Analysis of Centruroides (Scorpion) Immune F(ab’)2 (Equine) administration by slow intravenous push

Abstract Scorpion envenomation is a common emergency department presentation in Arizona and antivenom is often administered . This study evaluates the safety of Centruroides (Scorpion) Immune F(ab’)2 (Equine) administered as a single-vial-serial dosing strategy via slow intravenous push (IVP) over five minutes in the emergency department. This was a retrospective chart review of patients who received at least one vial of antivenom between April 1, 2019, and July 31, 2021. The primary outcome of this study was the rate of the serious antivenom administration-related adverse events. Twenty-five patients were included. One patient met criteria for a serious administration-related adverse event. No other serious administration, non-serious administration, or non-administration related adverse events were found. Neither grade of envenomation, repeat doses, nor total number of vials affected the rate of serious, non-serious, or non-administration-related adverse events. The primary outcome of a serious administration-related adverse event occurred in one patient (4%) with a grade IV envenomation.


Introduction
Scorpion envenomation is a common emergency department presentation in Arizona.The bark scorpion (Centruroides sculpturatus) is unique as it is the only species of scorpion in the United States that is potentially life-threatening, especially in the pediatric population [1][2][3][4].Centruroides sculpturatus is indigenous to Arizona but can be found in other Southwestern states including New Mexico, California, Nevada, and Texas [3].Bark scorpion venom causes a variety of clinical features ranging from local pain and paresthesia to cranial nerve and neuromuscular dysfunction which are graded on a four-point severity scale which are noted in Table 1 [1][2][3][4][5].Several toxins have been identified within scorpion venom.However, α-toxins have been identified as the most clinically relevant.These toxins bind to and inhibit the inactivation of the voltage-gated sodium channel which results in prolonged depolarization and, therefore, neuronal excitation.This excitation simulates both the sympathetic and parasympathetic systems resulting in the variety of clinical features seen [1].
Numerous approaches to target the physiological effects of envenomation were attempted throughout the twentieth century due to the scale of scorpion envenomations and attributed mortality [6].Pharmacologic treatments described in the literature during this time included phenobarbital, propranolol, midazolam infusions, intravenous calcium, corticosteroids, and other pharmacologic and non-pharmacologic treatment options [3,[6][7][8][9][10].Many attempted treatments did not demonstrate significant proven benefit [6].However, scorpion antivenom has existed in Mexico since 1926 and has been critical to treating patients [9].Antivenom usage and availability in Arizona has a complicated history including smuggled antivenom from Mexico and the use of a caprine serum antivenom from Arizona State College that was available outside of U.S. Food and Drug Administration (FDA) regulation [6,7].
Anascorp® (Centruroides (Scorpion) Immune F(ab') 2 (Equine)) was first approved in the U.S by the FDA in 2011.The labeled dose is three vials with each vial being reconstituted with five milliliters (mL) of normal saline and further diluted to a total volume of 50 mL.This final volume is then administered intravenously (IV) over 10 min [11].
Multiple studies have assessed both the efficacy and safety of intravenous administration of Centruroides (Scorpion) Immune F(ab') 2 (Equine) as well as evaluating potential cost minimalization with varying dosing strategies [5,[12][13][14][15][16].Two studies by Boyer et al. concluded that antivenom resulted in rapid symptom resolution (within four hours) [12,13].Quan, et al. compared a single-vial-serial dose strategy to a three-vial-first dose strategy and found that symptom resolution within four hours was not significantly different between the groups [5].Sinha et al. evaluated three dosing strategies (supportive care versus three-vial strategy versus single-vial-serial dosing) and found a lower patient cost with both the supportive care and single-vial-serial dosing strategies compared to the conventional three-vial dosing strategy [14].Two pharmacokinetic studies by Vazquez et al. evaluated pharmacokinetic parameters of an equine derived F(ab′)2 scorpion antivenom, Alacramyn® (which is a brand name not utilized in the United States, however, is comparable to Anascorp® and both are produced by the same company), given as an IV bolus or via the intramuscular (IM) route in a total of 14 healthy volunteers between both studies.These studies determined important pharmacokinetic parameters for IV administration including but not limited to: AUC, Vss, and T1/2 and determined that the IM route should not be utilized due to a considerable delay in achieving adequate plasma concentrations [15,16].
The study institution had been using the single-vial-serial dosing strategy for greater than 10 years with each single vial being diluted in 50 mL of normal saline and administered intravenously over 10 min until a practice change in preparation and administration in 2019.Currently, no literature is available evaluating the safety of slow intravenous push of Centruroides (Scorpion) Immune F(ab') 2 (Equine).The purpose of this study is to evaluate the safety of a single-vial-serial dosing strategy of Centruroides (Scorpion) Immune F(ab') 2 (Equine) administered as a slow intravenous push (IVP) over five minutes in the emergency department for treatment of scorpion envenomation.

Design
This study was a retrospective chart review for all patients who presented to either of two emergency departments within the health system between April 1, 2019, and July 31, 2021, and received at least one vial of Centruroides (Scorpion) Immune F(ab') 2 (Equine) administered by slow IVP over five minutes.The dosing strategy was single-vial-serial dosing.The antivenom was reconstituted with 10 mL of normal saline and administered via IVP.Patients were identified through a report generated via the EMR administration records for all Centruroides (Scorpion) Immune F(ab') 2 (Equine) administrations during the study timeframe.
Patients were excluded if there were significant data missing from the EMR.Demographic and clinical data collected included age, sex, and weight.This study was approved by the Institutional Review Board.

Study outcomes
The primary outcome for this study was the rate of serious administration-related adverse events.Serious administration-related adverse events were identified through thorough review of the EMR including provider notes, nursing notes, pharmacy documentation, the medication administration record, vitals, medication orders, non-medication orders (i.e.supplemental oxygen), and through review of the EMR for any return visits related to serious adverse events.For study purposes, serious administration related adverse events were defined as any one of the following: • Type 1 hypersensitivity reaction resulting in anaphylaxis requiring epinephrine administration • Type 1 hypersensitivity reaction (i.e.rash, urticaria, flushing, or pruritis) requiring administration of medication such as antihistamines and/or corticosteroids • Hypotension requiring intravenous fluid administration • Respiratory compromise requiring intervention (i.e.supplemental oxygen, noninvasive positive pressure ventilation, or intubation) • Nausea/vomiting not present prior to administration • Type III immune reaction (serum sickness) defined as new development of a combination of myalgias, arthralgias, fever, rash, urticaria several days after administration • Need for other intervention or higher level of care Secondary outcomes included the rate of non-serious or non-administration related adverse events, need for repeat dose(s), time between repeat dose(s), time to resolution of symptoms, disposition of the patient, need for adjunctive agents (which were included if they were given from the time of presentation to the emergency department through disposition and were identified through review of the medication administration record in the EMR), length of stay, and overall compliance with the administration technique.Additional secondary outcomes were how the grade of envenomation affects patient response to antivenom or rate of serious administration related adverse events as well as non-serious/ non-administration related adverse events and whether or not repeat doses or total number of vials affects rate of serious administration related adverse events as well as non-serious/non-administration related adverse events.For study purposes, patient response to antivenom was defined by the differences in median symptom resolution time, median number of vials administered, length of stay, and rate of discharge from the ED.

Statistical analysis
Differences in continuous variables were compared using a two-sided Wilcoxon rank-sum test with t-approximation.Differences in count variables were compared using Chi-square tests.The a priori significance level was set at 0.05.

Results
There were 25 encounters during the study period and no patients were excluded.The median [interquartile range (IQR)] age of the patients was four years (IQR: 2-6), 16 (64%) patients were male, and the median patient weight was 16.6 kilograms (IQR: 13.9-26).
The primar y outcome of a s erious administration-related adverse event occurred in one patient (4%) with a grade IV envenomation.This patient required supplemental oxygen at 1.5 liters/ minute for 1 h via nasal cannula 35 min following administration of antivenom for a single SpO 2 reading of 89%.The patient also received 1 mcg/kg IV fentanyl 15 min prior to this episode of desaturation.
None of the included patients had non-serious administration or non-administration related adverse events.All patients received one vial as an initial dose and four patients (16%) required more than one vial; three received two vials and one received three vials.
The median time between repeat doses was 54 min (IQR: 27.5-83.5).Twenty-two (88%) of patients had documentation of time to resolution of symptoms with a median time to resolution of symptoms of 72.5 min (IQR: 60-108.3).
Table 2 summarizes 18 (72%) patients receiving adjunctive medications.All doses of antivenom were documented as given correctly via slow IVP over five minutes.
Twenty-three (92%) of patients were discharged from the emergency department.One patient was admitted to the pediatric ICU (PICU) for medical complications unrelated to a scorpion envenomation or antivenom administration.This patient had a toxic exposure to methamphetamines which was discovered via additional laboratory testing that resulted after the administration of antivenom.Even though this was determined not to be a scorpion envenomation, since the patient still met study inclusion they were included in the study.One patient was transferred from the free-standing emergency department to another hospital outside of the health-system for further treatment of the envenomation.This patient presented with a severe grade IV envenomation with concern for a concomitant anaphylactic reaction which was treated as such by emergency medical services (EMS) prior to arrival to the emergency department.Due to ongoing difficulty breathing and wheezing in the emergency department, additional treatment with IM epinephrine, diphenhydramine and famotidine was given for anaphylaxis.It is unclear if this patient truly had an anaphylactic reaction to the envenomation or if the patient's symptoms were related to the severity of the envenomation.This occurred prior to the administration of antivenom and the decision to transfer the patient was also initiated prior to administration of antivenom.After antivenom administration and prior to transportation to the outside hospital, the patient's symptoms had resolved.The length of stay was zero days for 24 (96%) of the patients and six days for the remaining patient who was admitted to the PICU for management of methamphetamine exposure.Nearly all adjunctive agents were given before or concurrently with antivenom.No medications were documented as rescue treatments for new or worsening symptoms.Medications that could interfere with Type 1 immune response were given prior to antivenom administration occurred in two patients.One patient, mentioned above, who received a second dose of epinephrine IM along with diphenhydramine and famotidine in the emergency department after receiving an initial dose of epinephrine IM prehospital.A second patient received diphenhydramine eight minutes after arrival to the emergency department and 32 min before antivenom administration without a clearly documented indication.
There were 17 (68%) patients with Grade IV envenomation, seven (28%) patients with Grade III envenomation, and one patient was determined to have a toxic ingestion instead of a scorpion envenomation.The median patient response was not significantly different between grades of envenomation (Table 3).
Repeat dosing and total number of vials did not affect the rate of serious administration-related or non-serious/non-administration related adverse events.

Discussion
This study shows that Centruroides (Scorpion) Immune F(ab') 2 (Equine) given as a single-vial-serial dosing strategy via slow IVP may be safely administered in the treatment of scorpion envenomation in the emergency department.
Analysis by Boyer, et al. of five clinical trials with scorpion antivenom and a historical control study showed a rate of Type 1 hypersensitivity reactions of 0.1% following antivenom administration in 50 mL of normal saline intravenously over 10 min [17].A recent study of scorpion envenomation patients who called the Arizona Poison and Drug Information Center and were treated with antivenom had no immediate or delayed hypersensitivity reactions and another study by Boyer et al. also reported no anaphylactic or serum sickness reactions [12,18].This study found the administration of antivenom given as a slow IVP was comparable to previous studies as it resulted in zero Type 1 hypersensitivity reactions or development of serum sickness.Previous studies looking at adverse events other than Type 1 hypersensitivity reactions or serum sickness are lacking but Boyer et al. reported no serious adverse events and a rate of 8% of any adverse event [12].This study had a low rate of serious administration-related adverse events with 4% experiencing a study defined adverse event.The definitions for a serious administration-related adverse event in the primary outcome were intentionally stringent to capture all possible safety concerns.One patient met criteria for a serious administration-related adverse event requiring supplemental oxygen due to desaturation and also received fentanyl 1 mcg/kg.It is unclear if the desaturation was due to antivenom or adjunctive medication administration.While the rate of serious administration-related adverse events found in this study were higher than that found by Boyer et al. it is difficult to compare and identify reasons this rate may be different as detailed information related to timing of adjunctive medications is not available in the previous study [12].No other patients developed serious or non-serious administration-related or non-administration related adverse events which was lower than that found by Boyer et al. [12].Due to limitations of this study, additional studies with a larger patient population size should be conducted to confirm these findings.
In this study, only four patients required repeat dosing of antivenom with a mean number of 1.2 (SD ±0.5) vials per patient and a median time between repeat doses of 54 min (IQR: 27.5-83.5).These findings are comparable to Quan, et al. who found a mean number of 1.49 (SD ±0.64) vials and 30 to 60 min between repeat doses [5].
Furthermore, this study found a median time to resolution of symptoms of 72.5 min (IQR: 60-108.3).This finding is similar to results from Quan, et al. which showed median time to complete resolution of symptoms of 90 min (IQR: 63-124) [5].
Patients in this study received adjunctive benzodiazepines (20% vs 13.8%), anticholinergic agents, glycopyrrolate or diphenhydramine, (28% vs 3.1%), opioids (44% vs 10.8%), and ondansetron (20% vs 0%) at higher rates than those reported by Quan, et al. [5].However, rates of adjunctive agent use are not well reported in the literature and certain adjuncts, such as benzodiazepines, have been reported in as high as 81% of patients [18].Nearly all adjunctive medications in this study were given before or at the same time as the antivenom, which is consistent with treatment of the common symptoms of envenomation.None of the adjunct agents were given for new or worsening symptoms which suggests their use is not as rescue treatment.The higher rate of reported adjunctive medication use compared to Quan, et al. could be due a number of factors that may include but are not limited to: limited number of patients included in this study vs comparator studies, provider preference of initial management of the envenomation as trends in assigned provider were not analyzed, extended time interval for collection of data related to adjunctive medication use (30 min prior to and 30 min after antivenom administration was used in this study), and expansion of collection of adjunctive medication to all of those administered versus certain classes of medications [5].
For disposition following antivenom administration, all but two patients were discharged from the emergency department.The high emergency department discharge rate observed in this study is similar Coorg, et al. that showed approximately 92% of patients were discharged and Quan, et al. that reported an 87.7% discharge rate [5,19].
The grade of envenomation did not appear to affect the patient's response to antivenom.There were no significant differences in median symptom resolution time, median number of vials administered, length of stay, and rate of discharge from the ED between patients with Grade III versus Grade IV envenomations.Grade of envenomation did not appear to affect the rate of serious administrationrelated adverse events either.Repeat dosing and total number of vials did not affect the rate of serious administration-related or non-serious/nonadministration related adverse events.
All administrations of antivenom were compliant with the administration technique.
Limitations to this study include the retrospective, single-health system design which may not be applicable outside of the specific health system.This study also did not have a control group to compare to.This study was reliant on accurate and complete documentation within the EMR.There is potential for bias due to inconsistencies in clinician documentation for data.There is also a potential that documentation was incomplete and missing key points that could affect the outcome.Additionally, our sample size was small which may have limited the ability to detect differences.

Conclusion
The primary outcome of a serious administration-related adverse event occurred in one patient (4%) with a grade IV envenomation.

Table 2 .
Rate of adjunctive medication use.

Table 3 .
grade of envenomation comparison.one patient was excluded from this table for receiving antivenom without an envenomation grade and was ultimately diagnosed with a toxic ingestion instead of a scorpion envenomation. d