ABSTRACT

Conclusion:

Hyperamilasemia, hyperglycemia, and elevated pro-BNP levels on admission may be warning signs of more severe (grade 3) patients. Mild-to-moderate mitral regurgitation may be more commonly observed echocardiography findings than systolic dysfunction in severe cases (grade 2 and 3).

Results:

It was found that there were 2,208 admissions to the intensive care unit during the study period (4 years), and 73 (3.3%) of these cases (35 female and 38 male) were followed up for severe scorpion envenomation. The median age was 52 (26-89) months. Yellow scorpions were described by parents or eyewitnesses in 65 patients (89%) and black scorpions in 8 (11%). Peripheral sympathetic activity (cold extremities, diaphoresis) signs (n=55, 75.3%), hypertension (n=35, 47.9%), and tachycardia (n=21, 28%) were the most common findings. The most common echocardiographic findings were mild-to-moderate mitral regurgitation and systolic dysfunction in 31 (42.5%) and 19 (25.9%) cases, respectively. Sixty-two (89%) patients had grade 2 envenomations findings and 12 (11%) had grade 3. High pro-BNP, hyperglycemia, and hyperamylasemia were observed more frequently in grade 3 than in grade 2 patients on admission. All patients received anti-venom therapy and 7 (9.5%) of them required a second dose of anti-venom therapy due to the unregressed clinical course. Twenty-seven patients (37%) required inotropics, s and the most commonly used inotropics were milrinone in 17 (23.3%) patients and dobutamine in 12 (16.4%) patients. The median PICU length of stay was 4 (3-5) days and the median hospital stay was 5 (4-6) days. All patients survived to discharge.

Methods:

This retrospective, cross-sectional study was conducted in 12 beds tertiary care PICU in Antalya Training and Research Hospital. Patients admitted to the PICU between 2017-2021 due to severe scorpion envenomation were admitted to the study.

Objective:

This study aimed to determine the general characteristics and warning signs for the more severe (grade 3) clinical course in severe scorpion envenomations in the pediatric intensive care unit (PICU).

INTRODUCTION

Scorpions, the oldest arthropod species living on Earth, have been a major problem throughout human history. Nearly 3,000 species of scorpions have been described worldwide, and they live everywhere in the world except Antarctica. In Turkey, 27 species of scorpion have been described in four families (Buthidae, Iuridae, Scorpionidae and Euscorpiidae) (1). The most medically important scorpion species in Turkey are Androctonus, Leiurus and Mesobuthus species from the family Buthidae (2). Although the most cases of scorpion envenomation in Turkey occur below the 39^th parallel (central and southern Aegean region, the Mediterranean region, and central, west, and southwestern region of Anatolia), the risk of scorpion envenomation exists in all regions of Turkey (3). The main causes of death in scorpion envenomation are hemodynamic disturbances and pulmonary edema. This study reveals the general characteristics of scorpion envenomation in children and determination of variables that may lead to early recognition of the most severe (grade 3) patients.

METHODS

This retrospective cross-sectional study was conducted in a 12-bed tertiary care pediatric intensive care unit (PICU) of Antalya Training and research Hospital that admits approximately 500 medical and surgical patients annually and is located on the southwestern coast of Turkey. The severity of the patients was determined according to the staging system used by Khattabi et al. (4). Only local manifestations are grade 1, non-life-threatening systemic manifestations (hypertension, nausea, convulsions, lethargy, tachycardia, etc.) are grade 2 (severe), and life-threatening systemic manifestations (hypotension, ventricular arrhythmia, bradycardia, collapse, respiratory failure, neurological failure) are defined as grade 3 (more severe). According to our scorpion stings protocol, only patients with systemic symptoms (grade 2 and 3) were admitted to the PICU.

Equine antivenom (Androctonus crassicauda) was used for anti-venom therapy. Before the anti-venom infusion, a skin test was performed routinely. Five milliliters (one ampoule) of anti-venom was diluted with 50 milliliters of normal saline and infused over 30 min in all patients.

Patient records (between 2017 and 2021) were retrospectively reviewed after University of Health Sciences Turkey, Antalya Training and Research Hospital Ethics Committee approval was obtained (decision no: 1/28, date: 04.03.2021). Patient demographics, signs and symptoms on admission, echocardiography findings, laboratory results, specific treatments (anti-venom, doxazosin), intensive care treatments (inotropic and vasoactive medications, sedatives, respiratory support), intensive care, and length of hospital stay were recorded. Patients, whom scorpion could not be observed and were treated with suspicion based on clinical findings were excluded from the study.

Systolic dysfunction was defined by an ejection fraction of less than 55% (40-55% mild, 30-40% moderate, and <30% severe). Hyperglycemia was defined as blood glucose level >140 mg/dL (5), elevated creatine kinase (CK) defined as CK level >200 U/L (laboratory upper limit), elevated troponin T defined as troponin level >14 ng/L (6), elevated myoglobin level defined as myoglobin level >72 ng/mL (laboratory upper limit), elevated pro-BNP defined as pro-BNP level >300 ng/L (7), hyperamylasemia defined as amylase level >110 U/L (8), hyperlipasemia defined as lipase level >160 U/L (9), and leukocytes (white blood cells) >10x10³/mm³ (laboratory upper limit) was defined as leukocytosis.

Statistical Analysis

Categorical variables were expressed as n (%) and continuous variables were expressed as median (interquartile range: 25p-75p). The chi-square test or Fisher’s Exact test was used to compare categorical variables between the two groups. Mann-Whitney U test was used for the comparison of continuous variables between the two groups. Statistical calculations were performed with the Statistical Package for Social Sciences (SPSS) for Windows version 23 and MedCalc for Windows version 14.8.1.

RESULTS

It was found that there were 2,208 admissions to the PICU during the study period (4 years), and 73 (3.3%) of these cases (35 female and 38 male) were followed up due to severe scorpion envenomation. Fifty-one (69.8%) of the patients were admitted to the PICU between June and September. Yellow scorpions were described by parents or eyewitnesses in 65 patients (89%) and black scorpions in 8 (11%). The demographic features of the patients are presented in Table 1.

Table 1

Peripheral sympathetic activity signs (cold extremities, diaphoresis) were the most common findings on admission (n=55, 75.3%). Other common findings were shortness of breath in 22 (30.1%) patients, hypertension in 35 (47.9%) patients, nausea in 27 (37%) patients, bradycardia in 2 (2.7%) patients, tachycardia in 21 (2.8%) patients, hypotension in 7 (9.6%) patients, priapism in 3 (4.1%) patients, and pulmonary edema in 5 (6.8%) patients.

Abnormal laboratory findings in the patients were as follows. Hyperglycemia in 19 (26.8%), leukocytosis in 47 (66.2%) patients, hyperamylasemia in 25 (42.4%) patients, elevated troponin T in 41 (59.4%) patients, elevated myoglobin in 31 (68.9%) patients, elevated pro-BNP in 17 (23.3%) patients, and elevated CK was detected in 49 (71%) patients (Table 2). Lipase elevation was not observed in the patient.

Table 2

The median ejection fraction of the patients on echocardiography was 63% (52-66). The most common abnormal echocardiographic finding was mild-to-moderate mitral regurgitation, which was noted in 31 (42.5%) patients. Other abnormal echocardiographic findings were mild systolic dysfunction in 17 (23.2%), moderate systolic dysfunction in 2 (2.7%) patients, and mild tricuspid regurgitation in 13 (17.8%) patients.

All patients received anti-venom therapy and 7 (9.5%) of them required a second dose of anti-venom because of the unregressed clinical course. The most commonly used treatment agent was doxazosin in 49 (67.1%) patients. Furosemide was used in 23 (31.5%) patients. Twenty-seven (37%) patients required inotropic and/or vasoactive support. The following inotropic and vasoactive agents were used in the patients: milrinone in 17 (23.3%) patients, dobutamine in 12 (16.4%) patients, epinephrine in 9 (12.3%) patients, dopamine in 4 (5.5%) patients, and norepinephrine in 5 (6.8%) patients. Dexmetatomidine was used in 21 (28.8%) patients for its sedative, analgesic, and sympatholytic properties. Seventeen patients (22.2%) required invasive positive pressure ventilation and five patients (5.6%) required invasive mechanical ventilation.

Cardiac arrest and cardiopulmonary resuscitation were required in two (2.7%) patients. The median PICU length of stay was 4 (3-5) days and the median hospital stay was 5 (4-6) days. All patients were discharged without morbidity or mortality, except for one patient who developed neuromotor disability because of cardiac arrest.

DISCUSSION

Scorpion envenomation is an important health problem in children, especially those under 5 years of age. This is because most of the reported deaths occur under the age of 5 years (10). It is recommended that patients with scorpion envenomation who present with systemic symptoms should be followed up in the PICU (11). In this study, we show the general characteristics and frequency of children with severe scorpion envenomations in our PICU. The main findings of this study are relevant to laboratory and echocardiographic results. Hyperglycemia, hyperamylasemia, and elevated pro-BNP occur more frequently in grade 3 cases than grade 2 cases. Echocardiographic findings show that mild-to-moderate mitral regurgitation is more common than systolic dysfunction. Although there was no death in our cases, pulmonary edema, which led to cardiac arrest in one case, was seen as the potentially most fatal complication.

It has been reported that the pancreas is frequently but transiently affected in systemic scorpion envenomations (12). Animal studies show that scorpion venom increases biliary and duodenal motility, causing increased pancreatic amylase production (13,14). Although there were no statistically significant differences between grade 2 and grade 3 patients in terms of amylase blood levels, there were significant differences in the frequency of hyperamylasemia between the groups. It seems that hyperamylasemia is more common in patients with grade 3 than in patients with grade 2. Although hyperamylasemia is a common manifestation of scorpion sting, we think that pancreatitis is rare because there was no lipase elevation in our patients.

Hyperglycemia is a well-known phenomenon in patients with scorpion envenomation. It is caused by increased catecholamine secretion and other hormonal mechanisms during scorpion envenomation. It has been reported that hyperglycemia during scorpion envenomation is an indicator of disease severity (15). In our study, hyperglycemia was observed in 26.8% of all cases. However, it was observed with a frequency of 81.9% in grade 3 patients and was significantly different from grade 2.

Myocardial injury during scorpion envenomation is a known entity and it is thought that the underlying mechanism may be direct or indirect (severe hypertension) myocardial damage associated with elevated catecholamines or direct myocardial toxicity of scorpion toxins (16,17). Cardiac troponins are the most sensitive biomarkers of myocardial damage. In the early phase (first six hours) of myocardial injury, the most sensitive biomarker is myoglobin (18). However, myoglobin is found not only in the heart but also in greater amounts in striated muscle. In cases such as scorpion bites, where striated muscle may be affected, elevated myoglobin levels may be observed independently of cardiac injury. In a study conducted in southeastern Turkey, it has been reported that severe cases of scorpion envenomation had higher CK levels than mild and moderate cases (11). In our study, grade 3 patients had higher myoglobin, troponin, lactate, and pro-BNP levels than grade 2 patients.

Echocardiographic examination of scorpion bites can determine the degree of heart failure and other dysfunctions (19). In a prospective echocardiographic study conducted in India, it has been reported that heart failure associated with scorpion envenomation can be diagnosed with a frequency of approximately 70% (20). In another study conducted in Israel, the incidence of heart failure was reported to be about 10%. In a study conducted in the Egean region in Turkey (Mesobuthus gibbosus), heart failure and associated pulmonary edema occurred with a frequency of 8.7% (21). In our study, echocardiographic heart failure (low ejection fraction) was found with a frequency of 26%. However, the patients included in our study were those with systemic symptoms, so they do not represent all emergency admissions. Although systolic dysfunction is frequently mentioned in the echocardiographic findings in all studies, our study shows that mitral valve dysfunction (mild to moderate regurgitation) may be seen more frequently.

Antitoxin infusions, inotropic and vasodilator treatments are the main methods of treatment in children with severe scorpion envenomation. In severe cases, the administration of scorpion antitoxin as early as possible increases efficacy (22,23) Bawaskar and Bawaskar (24,25) reported that prazosin is a promising agent to reduce mortality in children with severe scorpion envenomation. The mortality-reducing effect of prazosin was clarified by controlled studies (historical controls) in the following years (26). Doxazosin is an alpha-adrenoreceptor blocker like prazosin but has a longer elimination half-life than prazosin (22 versus 3 h). It has been reported that doxazosin may have the same success rate as prazosin when prazosin is unavailable (27). We used doxazosin instead of prazosin because prazosin was not available at our hospital.

Milrinone is a medicine that has inotropic, lusitropic, and vasodilatory effects. It has the advantage over dobutamine that it does not show tolerance or attenuation of its effects and has a better systemic vasodilatory effect (28). These effects make milrinone a promising agent for treating scorpion envenomation (29). There is no comparative randomized controlled trial of milrinone and dobutamine in scorpion envenomation.

Pulmonary edema is the most dangerous manifestation of scorpion envenomations. There are two different mechanisms responsible for developing pulmonary edema after scorpion envenomation. One of them is the increased permeability of the alveolocapillary membrane due to the direct damage caused by the scorpion venom (30). The other type of pulmonary edema is the cardiogenic type, which is associated with biventricular failure because of venom toxicity (31). In this study, pulmonary edema occurred in only five patients and one of them suffered cardiac arrest due to acute severe hypoxemia.

Single-center data and a retrospective study design are the main limitations of this study. The causative scorpion species could not be clearly defined because the parents’ descriptions did not provide sufficient data to clearly identify the scorpion species. Only patients with severe scorpion envenomation were included in this study, so the results cannot be generalized to all cases of scorpion bites.

CONCLUSION

Scorpion envenomation is an important public health issue. Hyperamilasemia, hyperglycemia, and elevated pro-BNP levels on admission may be warning signs of more severe patients. Mild-to-moderate mitral regurgitation may be more common than systolic dysfunction in severe cases.

ETHICS

Ethics Committee Approval: This study was reviewed and approved by University of Health Sciences Turkey, Antalya Training and Research Hospital Ethics Committee (decision no: 1/28, date: 04.03.2021).

Informed Consent: Informed consent could not be obtained because of the retrospective study design.

Authorship Contributions

Surgical and Medical Practices: H.S.K., G.Ö., A.K., Y.B., E.A.O., Concept: H.S.K., E.A.O., Design: H.S.K., G.Ö., A.K., Y.B., E.A.O., Data Collection or Processing: H.S.K., Analysis or Interpretation: H.S.K., G.Ö., A.K., Y.B., E.A.O., Literature Search: H.S.K., Writing: H.S.K.

Conflict of Interest: The authors declare that they have no conflict of interest.

Financial Disclosure: The authors declared that this study received no financial support.

References

Gümüştekin M, Sarıçoban B, Gürkan M. Antivenoms and Principles of Application. Dokuz Eylül Üniversitesi Tıp Fakültesi Dergisi 2020;34:73-83.

Caliskan F. Scorpion Venom Research Around the World: Turkish Scorpions. ScorpionVenoms. Dordrecht: Springer Netherlands; 2015. p. 327-49.

Ozkan O, Uzun R, Adiguzel S, Cesaretli Y, Ertek M. Evaluation of scorpion sting incidence in Turkey. J Venom Anim Toxins incl Trop Dis 2008;14:128-40.

Khattabi A, Soulaymani-Bencheikh R, Achour S, Salmi LR; Scorpion Consensus Expert Group. Classification of clinical consequences of scorpion stings: consensus development. Trans R Soc Trop Med Hyg 2011;105:364-9.

Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D, Hellman R, Hirsch IB, et al. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Endocr Pract 2009;15:353-69.

Karlén J, Karlsson M, Eliasson H, Bonamy AE, Halvorsen CP. Cardiac troponin T in healthy full-term infants. Pediatr Cardiol 2019;40:1645-54.

Lin C-W, Zeng X-L, Jiang S-H, Wu T, Wang J-P, Zhang J-F, et al. Role of the NT-proBNP level in the diagnosis of pediatric heart failure and investigation of novel combined diagnostic criteria. Experimental and Therapeutic Medicine 2013;6:995-9.

Lam R, Muniraj T. Hyperamylasemia. [Updated 2021 Dec 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559273/

Hameed AM, Lam VW, Pleass HC. Significant elevations of serum lipase not caused by pancreatitis: a systematic review. HPB (Oxford) 2015;17:99-112.

Baseer KA, Naser MAA. Predictors for mortality in children with scorpion envenomation admitted to pediatric intensive care unit, Qena Governorate, Egypt. Am J Trop Med Hyg 2019;101:941-5.

Bosnak M, Ece A, Yolbas I, Bosnak V, Kaplan M, Gurkan F. Scorpion sting envenomation in children in Southeast Turkey. Wilderness Environ Med 2009;20:118-24.

Sofer S, Shalev H, Weizman Z, Shahak E, Gueron M. Acute pancreatitis in children following envenomation by the yellow scorpion Leiurus quinquestriatus. Toxicon 1991;29:125-8.

Chen JW, Shi CX, Teng MJ, Schloithe AC, Toouli J, Saccone GT. Scorpion venom stimulates biliary/duodenal motility and pancreatic exocrine secretion. Neurogastroenterol Motil 2004;16:447-54.

Bartholomew C, Murphy JJ, McGeeney KF, Fitzgerald O. Exocrine pancreatic response to the venom of the scorpion, Tityus trinitatis. Gut 1977;18:623-5.

Bahloul M, Turki O, Chaari A, Bouaziz M. Incidence, mechanisms and impact outcome of hyperglycaemia in severe scorpion-envenomed patients. Ther Adv Endocrinol Metab 2018;9:199-208.

Meki AR, Mohamed ZM, Mohey El-deen HM. Significance of assessment of serum cardiac troponin I and interleukin-8 in scorpion envenomed children. Toxicon 2003;41:129-37.

Al B, Sucu M, Çavdar M, Yılmaz DA, Yıldırım C, Davutoğlu V. Electrocardiographic abnormalities in patients bitten by Scorpions. JAEM 2009;8:51-5.

Al-Hadi HA, Fox KA. Cardiac markers in the early diagnosis and management of patients with acute coronary syndrome. Sultan Qaboos Univ Med J 2009;9:231-46.

Sofer S, Zucker N, Bilenko N, Levitas A, Zalzstein E, Amichay D, et al. The importance of early bedside echocardiography in children with scorpion envenomation. Toxicon 2013;68:1-8.

Sagarad SV, Kerure SB, Thakur B, Reddy SS, K B, Joshi RM. Echocardiography guided therapy for myocarditis after scorpion sting envenomation. J Clin Diagn Res 2013;7:2836-8.

Zengin N, Anıl M, Anıl AB, Kamit Can F, Bal A, Bıcılıoğlu Y, et al. Clinical characteristics of pediatric scorpion envenomation in the Aegean Region: an experience of a training and research Hospital. Turkish Journal of Pediatric Emergency and Intensive Care Medicine 2016;69-75.

Ghalim N, El-Hafny B, Sebti F, Heikel J, Lazar N, Moustanir R, et al. Scorpion envenomation and serotherapy in Morocco. Am J Trop Med Hyg 2000;62:277-83.

Boyer LV, Theodorou AA, Berg RA, Mallie J, Chávez-Méndez A, García-Ubbelohde W, et al. Antivenom for critically ill children with neurotoxicity from scorpion stings. N Engl J Med 2009;360:2090-8.

Bawaskar HS, Bawaskar PH. Prazosin in management of cardiovascular manifestations of scorpion sting. Lancet 1986;1:510-1.

Bawaskar HS, Bawaskar PH. Prazosin for vasodilator treatment of acute pulmonary oedema due to scorpion sting. Ann Trop Med Parasitol 1987;81:719-23.

Gupta V. Prazosin: a pharmacological antidote for scorpion envenomation. J Trop Pediatr 2006;52:150-1.

Konca C, Tekin M, Turgut M. Doxazosin in the treatment of scorpion envenomation. Indian J Pediatrb2015;82:499-503.

Colucci WS, Wright RF, Jaski BE, Fifer MA, Braunwald E. Milrinone and dobutamine in severe heart failure: differing hemodynamic effects and individual patient responsiveness. Circulation 1986;73:III175-83.

Cavari Y, Sofer S, Bilenko Y, Rosen GB. The intensive care management of children with scorpion envenomation. Journal of y Clin Toxicol 2015;05.

Andrade MV, Caramez MPR, Abreu EMNN, Dolnikoff M, Omar ED, Velasco IT, et al. Lung compliance, plasma electrolyte levels and acid-base balance are affected by scorpion envenomation in anesthetized rats under mechanical ventilation. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 2004;138:97-104.

Teixeira AL, Fontoura BF, Freire-Maia L, Machado CR, Camargos ER, Teixeira MM. Evidence for a direct action of Tityus serrulatus scorpion venom on the cardiac muscle. Toxicon 2001;39:703-9.

Severe Scorpion Envenomations in Pediatric Intensive Care Unit