a b s t r a c t

Background: scorpion envenomation may cause local symptoms as well as life-threatening situations includ- ing shock, and death. antivenom administration is the cornerstone of therapy, meticulous patient selection is needed because of the possible side effects of the antivenom including anaphylaxis. Peripheral perfusion index (PPI) is a simple, non-invasive test that is widely used for the detection of peripheral hypoperfusion. We aimed to investigate the value of using PPI to predict the need for antivenom administration for scorpion envenomation.

Methods: This prospective observational study was conducted in the ED of a tertiary care center. We consecu- tively enrolled patients with scorpion envenomation on the extremities who are over 18 years old without preg- nancy and a peripheral arterial disease between March 1, 2021, to October 31, 2021. Demographics included age, sex, sting zone, the time between sting and the ED admission, and vital parameters, we blindly measured PPI both on affected and contralateral extremities before any therapeutic intervention. We compared PPI levels, vital parameters, and the outcome including discharge from the ED, admission to ward or ICU, and death between patients who received antivenom and those who did not.

Results: Twenty-nine male (58.0%) and 21 (42.0%) female patients with scorpion envenomation were en- rolled in the study. The median age was 46.5 [IQR 33.3]. Thirty-eight (76.0%) patients had Class I, 12 (24.0%) patients had Class II and III envenomation. The median duration of the ED admission after the sting was 90 [IQR 120] minutes. Antivenom was administered in 13 (26.0%) patients. PPI was significantly lower both on the affected and the contralateral extremities (p = 0.043 and p = 0.045, respectively) in pa- tients who required antivenom. With a cut-off value of 2.4, PPI can predict the need for antivenom with a sensitivity of 61.54%, a specificity of 86.5%, a positive likelihood ratio of 4.55, a negative likelihood ratio of 0.44, a positive predictive value of 61.54%, a negative predictive value of 86.49%, and an accuracy of 80% (AUC 0.691, p < 0.05).

Conclusion: PPI can better reflect the ongoing systemic inflammation and the need for antivenom compared to other vital parameters. Therefore, we suggest this noninvasive and objective test may have a significant role in detecting patients who need antivenom in the early phase of scorpion envenomation. However, more studies are needed to elucidate the role of PPI in scorpion envenomation.

(C) 2022

1. Introduction

Scorpion envenomation may lead to clinical manifestations that are localized, such as pain and swelling, or systemic, including nausea, vomiting, hypersalivation, chest pain, hypotension, shock, and even death [1]. In patients with severe envenomation, administration of anti- venom is the standard of care [2]. However, scorpion antivenom may

* Corresponding author at: Adnan Menderes University Hospital, Kepez Mevkii, 09100, Efeler, Aydin, Turkey.

E-mail address: [email protected] (Y.E. Ozluer).

trigger anaphylaxis, and its use should be limited to appropriately se- lected patients.

The peripheral perfusion index (PPI), measured as the ratio of pulsa- tile blood over non-pulsatile blood in the peripheral tissues, is a rou- tinely used, simple, and noninvasive method to diagnose peripheral hypoperfusion in various clinical settings [3-5]. It has been shown that PPI values lower than 1.4 are highly associated with poor peripheral perfusion [6]. To our knowledge, its application in scorpion envenom- ation therapy has not been documented. We investigated the value of using PPI to predict the need for antivenom administration for scorpion envenomation in the emergency department (ED).

https://doi.org/10.1016/j.ajem.2022.03.056

0735-6757/(C) 2022

1. Methods
   1. Endemic scorpion species and the features of the antivenom used

In our region, Mesobuthus and Androctonus species are endemic scor- pions that may cause mild to life-threatening severe envenomation. A monovalent scorpion antivenom derived from envenomated horse plasma which is produced at Refik Saydam Hygiene Center (Ankara, Turkey) is used for scorpion envenomation in Turkey since 1942.

• 1. Patient enrollment and data collection

This prospective, cross-sectional study was conducted at an ED of a tertiary care center between March 2021 and October 2021 and was ap- proved by the local ethics committee (Approval number: 2021/55). Pa- tients older than 18 years who were admitted to the ED with scorpion stings on the upper or lower extremities were consecutively enrolled in the study. Patients younger than 18 years, those who had a peripheral arterial disease or pregnancy, people who did not give consent, and pa- tients referred from another hospital to our facility post-antivenom treatment were excluded. All enrolled participants provided written consent. Demographic data including age, sex, the affected extremity, time between the incident and the ED admission, vital parameters in- cluding blood pressure, heart rate, and oxygen saturation, and the grade of the scorpion sting as outlined by the Scorpion Consensus Ex- pert Group were recorded as this consensus is currently being followed in the management of scorpion envenomation in our ED [7]. The authors of this study were not involved in grading envenomation or treatment. A Pulse oximeter (Radical-7 Pulse CO-Oximeter, Masimo Corporation, Irvine, CA, United States) was used to measure PPI on the affected and contralateral (nonaffected) extremities at the initial physical exam. To determine if antivenom administration altered PPI, PPI of the affected extremity was measured one hour after antivenom infusion. We did the same measurement on the affected extremity one hour later in pa- tients who did not receive antivenom. Treatment outcomes were re- corded as discharge from the ED, admittance to the ward or the intensive care unit (ICU), or death.

• 1. Statistical analysis

Statistical analysis was conducted using SPSS for Windows version

18.0 (IBM, Armonk, NY, United States) and Jamovi version 2.2.3 (https://www.jamovi.org). Continuous variables were presented as means with standard deviation or medians with interquartile range [IQR] as per normality tests. Categorical variables were expressed as the number of cases (n) with percentages (%). The ?2 and Fisher’s exact tests were used to analyze categorical variables, and the Student’s t and Mann-Whitney U tests were used to analyze continuous variables. The Kruskal-Wallis test was used for multiple group analyses of contin- uous dependents, and the Wilcoxon test was used to analyze repeated measurements. The data were evaluated with the assumption that the variances were equal, and p < 0.05 was considered significant.

1. Results

Table 1

Demographics, vital signs, and peripheral Perfusion index measurements of the patients.

Age (years), median [IQR]	46.5 [33.3]
Male sex, n (%)	29 (58)
Systolic BP (mmHg), median [IQR]	135 [22.8]
Diastolic BP (mmHg)	81.2 +- 14.3
MAP (mmHg)	101 +- 15.2
Heart rate (beats/min),	82.7 +- 14.4
Oxygen saturation (%), median [IQR]	98 [1.75]
PPI on the affected extremity, median [IQR]	3.9 [5.2]
PPI on the contralateral extremity, median [IQR]	4.4 [6.3]

BP = Blood pressure, MAP = Mean arterial pressure, PPI = Peripheral perfusion index.

patients (76.0%) had Class I (local), five (10.0%) had Class II (non-life threatening), and seven (14.0%) had Class III (life-threatening) stings. Out of 50 patients, 46 (92.0%) were discharged from the ED; four (8.0%) patients were admitted to the intensive care unit, and their me- dian length of stay was 1 day [IQR 1]. Surgical intervention was not needed in any case, and all patients survived.

Upon admission to the ED, the median PPI was 3.9 [IQR 5.2] on the affected extremity and 4.3 [IQR 5.8] on the contralateral extremity. There was no statistically significant difference in PPI between affected and contralateral extremities (p = 0.975) or between upper and lower extremities (p = 0.602).

Including one patient whose envenomation grade progressed, scor- pion antivenom was administered to 13 patients (26.0%) who were moderately and severely envenomated (Table 2). None of the patients had an allergic reaction to or other adverse effects from antivenom. The median number of antivenom vials administered was 2 [IQR 1]. Ini- tial PPI values of both affected and contralateral extremities were statis- tically significantly different between patients receiving antivenom compared with patients not given that therapy (p = 0.043 and p = 0.045, respectively) (Table 2). In patients who did not have antivenom infusions, the initial median PPI on the affected extremity was 4.9 [IQR 7.8] and 6.2 [IQR 6.5] one hour after the ED admission (p = 0.367). In patients who had antivenom infusions, the median PPI measured on the affected extremity was 1.90 [IQR 3.7] before administration and

4.60 [IQR 2.33] one hour after administration (p = 0.070). The diagnos- tic accuracy of measuring PPI of the affected extremity to determine the need for antivenom administration with a cutoff value of 2.4 (Area under curve = 0.691, p < 0.05) is presented in Table 3. This cut-off value was determined as it corresponds to the maximum Youden index when performing the receiver operating characteristics (ROC) Analysis.

1. Discussion

Per this study, PPI may be used to predict the need for antivenom in neutralizing scorpion stings; this objective parameter may considerably

Table 2 Demographics, vital signs, and peripheral perfusion index measurements according to an- tivenom administration status.

Antivenom Administration

Among 72 consecutive admissions to the ED with scorpion stings, eight patients who did not give consent to participate in the study,

Yes

(n = 13)

No

(n = 37)

p value

seven patients referred from another hospital following antivenom ad- ministration, four pregnant patients, and three patients with peripheral arterial disease were excluded. A total of 50 patients were enrolled in this study. Demographics, vital signs, and PPI measurements are pre- sented in Table 1. Scorpion stings most frequently occurred on the

Age (years) 49.8 +- 20.2 48.1 +- 19.2 0.796

Male sex, n (%) 4 (30.8) 25 (32.4) 0.021

Systolic BP (mmHg), median [IQR] 138 [50] 132 [16] 0.740

Diastolic BP (mmHg) 80.7 +- 13.3 81.4 +- 14.9 0.879

MAP (mmHg), mean +- SD 102 +- 15.9 101 +- 15.2 0.837

Heart rate (beats/min), median [IQR] 86 [4] 78 [19] 0.394

right upper extremity (n = 18, 36.0%), followed by the right lower ex-	Oxygen saturation (%), median [IQR]	98 [1]	98 [2]	0.170
tremity (n = 12, 24.0%), left upper extremity (n = 11, 22.0%), and left	PPI on the affected extremity	1.9 [3.7]	4.9 [7.8]	0.043
lower extremity (n = 9, 18.0%). The median duration from the sting in-	PPI on the contralateral extremity	2.2 [3.3]	4.9 [6.2]	0.045

cident to admission to the ED was 90 [IQR 120] minutes. Thirty-eight

BP = Blood pressure, MAP = Mean arterial pressure, PPI = Peripheral perfusion index.

Table 3

Diagnostic features of peripheral perfusion index measurement on the affected extremity to determine the need for antivenom administration (PPI cut-off value is <=2.4).

Result 95% CI

Sensitivity 61.54% 31.58% - 86.14%

Specificity 86.5% 71.23% - 95.46%

Positive Likelihood Ratio 4.55 1.81-11.43

Negative Likelihood Ratio 0.44 0.22-0.89

Positive Predictive Value 61.54% 38.90% - 80.08%

Negative Predictive Value 86.49% 76.08% - 92.79%

Accuracy 80.0% 66.28% - 89.97%

aid Treatment decisions, especially as the current grading systems for envenomation have some discrepancies between them [7-9]. There is a tendency to administer scorpion antivenom in patients with systemic symptoms, life-threatening or not [10]. Approximately 1/3 of patients with scorpion stings receive antivenom, though the figure varies by ge- ography; our data reflected this number (26.0%) [11]. We found that PPI was the only statistically different vital parameter at the early phase of envenomation between patients who required antivenom and those who did not. Therefore, we assume that using PPI in the management of scorpion envenomation may help clinicians to decide which patient needs or benefits from antivenom and may prevent unnecessary anti- venom administration.

Patients who require antivenom administration are considered to be more severely envenomated. We observed that initial PPI was signifi- cantly lower on the affected extremity in those patients, which may be explained by the greater increase in non-pulsatile blood flow present in severe localized edema. However, the difference of severity of the systemic toxicity could be the main factor causing this variance in PPI between patient groups. In our study, the median time from the sting incident to ED admission was 90 min, an adequate period for both local edema formation as well as and systemic inflammation to have de- veloped.

Although not statistically significant, PPI of the affected extremity in patients receiving antivenom trended upward one hour following ad- ministration. This may be due to the neutralizing effect of the anti- venom that suppresses the systemic inflammatory storm. Future studies with larger and more severely envenomated patient popula- tions may elucidate this change as well as appraise the utility of PPI in assessing antivenom efficacy. Further investigation could evaluate the relevance of PPI in envenomated patients needing surgical interven- tions, including fasciotomy, and in managing envenomation by scorpion species different from the Androctonus and Mesobuthus types found in our area, e.g., Centruroides [12].

Our study has several limitations. First, the number of patients who received antivenom was relatively low-our patient population mostly consisted of patients with Grade I scorpion stings-which may hinder the generalization of our results. Second, we did not exclude patients taking peripheral vasodilators, such as dihydropyridine-derived calcium channel blockers, which may influence PPI readings. Third, the most common scorpion species in our region may differ from those in other parts of the world; this study should be repeated with patients who were envenomated by other species.

1. Conclusion

Compared with other vital parameters, the peripheral perfusion index may better reflect ongoing systemic inflammation and the need

for antivenom in scorpion stings. This noninvasive, readily available, and repeatable test may have a significant role when detecting patients who need antivenom in the early phase of scorpion envenomation. More studies are needed to elucidate the relevance of PPI in scorpion stings and in envenomation caused by other animals.

Declarations of Competing Interest

None.

Funding

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors and not previ- ously presented at any meeting or an organization.

Credit authorship contribution statement

Yunus Emre Ozluer: Writing - review & editing, Writing - original draft, Investigation, Formal analysis, Data curation, Conceptualization. Kivanc Karaman: Writing - original draft, Methodology, Investigation, Conceptualization. Dogukan Kayaoz: Writing - original draft, Method- ology, Data curation. Mucahit Avcil: Writing - review & editing, Writing - original draft, Supervision, Methodology, Conceptualization.

References

1. Yilmaz F, Arslan ED, Demir A, et al. Epidemiological, clinical characteristics and out- comes of scorpion sting in southeastern region of Turkey. Ulus Travma Acil Cerrahi Derg. 2013;19(5):417-22. https://doi.org/10.5505/tjtes.2013.52333.
2. Isbister GK, Bawaskar HS. Scorpion envenomation. N Engl J Med. 2014;371(5): 457-63. https://doi.org/10.1056/NEJMra1401108.
3. Shi X, Xu M, Yu X, Lu Y. Peripheral perfusion index predicting prolonged ICU stay earlier and better than lactate in surgical patients: an observational study. BMC Anesthesiol. 2020;20(1):153. https://doi.org/10.1186/s12871-020-01072-0.
4. Karaman K, Saglam Gurmen E. The role of peripheral perfusion index in differential diagnosis of cardiac and pulmonary-origin dyspnea in emergency service. Hong Kong J Emerg Med. 2020. https://doi.org/10.1177/1024907920944050. Published online July 22. 1024907920944050.
5. Das M, Bardakci O, Siddikoglu D, et al. prognostic performance of peripheral perfu- sion index and Shock Index combined with ESI to predict hospital outcome. Am J Emerg Med. 2020;38(10):2055-9. https://doi.org/10.1016/j.ajem.2020.06.084.
6. Lima AP, Beelen P, Bakker J. Use of a peripheral perfusion index derived from the pulse oximetry signal as a noninvasive indicator of perfusion. Crit Care Med. 2002; 30(6):1210-3. https://doi.org/10.1097/00003246-200206000-00006.
7. Khattabi A, Soulaymani-Bencheikh R, Achour S, Salmi LR. Classification of clinical consequences of scorpion stings: consensus development. Trans R Soc Trop Med Hyg. 2011;105(7):364-9. https://doi.org/10.1016/j.trstmh.2011.03.007.
8. Abroug F, ElAtrous S, Nouira S, Haguiga H, Touzi N, Bouchoucha S. Serotherapy in scorpion envenomation: a randomised controlled trial. Lancet. 1999;354(9182): 906-9. https://doi.org/10.1016/s0140-6736(98)12083-4.
9. Nouira S, Boukef R, Nciri N, et al. A Clinical score predicting the need for hospitaliza- tion in scorpion envenomation. Am J Emerg Med. 2007;25(4):414-9. https://doi. org/10.1016/j.ajem.2006.08.021.
10. Bomba A, Favaro P, Haus R, et al. Review of scorpion stings and snakebites treated by the French military health service during overseas operations between 2015 and 2017. Wilderness Environ Med. 2020;31(2):174-80. https://doi.org/10.1016/j. wem.2020.01.006.
11. Sahin A. Antivenom use in cases of bites and stings presenting to a public hospital. Ulus Travma Acil Cerrahi Derg. 2018. https://doi.org/10.5505/tjtes.2017.99692. Derg Published online.
12. Ozkan O, Uzun R, Adiguzel S, Cesaretli Y, Ertek M. Evaluation of scorpion sting inci- dence in Turkey. J Venom Anim Toxins Incl Trop Dis. 2008;14:128-40. https://doi. org/10.1590/S1678-91992008000100010.