION
Scorpion envenomation is a common and dreaded event in tropical and subtropical regions and a serious public health concern in many developing countries. 1-3 In Tunisia, Androctonus australis scorpion envenomation is of major concern; 40,000 stings are reported yearly, yielding a crude incidence of 4.5 to 20 per thousand. 4 The clinical manifestations of scorpion envenomation are remarkably similar despite the diversity of species and toxins. 2,3 Almost 2.5% of envenomated patients exhibit systemic manifestations severe enough to require hospital or ICU admission; 2 of these, 10% ultimately die. 4 Cardiogenic shock and pulmonary edema account for the 1% to 2% overall mortality of scorpion envenomation. 3-6 Antivenom is the only available specific treatment for scorpion envenomation. However, its indications have never been clearly outlined, leading to persisting controversies about its use. r-is Moreover, the usefulness of antivenom in reversing the cardiovascular manifestations of scorpion envenomation has been questioned.6, s2 Furthermore, the scarceness and cost of antivenom make the evaluation of alternative therapies worthwhile. Several drugs are used to treat symptomatic envenomated patients on the sole basis of physiopathologic assumptions. Drugs such as steroids, nonsteroidal antiinflammatory agents, aspirin, and vasodilators are commonly used and hence recommended. 13-1r In 1994 the Tunisian health ministry reported the use of only 16,000 vials of scorpion antivenom in 40,000 envenomated patients, compared with 72,000 hydrocortisone doses# The postulated beneficial effects of steroids in scorpion envenomation include the modulation of inflammatory mediators and correction of putative acute adrenal insufficiency. 13 Although a single experimental study supports the usefulness of steroids, no clinical evaluation has been reported. 13 We report a prospective, randomized, controlled study of the efficacy and safety of systematic infusion of high-dose hydrocortisone hemisuccinate in scorpion-envenomated patients. MATERIALS AND METHODS
We conducted this study from June 1993 to October 1994 in the ED and ICU of a community-based nonteaching hospital located in an area endemic for scorpionism (H0pital Regional de Tozeur, Tozeur, Tunisia). All patients older than 10 years who were referred to the ED after being stung by a scorpion were enrolled. Patients whose clinical condition warranted advanced monitoring or active intensive care were
2 4
transfered to the medical ICU of a teaching hospital (Centre Hospitalo-Universitaire, Monastir, Tunisia). Diagnosis of scorpion envenomation was based on history of scorpion sting with the scorpion seen or captured. Patients who had been treated with systemic corticosteroids in the preceding 4 hours were excluded. The protocol was approved by our institutional review board, who waived the need for informed consent because the efficacy of steroids in scorpion envenomation has not been established. Eligible patients were examined by a study investigator, who recorded baseline data. Patients in whom scorpion sting caused a limited local reaction (pain, erythema, or both, with no systemic signs or symptoms) were classified as grade 1. Those with systemic symptoms of envenomation were classified as grade 2. Patients were randomly assigned to treatment with intravenous hydrocortisone hemisuccinate (Roussel-Uclaf, Paris, France) or placebo (normal saline solution). Randomization was performed separately for grade 1 and 2 patients. The investigators, patients and clinicians were all blinded to the patients' assignments. Patients with life-threatening envenomation were immediately admitted to the ICU; the rest were treated in the ED, where they remained for up to 4 hours after drug infusion. Clinical severity was reassessed at the 4-hour limit. Patients who became asymptomatic or had only local symptoms were discharged (eg, patients who improved from grade 2 to grade 1; grade 1 patients whose condition did not worsen). Patients classified as grade 2 at the 4-hour evaluation were admitted to the ICU. Outcome, duration of stay, and need for mechanical ventilation were recorded in patients treated in the ICU. All patients discharged home at the end of the 4-hour evaluation were encouraged to return to the ED if their condition worsened. Patients in the steroid group received hydrocortisone succinate 50mg/kg (maximum dose, 3 g) diluted in 250 mL of normal saline solution and infused over 15 minutes. Hospitalized patients had repeated infusions of the same dose every 6 hours with a total maximum dose of 12 g (four doses). For the control group, 250 mL of normal saline solution was infused over 15 minutes and repeated every 6 hours in hospitalized patients. When pulmonary edema was present, the amount of fluid administered was reduced to 50 mL per infusion. All other symptom-related and specific medications were administered at the physician's discretion. The efficacy of high-dose hydrocortisone was assessed on the basis of its clinical effects at the 4-hour evaluation (improvement from grade 2 to grade 1) and the mortality rate in each group. Preventive effects of hydrocortisone were inferred from the lack of progression from grade 1 to grade
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2. Supplementary analysis included the duration of stay and need for mechanical ventilation. We used unpaired Student t tests and the X2 test with Fisher's exact test, as appropriate, to compare study population distribution between severity grades at baseline and after treatment. P values less than .05 were considered statistically significant. RESULTS
Of the 600 consecutive patients enrolled (320 men, 280 women; age range, 12 to 98 years), 305 received hydrocortisone hemisuccinate and 295 placebo. We detected no statistically significant differences between the patients in the two groups at presentation with regard to demographic characteristics, time between envenomation and ED arrival, or nonstudy treatments administered before randomization (Table 1). Ninety-nine patients were classified as grade 2 on admission; 50 received steroids and 49 placebo. Shock, which was found in four patients (two in each group), was the most severe presentation of scorpion envenomation. Pulmonary edema and shock were present in 12 patients (7 in the steroid group, 5 in the placebo group). Two patients in the placebo group demonstrated an altered level of consciousness (Glasgow Coma Scale score <10) (Table 2). In the steroid group, hydrocortisone was administered at a total dosage of 3 g to 276 patients and 12 g in 29 patients. Thirty-three of 50 grade 2 patients (66%) in the steroid group and 38 of 49 (78%) in the placebo group demonstrated improved clinical condition, from grade 2 to grade 1. The difference was not statistically significant. In three of
these patients, envenomation was deemed life threatening presentation. The remaining patients (17 and 11 in the steroid and placebo groups, respectively) were hospitalized after the 4-hour evaluation. One patient in each group died as a consequence of uncontrolled shock and pulmonary edema despite mechanical ventilation and inotropic support. All hospitalized patients, except the two who died, had favorable outcomes and were discharged without sequelae. The mean duration of hospital stay was not significantly different in the two groups (.52+.6 days and .58_+.8 days, respectively, in the steroid and placebo groups). Mechanical ventilation was required in two patients in each group. No patient discharged home at the end of the 4-hour evaluation returned to the ED. During the 4-hour observation period, 11 patients in the treatment group (4%) and 6 in the placebo group (2%) progressed from grade 1 to grade 2 and were admitted to the ICU. No life-threatening condition occurred as a result of envenomation during ED observation or thereafter. The distributions of patients in the two groups on the basis of severity grade after 4-hour evaluation were not significantly different (Figure 1, Table 3). On the basis of the exchange rate at this writing (1 Tunisian dinar=l US dollar), the cost of a 3-g dose of hydrocortisone hemisuccinate is US$23 (US$92 for a hospitalized patient). According to the reported scorpion sting incidence of 40,000/year and a hospitalization rate of 2.5%, the total cost of systematic administration of high-dose hydrocortisone hemisuccinate is US$989,000 per year ($92,000 for hospitalized patients and US$897,000 for patients treated without hospitalization). Table 2.
Table 1.
Demographic characteristics and prehospital treatment in the placebo and steroid groups.
Baseline clinical characteristics of treatment groups. Grade
Parameters
Placebo (n=295)
Demographic data Age (years) [mean+SD] 34 +12 Sex (M/F) 150/145 Time to treatment (minutes) 62+72 [mean_+SDl Prehospital treatment (%) Antivenom* 75 (25) Hydroxyzine i 0 (3) Adrenaline 2 (.6) Nifedipine 1 (.3) Phenobarbital 1 (.3) Aspirin 1 (.3) *Scorpionantivenom;InstitutPasteurTunis(10 mL; 10 LDso/mL).
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Steroid (n=305) 33+11 170/135 54+60 61 (20) 6 (2) 0 3 (1) 2 (.8) 2 (.8)
Placebo 1%)
1 246 (83.5} 2* 49 (16.5) Hypertension 13 (26) Sweating 26 (53) Fever 22 (45) Shivering 1 (2) Vomiting 1 (2) Priapism 2 {4) Cardiogenic shock 2 (4) Pulmonary edema 5 (10) Altered consciousness 2 (4) (Glasgow Coma Scale score <10) Total 295 *Somepatientsexhibitedmorethan one sign or symptom.
Steroid (°/o) 255 (83) 50 (17) 15 (30) 28 (56) 15 (30) 4 (8) 0 (12) 5 (10) 2 (4) 7 (14) 0
305
25
SCORPION Abroug et al
DISOUSSION
Our results indicate that high-dose hydrocortisone hemisuccinate did not reduce clinical severity, the mortality rate, the rate of mechanical ventilation, or the duration of hospital stay. This finding challenges the usefulness of such practice and underscores the considerable financial burden. Almost US$1 million could be saved if systematic administration of high-dose hydrocortisone hemisuccinate was abandoned. In keeping with the reported 10% mortality rate in patients presenting with systemic symptoms of scorpion envenomation, a conclusive study would require almost 700 grade 2 patients in each arm to accurately detect a 50% reduction in mortality with a power of 90% at a P value of .05. A much larger sample would be required to detect any potential mortality difference if the mortality rate observed in our study (2%) was used. It should be noted that the mortality rate among our patients was lower than expected, probably because of study location (proximity of the ED, availability of the ICU). Figure.
Distribution of study population between severitygrades at A, baseline (top) and at B, 4-hour evaluation.
A
No. of Patients
300-
255
246
•
200-
Steroid
Many nonspecific treatments for scorpion envenomation have been proposed. These are proposed to treat relevant clinical manifestations (antihypertensive drugs, neuroleptic agents) or to interfere with presumed physiopathologic consequences of scorpion envenomation. 13-17 Accordingly, antihistamines, steroids, aspirin, and other drugs have been administered with the aim of modulating the expression of different neurohormonal systems. Little properly controlled evidence supports any of these therapeutic options, including corticosteroids, which are systematically administered to envenomated patients in many countries and recommended by the Tunisian health ministry despite the lack of clinical evaluation. Careful literature review disclosed only one animal study providing a rationale for therapeutic use of steroids in scorpion envenomation. 13 In a rescue experiment in rats, intravenous infusion of hydrocortisone 50 mg/kg significantly prolonged the survival time of animals challenged 10 minutes before with twice-minimal lethal doses of the venom from the scorpion Le/rus quinquestriatus. Survival time in the treated animals was almost double that in the controls. 13 The experimental findings were explained by a reversal of hypothesized acute adrenal insufficiency and consecutive hypovolemic shock induced by scorpion envenomation, s8,19 Our study is the first to address the issue of steroids as a nonspecific treatment for scorpion envenomation in human beings. Our results do not provide evidence of their efficacy. It is unclear why hydrocortisone failed to demonstrate a beneficial effect in envenomated patients. It is noteworthy that the dose regimen used in our study was similar
[] Placebo Table 3.
100-
50
Clinical characteristics of treatment groups at the 4-hour evaluation.
49
0 - -
Grade 1
B 300
Grade 2
No. of Patients
277
278
-j Io
209
100
Placebo (%)
Steroid (%)
1
278 (94)
277 (91)
2*
17 (6)
28 (9)
Hypertension Sweating Fever Shivering Vomiting Priapism Cardiogenicshock Pulmonaryedema Altered consciousness (Glasgow Coma Scale score <10)
4 (23) 13 (76) 14 (82) 2 (12) 0 0 2 (12) 5 (29} 0
5 (18) 16 (57) 10 (36) 4 (14) 4 (14) 2 (7) 2 (7) 6 (21) 0
Grade
Total Grade 1
26
Grade 2
295
305
*Some patients exhibited morethan one sign or symptom.
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to that used in the sole experimental trial of steroid treatment in scorpion envenomation. 13 A potentially important source of discrepancy between the animal and human trials is the severity of envenomation. In the animal study, rats were injected with twice the 50% lethal dose of scorpion venom, an amount that killed all the animals within 40 minutes. This situation may correspond to the most severe presentation of human scorpion envenomation, characterized by circulatory and respiratory failure. In our clinical trial, hydrocortisone was administered to all envenomated patients. However, the sample of patients who presented with life-threatening envenomation was too small to permit analysis of this subset. Another explanation is that the speculated mechanism of action of steroids doesn't fully apply to the actual physiopathologic disturbances of scorpion envenomation. Ismail et a113 attributed the shock induced by scorpion envenomation to acute adrenal insufficiency, z3 However, acute adrenal insufficiency has never been documented in human envenomation. Moreover, recent studies have shown that shock caused by scorpion venom ts cardiogenic, with simultaneous alteration of right and left ventricular function. <5,2°,21 Alternative explanations of the prolongation of survival time by hydrocortisone include inhibitor effects on some mediators activated by the venom and presumed action on cellular receptors or ionic channels. 22-z4 Ismail et a113 suggested the involvement of prostaglandms and kallikrein-kinin systems, the expression of which is likely modulated by steroids. Finally, the delayed administration of steroids to envenomated patients may account for these drugs' lack of efficacy. Although the mean time between scorpion sting and treatment in our patients was not prolonged from a clinical point of view (almost 1 hour), it may have been too long with regard to the rapid onset of the effects of the venom after scorpion sting in animal models. 25,26 In summa~ because of the need for rigorous evaluation of physicians' interventions and the marginal cost-effectiveness of systematic administration of steroids in scorpion envenomation, we conclude that this practice should be strongly discouraged. REFERENCES 1. Goyffon M, Vachon M, Breglio N: Epidemiologicaland clinical characteristics of the scorpion envenomation in Tunisia. Toxicen1982;20:337-344. 2. Gueron M, Ilia R, Sofer S: The cardiovascular system after scorpion envenomation: A review. Clio Toxico11992;30:245-258. 3. Ismail M: The scorpion envenoming syndrome. Toxicon1995;33:825-858. 4, Minist~re de la Santo Publique, Direction des Soins de Sant~ de Base. R#unionMaghr#bine sur los envenimations scorpioniques: Rapport final. Tunis, Tunisia: April 1995.
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5. Abroug F, Boujdaria R, Belghith M, et el: Cardiacdysfunction and pulmonary edema following scorpion envenomation. Chest 1991;100:1057-1059. 6. Abrou9 F, Ayari M, Nouira S, et el: Assessmentof left ventricular function in severe scorpion envenomation:Combinedhemedynamicand echo-Dopplerstudy. Intens CareMed1995;21:629-635. 7. Sofer S, Shahak E, Gueron M: Scorpion envenomation and antivenom therapy. J Pediatr 1994;124:973-978. 8. De RezendeNA, Borges Bias M, Campolina D, et el: Efficacy of antivenom therapy for neutralizing circulating venom antigens in patients stung by Tityus serrulatus scorpions. Am J TropPied Hyg 1995;52:277-280. 9, Bond GB: Antivenin administration for Centrurofdesscorpion sting: Risks and benefits. Ann Emerg Mad 1992;21:788-791. 10. Ismaif M: The treatment of the scorpion envenoming syndrome:The Saudi experiencewith serotherapy. Toxicon1994;32:1019-1026. 11. Ismail M: Serotherapyof the scorpion envenoming syndrome is irrationally convicted without trial [response]. Toxicon1993;31:1077-1083.
12. Brant J: Injuries due to toxins and environmental poisons. Curr Opin Crit Care 1996;2:236-241. 13. Ismail M, Fatani AJY, DabeesTf: Experimentaltreatment protocols for scorpion envenomation: A review of common therapies and an effect of kailicrein-kinin inhibitors. Toxicon 1992;30:1257-1279 14. Guieu R, KopeyanC, Rochat H: Utibzation of aspirin, quinine and verapamil in the prevention and treatment of scorpion venom intoxication. Life Sci 1993;53:1935-1946. 15. gofer S, Gueron M: Vasodilators and hypertensive encephalopathyfollowing scorpion envenemotion in children. Chest 1998;97:118-I20. t6. Bawaskar HS, Bawaskar PH: Management of the cardiovascular manifestations of poisoning by the Indian red scorpion (Mesobuthus tame/us). Br Heart J I992;68:478-480. 17. Bawaskar HS, Bawaskar PH: Prazosinfor vasodiiator treatment of acute pulmonary oedema due to scorpion sting. Ann Trop Mad 1987;81:719-723. 18. Mohammed AH, RohayemH, Zaky O: The action of scorpion toxin on blood sodium and potassium. J TropMad Hyg 1954;57:85-87. 19. Ismail M, Guinea KA, Osman OH, eta[: Effect of Buthus minax(L. Koch)scorpion venom on plasma and urinary electrolyte levels. Toxicon1978;18:385-392. 20- Nouira S, Abroug F, Haguiga H, et el: Right ventricular dysfunction following severe scorpion envenomation. Chest 1995;108:682-687. 21. Nouira S, Abreug F, Boujdaria R, et ah M~canisme de I'oedeme pulmonaire et de la dysfonction cadiaqueau cours de I'envenimationscorpioniquegrave. R#animationUrgences1996;5:17-24. 22. Post JM, Hume JR, Archer SL, et al: Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction. Am J Physiot i992;262:0882-C890. 23. Gwee MCE, CheahLS, GopalakrishnakoneP: Involvement of the L-arginine-nitric oxide synthase pathway in the relaxant responsesof the rat isolated anococcygeusmuscle to a scorpion (Leirus quinquastriatus)venom, Toxicon1995;33:1141-I150. 24. Freire-maiaL, De Mates IM: Heparin or a PAF antagonist (BN-520021}prevents the acute pulmonary edema induced by Tityus sarrulatus scorpion venom in the rat. Toxicon1993;31:12071210. 25. Gueron M, Adolph RJ, Grupp IL, et al: Hemodynamicand myocardial consequencesof scorpion venom. Am J Carflio11980;45:979-986. 26. Tarasiuk A, Sofer S, Huberflo S, et al: Hemodynamiceffects following injection of venom from the scorpion Leires quinquestriatus. J Crit Care 1994;4:134-140.
Reprint no. 47/1/81994 Address for reprints: Dr Fekri Abroug Service de R6animation Polyvalente CHU F Bourguiba 5019 Monastir Tunisia
27
High-DoseHydrocortisone Hemisuccinate in Scorpion Envenomation From the Intensive Care Unit, Centre Hospitalo-Universitaire Fattouma Bourguiba, Monastir;* and the Intensive Care Unit* and the Emergency Department, ~ HOpital Regonal, Tozeur, Tunisia. Receivedfor publication June 26, 1996. Revision received November 12, 1996. Accepted for publication December I8, 1996.
Fekri Abroug, MD* Semir Nouira, MD* Habib Haguiga, MD*§ Souheil Elatrous,MD* Makhlouf Belghith, MD* Rafik Boujdaria, MD* Naceur Touzi, MD*~ Slah Bouchoucha,MD*
Copyright © by the American College of Emergency Physicians.
Study objective: Scorpion envenomation is a common lifethreatening hazard in tropical and subtropical countries. Standard treatment is not clearly defined. Many therapies, such as steroids, are prescribed without experimental justification. We sought to assess the efficacy of systematic administration of intravenous hydrocortisone hemisuccinate (50 mg/kg)in scorpion envenomation. Methods: Six hundred consecutive envenomated patients older than 10 years who presented to the ED of a nonteaching secondary hospital in an area of Tunisia endemic for scorpion envenomation were randomly assigned to receive hydrocortisone hemisuccinate 50 mg/kg (n=305) or placebo (n=295)in addition to standard medical care. Patients in the two groups had similar clinical characteristics on initial clinical evaluation. Each was categorized as grade 1 (absence of systemic symptoms) or grade 2 (systemic symptoms of scorpion envenomatien). Patients were treated in the ED for up to 4 hours or in the ICU, depending on clinical severity. Steroid and placebo groups were compared according to mortality rate, change of severity grade 4 hours after presentation and treatment, and duration of hospital stay. Results: Distribution of patients with respect to severity grade was similar in the two groups at the 4-hour clinical evaluation. We detected no significant difference at the time of discharge between steroid- and placebo-treated patients with respect to mortality (one patient in each group) or duration of hospital stay. Extra costs incurred through steroid administration totaled US$989,000. Conclusion: Our findings do not support the use of intravenous high-dose steroids in scorpion-envenomated patients. The discontinuation of this practice would reduce costs substantially. [Abroug E Nouira S, Haguiga H, Elatrous S, Belghith M, Boujdaria R, Touzi N, Bouchoucha S: High-dose hydrocortisone hemisuccinate in scorpion envenomation. Ann EmergMedJuly1997;30:23-27.]
JULY
1997
30:!
ANNALS 0£ EMERGENCY MEDICINE
23
SCORPION
Abroug et al
INTRODUCTION
Scorpion envenomation is a common and dreaded event in tropical and subtropical regions and a serious public health concern in many developing countries. 1-3 In Tunisia, Androctonus australis scorpion envenomation is of major concern; 40,000 stings are reported yearly, yielding a crude incidence of 4.5 to 20 per thousand. 4 The clinical manifestations of scorpion envenomation are remarkably similar despite the diversity of species and toxins. 2,3 Almost 2.5% of envenomated patients exhibit systemic manifestations severe enough to require hospital or ICU admission; 2 of these, 10% ultimately die. 4 Cardiogenic shock and pulmonary edema account for the 1% to 2% overall mortality of scorpion envenomation. 3-6 Antivenom is the only available specific treatment for scorpion envenomation. However, its indications have never been clearly outlined, leading to persisting controversies about its use. r-is Moreover, the usefulness of antivenom in reversing the cardiovascular manifestations of scorpion envenomation has been questioned.6, s2 Furthermore, the scarceness and cost of antivenom make the evaluation of alternative therapies worthwhile. Several drugs are used to treat symptomatic envenomated patients on the sole basis of physiopathologic assumptions. Drugs such as steroids, nonsteroidal antiinflammatory agents, aspirin, and vasodilators are commonly used and hence recommended. 13-1r In 1994 the Tunisian health ministry reported the use of only 16,000 vials of scorpion antivenom in 40,000 envenomated patients, compared with 72,000 hydrocortisone doses# The postulated beneficial effects of steroids in scorpion envenomation include the modulation of inflammatory mediators and correction of putative acute adrenal insufficiency. 13 Although a single experimental study supports the usefulness of steroids, no clinical evaluation has been reported. 13 We report a prospective, randomized, controlled study of the efficacy and safety of systematic infusion of high-dose hydrocortisone hemisuccinate in scorpion-envenomated patients. MATERIALS AND METHODS
We conducted this study from June 1993 to October 1994 in the ED and ICU of a community-based nonteaching hospital located in an area endemic for scorpionism (H0pital Regional de Tozeur, Tozeur, Tunisia). All patients older than 10 years who were referred to the ED after being stung by a scorpion were enrolled. Patients whose clinical condition warranted advanced monitoring or active intensive care were
2 4
transfered to the medical ICU of a teaching hospital (Centre Hospitalo-Universitaire, Monastir, Tunisia). Diagnosis of scorpion envenomation was based on history of scorpion sting with the scorpion seen or captured. Patients who had been treated with systemic corticosteroids in the preceding 4 hours were excluded. The protocol was approved by our institutional review board, who waived the need for informed consent because the efficacy of steroids in scorpion envenomation has not been established. Eligible patients were examined by a study investigator, who recorded baseline data. Patients in whom scorpion sting caused a limited local reaction (pain, erythema, or both, with no systemic signs or symptoms) were classified as grade 1. Those with systemic symptoms of envenomation were classified as grade 2. Patients were randomly assigned to treatment with intravenous hydrocortisone hemisuccinate (Roussel-Uclaf, Paris, France) or placebo (normal saline solution). Randomization was performed separately for grade 1 and 2 patients. The investigators, patients and clinicians were all blinded to the patients' assignments. Patients with life-threatening envenomation were immediately admitted to the ICU; the rest were treated in the ED, where they remained for up to 4 hours after drug infusion. Clinical severity was reassessed at the 4-hour limit. Patients who became asymptomatic or had only local symptoms were discharged (eg, patients who improved from grade 2 to grade 1; grade 1 patients whose condition did not worsen). Patients classified as grade 2 at the 4-hour evaluation were admitted to the ICU. Outcome, duration of stay, and need for mechanical ventilation were recorded in patients treated in the ICU. All patients discharged home at the end of the 4-hour evaluation were encouraged to return to the ED if their condition worsened. Patients in the steroid group received hydrocortisone succinate 50mg/kg (maximum dose, 3 g) diluted in 250 mL of normal saline solution and infused over 15 minutes. Hospitalized patients had repeated infusions of the same dose every 6 hours with a total maximum dose of 12 g (four doses). For the control group, 250 mL of normal saline solution was infused over 15 minutes and repeated every 6 hours in hospitalized patients. When pulmonary edema was present, the amount of fluid administered was reduced to 50 mL per infusion. All other symptom-related and specific medications were administered at the physician's discretion. The efficacy of high-dose hydrocortisone was assessed on the basis of its clinical effects at the 4-hour evaluation (improvement from grade 2 to grade 1) and the mortality rate in each group. Preventive effects of hydrocortisone were inferred from the lack of progression from grade 1 to grade
ANNALS OF EMERGENCY MEDICINE
30:1
JULY 1997
SCORPION Abroug et al
2. Supplementary analysis included the duration of stay and need for mechanical ventilation. We used unpaired Student t tests and the X2 test with Fisher's exact test, as appropriate, to compare study population distribution between severity grades at baseline and after treatment. P values less than .05 were considered statistically significant. RESULTS
Of the 600 consecutive patients enrolled (320 men, 280 women; age range, 12 to 98 years), 305 received hydrocortisone hemisuccinate and 295 placebo. We detected no statistically significant differences between the patients in the two groups at presentation with regard to demographic characteristics, time between envenomation and ED arrival, or nonstudy treatments administered before randomization (Table 1). Ninety-nine patients were classified as grade 2 on admission; 50 received steroids and 49 placebo. Shock, which was found in four patients (two in each group), was the most severe presentation of scorpion envenomation. Pulmonary edema and shock were present in 12 patients (7 in the steroid group, 5 in the placebo group). Two patients in the placebo group demonstrated an altered level of consciousness (Glasgow Coma Scale score <10) (Table 2). In the steroid group, hydrocortisone was administered at a total dosage of 3 g to 276 patients and 12 g in 29 patients. Thirty-three of 50 grade 2 patients (66%) in the steroid group and 38 of 49 (78%) in the placebo group demonstrated improved clinical condition, from grade 2 to grade 1. The difference was not statistically significant. In three of
these patients, envenomation was deemed life threatening presentation. The remaining patients (17 and 11 in the steroid and placebo groups, respectively) were hospitalized after the 4-hour evaluation. One patient in each group died as a consequence of uncontrolled shock and pulmonary edema despite mechanical ventilation and inotropic support. All hospitalized patients, except the two who died, had favorable outcomes and were discharged without sequelae. The mean duration of hospital stay was not significantly different in the two groups (.52+.6 days and .58_+.8 days, respectively, in the steroid and placebo groups). Mechanical ventilation was required in two patients in each group. No patient discharged home at the end of the 4-hour evaluation returned to the ED. During the 4-hour observation period, 11 patients in the treatment group (4%) and 6 in the placebo group (2%) progressed from grade 1 to grade 2 and were admitted to the ICU. No life-threatening condition occurred as a result of envenomation during ED observation or thereafter. The distributions of patients in the two groups on the basis of severity grade after 4-hour evaluation were not significantly different (Figure 1, Table 3). On the basis of the exchange rate at this writing (1 Tunisian dinar=l US dollar), the cost of a 3-g dose of hydrocortisone hemisuccinate is US$23 (US$92 for a hospitalized patient). According to the reported scorpion sting incidence of 40,000/year and a hospitalization rate of 2.5%, the total cost of systematic administration of high-dose hydrocortisone hemisuccinate is US$989,000 per year ($92,000 for hospitalized patients and US$897,000 for patients treated without hospitalization). Table 2.
Table 1.
Demographic characteristics and prehospital treatment in the placebo and steroid groups.
Baseline clinical characteristics of treatment groups. Grade
Parameters
Placebo (n=295)
Demographic data Age (years) [mean+SD] 34 +12 Sex (M/F) 150/145 Time to treatment (minutes) 62+72 [mean_+SDl Prehospital treatment (%) Antivenom* 75 (25) Hydroxyzine i 0 (3) Adrenaline 2 (.6) Nifedipine 1 (.3) Phenobarbital 1 (.3) Aspirin 1 (.3) *Scorpionantivenom;InstitutPasteurTunis(10 mL; 10 LDso/mL).
JULY 1997 30:1 ANNALS OF EMERGENCY MEDICINE
Steroid (n=305) 33+11 170/135 54+60 61 (20) 6 (2) 0 3 (1) 2 (.8) 2 (.8)
Placebo 1%)
1 246 (83.5} 2* 49 (16.5) Hypertension 13 (26) Sweating 26 (53) Fever 22 (45) Shivering 1 (2) Vomiting 1 (2) Priapism 2 {4) Cardiogenic shock 2 (4) Pulmonary edema 5 (10) Altered consciousness 2 (4) (Glasgow Coma Scale score <10) Total 295 *Somepatientsexhibitedmorethan one sign or symptom.
Steroid (°/o) 255 (83) 50 (17) 15 (30) 28 (56) 15 (30) 4 (8) 0 (12) 5 (10) 2 (4) 7 (14) 0
305
25
SCORPION Abroug et al
DISOUSSION
Our results indicate that high-dose hydrocortisone hemisuccinate did not reduce clinical severity, the mortality rate, the rate of mechanical ventilation, or the duration of hospital stay. This finding challenges the usefulness of such practice and underscores the considerable financial burden. Almost US$1 million could be saved if systematic administration of high-dose hydrocortisone hemisuccinate was abandoned. In keeping with the reported 10% mortality rate in patients presenting with systemic symptoms of scorpion envenomation, a conclusive study would require almost 700 grade 2 patients in each arm to accurately detect a 50% reduction in mortality with a power of 90% at a P value of .05. A much larger sample would be required to detect any potential mortality difference if the mortality rate observed in our study (2%) was used. It should be noted that the mortality rate among our patients was lower than expected, probably because of study location (proximity of the ED, availability of the ICU). Figure.
Distribution of study population between severitygrades at A, baseline (top) and at B, 4-hour evaluation.
A
No. of Patients
300-
255
246
•
200-
Steroid
Many nonspecific treatments for scorpion envenomation have been proposed. These are proposed to treat relevant clinical manifestations (antihypertensive drugs, neuroleptic agents) or to interfere with presumed physiopathologic consequences of scorpion envenomation. 13-17 Accordingly, antihistamines, steroids, aspirin, and other drugs have been administered with the aim of modulating the expression of different neurohormonal systems. Little properly controlled evidence supports any of these therapeutic options, including corticosteroids, which are systematically administered to envenomated patients in many countries and recommended by the Tunisian health ministry despite the lack of clinical evaluation. Careful literature review disclosed only one animal study providing a rationale for therapeutic use of steroids in scorpion envenomation. 13 In a rescue experiment in rats, intravenous infusion of hydrocortisone 50 mg/kg significantly prolonged the survival time of animals challenged 10 minutes before with twice-minimal lethal doses of the venom from the scorpion Le/rus quinquestriatus. Survival time in the treated animals was almost double that in the controls. 13 The experimental findings were explained by a reversal of hypothesized acute adrenal insufficiency and consecutive hypovolemic shock induced by scorpion envenomation, s8,19 Our study is the first to address the issue of steroids as a nonspecific treatment for scorpion envenomation in human beings. Our results do not provide evidence of their efficacy. It is unclear why hydrocortisone failed to demonstrate a beneficial effect in envenomated patients. It is noteworthy that the dose regimen used in our study was similar
[] Placebo Table 3.
100-
50
Clinical characteristics of treatment groups at the 4-hour evaluation.
49
0 - -
Grade 1
B 300
Grade 2
No. of Patients
277
278
-j Io
209
100
Placebo (%)
Steroid (%)
1
278 (94)
277 (91)
2*
17 (6)
28 (9)
Hypertension Sweating Fever Shivering Vomiting Priapism Cardiogenicshock Pulmonaryedema Altered consciousness (Glasgow Coma Scale score <10)
4 (23) 13 (76) 14 (82) 2 (12) 0 0 2 (12) 5 (29} 0
5 (18) 16 (57) 10 (36) 4 (14) 4 (14) 2 (7) 2 (7) 6 (21) 0
Grade
Total Grade 1
26
Grade 2
295
305
*Some patients exhibited morethan one sign or symptom.
ANNALS OF EMERGENCY MEDICINE
30:1
JULY 1997
SCORPION
Abroug et al
to that used in the sole experimental trial of steroid treatment in scorpion envenomation. 13 A potentially important source of discrepancy between the animal and human trials is the severity of envenomation. In the animal study, rats were injected with twice the 50% lethal dose of scorpion venom, an amount that killed all the animals within 40 minutes. This situation may correspond to the most severe presentation of human scorpion envenomation, characterized by circulatory and respiratory failure. In our clinical trial, hydrocortisone was administered to all envenomated patients. However, the sample of patients who presented with life-threatening envenomation was too small to permit analysis of this subset. Another explanation is that the speculated mechanism of action of steroids doesn't fully apply to the actual physiopathologic disturbances of scorpion envenomation. Ismail et a113 attributed the shock induced by scorpion envenomation to acute adrenal insufficiency, z3 However, acute adrenal insufficiency has never been documented in human envenomation. Moreover, recent studies have shown that shock caused by scorpion venom ts cardiogenic, with simultaneous alteration of right and left ventricular function. <5,2°,21 Alternative explanations of the prolongation of survival time by hydrocortisone include inhibitor effects on some mediators activated by the venom and presumed action on cellular receptors or ionic channels. 22-z4 Ismail et a113 suggested the involvement of prostaglandms and kallikrein-kinin systems, the expression of which is likely modulated by steroids. Finally, the delayed administration of steroids to envenomated patients may account for these drugs' lack of efficacy. Although the mean time between scorpion sting and treatment in our patients was not prolonged from a clinical point of view (almost 1 hour), it may have been too long with regard to the rapid onset of the effects of the venom after scorpion sting in animal models. 25,26 In summa~ because of the need for rigorous evaluation of physicians' interventions and the marginal cost-effectiveness of systematic administration of steroids in scorpion envenomation, we conclude that this practice should be strongly discouraged. REFERENCES 1. Goyffon M, Vachon M, Breglio N: Epidemiologicaland clinical characteristics of the scorpion envenomation in Tunisia. Toxicen1982;20:337-344. 2. Gueron M, Ilia R, Sofer S: The cardiovascular system after scorpion envenomation: A review. Clio Toxico11992;30:245-258. 3. Ismail M: The scorpion envenoming syndrome. Toxicon1995;33:825-858. 4, Minist~re de la Santo Publique, Direction des Soins de Sant~ de Base. R#unionMaghr#bine sur los envenimations scorpioniques: Rapport final. Tunis, Tunisia: April 1995.
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ANNALS OF EMERGENCY MEDICINE
5. Abroug F, Boujdaria R, Belghith M, et el: Cardiacdysfunction and pulmonary edema following scorpion envenomation. Chest 1991;100:1057-1059. 6. Abrou9 F, Ayari M, Nouira S, et el: Assessmentof left ventricular function in severe scorpion envenomation:Combinedhemedynamicand echo-Dopplerstudy. Intens CareMed1995;21:629-635. 7. Sofer S, Shahak E, Gueron M: Scorpion envenomation and antivenom therapy. J Pediatr 1994;124:973-978. 8. De RezendeNA, Borges Bias M, Campolina D, et el: Efficacy of antivenom therapy for neutralizing circulating venom antigens in patients stung by Tityus serrulatus scorpions. Am J TropPied Hyg 1995;52:277-280. 9, Bond GB: Antivenin administration for Centrurofdesscorpion sting: Risks and benefits. Ann Emerg Mad 1992;21:788-791. 10. Ismaif M: The treatment of the scorpion envenoming syndrome:The Saudi experiencewith serotherapy. Toxicon1994;32:1019-1026. 11. Ismail M: Serotherapyof the scorpion envenoming syndrome is irrationally convicted without trial [response]. Toxicon1993;31:1077-1083.
12. Brant J: Injuries due to toxins and environmental poisons. Curr Opin Crit Care 1996;2:236-241. 13. Ismail M, Fatani AJY, DabeesTf: Experimentaltreatment protocols for scorpion envenomation: A review of common therapies and an effect of kailicrein-kinin inhibitors. Toxicon 1992;30:1257-1279 14. Guieu R, KopeyanC, Rochat H: Utibzation of aspirin, quinine and verapamil in the prevention and treatment of scorpion venom intoxication. Life Sci 1993;53:1935-1946. 15. gofer S, Gueron M: Vasodilators and hypertensive encephalopathyfollowing scorpion envenemotion in children. Chest 1998;97:118-I20. t6. Bawaskar HS, Bawaskar PH: Management of the cardiovascular manifestations of poisoning by the Indian red scorpion (Mesobuthus tame/us). Br Heart J I992;68:478-480. 17. Bawaskar HS, Bawaskar PH: Prazosinfor vasodiiator treatment of acute pulmonary oedema due to scorpion sting. Ann Trop Mad 1987;81:719-723. 18. Mohammed AH, RohayemH, Zaky O: The action of scorpion toxin on blood sodium and potassium. J TropMad Hyg 1954;57:85-87. 19. Ismail M, Guinea KA, Osman OH, eta[: Effect of Buthus minax(L. Koch)scorpion venom on plasma and urinary electrolyte levels. Toxicon1978;18:385-392. 20- Nouira S, Abroug F, Haguiga H, et el: Right ventricular dysfunction following severe scorpion envenomation. Chest 1995;108:682-687. 21. Nouira S, Abreug F, Boujdaria R, et ah M~canisme de I'oedeme pulmonaire et de la dysfonction cadiaqueau cours de I'envenimationscorpioniquegrave. R#animationUrgences1996;5:17-24. 22. Post JM, Hume JR, Archer SL, et al: Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction. Am J Physiot i992;262:0882-C890. 23. Gwee MCE, CheahLS, GopalakrishnakoneP: Involvement of the L-arginine-nitric oxide synthase pathway in the relaxant responsesof the rat isolated anococcygeusmuscle to a scorpion (Leirus quinquastriatus)venom, Toxicon1995;33:1141-I150. 24. Freire-maiaL, De Mates IM: Heparin or a PAF antagonist (BN-520021}prevents the acute pulmonary edema induced by Tityus sarrulatus scorpion venom in the rat. Toxicon1993;31:12071210. 25. Gueron M, Adolph RJ, Grupp IL, et al: Hemodynamicand myocardial consequencesof scorpion venom. Am J Carflio11980;45:979-986. 26. Tarasiuk A, Sofer S, Huberflo S, et al: Hemodynamiceffects following injection of venom from the scorpion Leires quinquestriatus. J Crit Care 1994;4:134-140.
Reprint no. 47/1/81994 Address for reprints: Dr Fekri Abroug Service de R6animation Polyvalente CHU F Bourguiba 5019 Monastir Tunisia
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