Selected Topics: Toxicology
Selected Topics: Toxicology
Selected Topics: Toxicology
854–861, 2017
2017 Elsevier Inc. All rights reserved. 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2017.08.095
Selected Topics:
Toxicology
Elizabeth M. VanWert, PHARMD,{ Conrado D. Gamboa, BS,*†‡ and John G. Myers, MDk
*Department of Pharmacy, University Health System, San Antonio, Texas, †Pharmacotherapy Division, the University of Texas at Austin
College of Pharmacy, Austin, Texas, ‡Pharmacotherapy Education and Research Center, the University of Texas Health Science Center at San
Antonio, San Antonio, Texas, §Department of Emergency Medicine, the University of Texas Health Science Center at San Antonio, San
Antonio, Texas, kDepartment of Trauma and Emergency Surgery, the University of Texas Health Science Center at San Antonio, San Antonio,
Texas, and {Department of Pharmacy, University of Michigan Health System, Ann Arbor, Michigan
, Abstract—Background: Crotaline envenomation clinical antivenin, n = 80 (90.9%) in the pre-protocol group and n = 47
manifestations vary considerably among patients. Current (81.0%) in the post-protocol group. Median total number of
recommendations for treatment with Crotalidae polyvalent antivenin vials per patient was lower in the post-protocol group
immune Fab require assessment of envenomation control. than the pre-protocol group, 16 (10–24 interquartile range) vs.
Determining control of envenomation, particularly when 12 (10–16 interquartile range), p = 0.006. This decreased
patients are evaluated by different providers in separate clinical utilization correlates to an approximate $13,200 savings per
settings, can be difficult. Objective: To determine if a difference patient. Hospital and intensive care unit length of stay, opioid
in total vials of Crotalidae antivenin therapy exists between pre- use, incidence of blood product transfusion, need for surgical
protocol and post-Snakebite Severity Score (SSS) protocol. intervention, or need for intubation were not different between
Methods: Retrospective medical record review at an academic groups. Conclusions: A snakebite protocol with SSS utilization
medical and regional Level I trauma center. Resource utilization to guide antivenin administration results in significantly
in patients with a diagnosis of ‘‘snakebite’’ was compared decreased antivenin therapy in snakebite patients without
between patients treated pre- and post-SSS protocol increase in other health care utilization. 2017 Elsevier Inc. All
implementation. Results: One hundred forty-six patients were
rights reserved.
included in the evaluation. One hundred twenty-seven (87.0%)
patients received
, Keywords—snake bite; envenomation; antivenin; clinical
pharmacy; outcomes; pharmacoeconomics
Resource Utilization After Snakebite Severity Score Treatment Algorithm 855
854
rarely fatal, with fewer than three deaths due to snakebite The Unified Treatment Algorithm (UTA) for crotaline
reported annually in Texas since 1987 (2–4). Crotaline snakebite management in the United States provides a
envenomation clinical manifestations vary considerably treatment guideline for managing crotaline snakebite (6).
among patients. Symptoms range from local to multi- Similar to the FabAV package insert, UTA
organ system derangements and life- or limbthreatening recommendations require provider determination of
medical emergencies (3–6). Patients should be monitored envenomation control to direct further treatment.
for compartment syndrome development in affected Objective envenomation control evaluation is a
limbs (4). Consumptive coagulopathies may occur, significant challenge in snakebite management,
evidenced by a prolonged international normalized ratio, particularly when patients are assessed by different
prolonged activated partial thromboplastin time, providers in separate clinical settings (e.g., emergency
hypofibrinogenemia, and thrombocytopenia (3–6). department [ED] and intensive care unit [ICU]). The
Additional systemic manifestations are listed in Table 1 Snakebite Severity Score (SSS) is an objective symptom
(3–6). severity scoring tool developed and validated by Dart et
Crotalidae polyvalent immune Fab (FabAV) is al. for the evaluation of initial severity and crotaline
antivenin for crotaline envenomation treatment (7). The envenomation progression (5). Symptoms are scored in
product is purified immunoglobulin G Fab particles from six categories: cardiovascular, pulmonary,
sheep inoculated with venom from four common species gastrointestinal, local wound, hematologic, and
in the Crotalinae subfamily (7,8). The FabAV package neurologic (Figure 1). Total scores range from 0 to 20;
insert recommends an initial four- to six-vial loading dose higher scores indicate greater severity. Importantly, this
for patients with moderate or severe envenomation (7). score has been validated only to detect symptom
Envenomation control, defined as 1) swelling and progression in an individual patient and is not used for
tenderness not progressing, 2) prothrombin time, inter-patient comparison (5). Therefore, the SSS may be
fibrinogen, and platelets either normal or clearly used to objectively assess envenomation control for an
improving, and 3) patient hemodynamic and neurologic individual patient; however, no particular score indicates
stability, should be assessed within 1 h of antivenin antivenin therapy initiation, which should remain the
infusion completion. Patients should receive subsequent judgement of a provider.
loading doses until envenomation control is FabAV cost presents another challenge to health
accomplished. Once envenomation control is established, systems. Averagewholesale price (AWP) was
a maintenance phase of two vials every 6 h for three doses approximately $3300 per vial in October 2016 (9). UTA
is recommended (7). and package insert dosing recommendations suggest
four- to six-vial loading doses, or even eight to 12 vials
for patients in
Table 1. Crotaline Snakebite Symptoms (3–8)
856 A. L. Fowler et al.
Pulmonary system
No symptoms/signs 0
Cardiovascular system
No symptoms/signs 0
Tachycardia (126 – 175 beats/minute) or hypotension with systolic blood pressure > 100 mm Hg 2
Extreme tachycardia (>175 beats/minute), hypotension with systolic blood pressure < 100 mm Hg, malignant 3
dysrhythmia, or cardiac arrest
Local wound
No symptoms/signs 0
Pain, swelling, or ecchymosis involving less than half the extremity (7.5 – 50 cm from bite site) 2
Pain, swelling, or ecchymosis involving half to all of extremity (50 – 100 cm from bite site) 3
Resource Utilization After Snakebite Severity Score Treatment Algorithm 857
Pain, swelling, or ecchymosis extending beyond affected extremity (more than 100 cm from bite site) 4
Gastrointestinal system
No symptoms/signs 0
Vomiting or diarrhea 2
Hematologic system
No symptoms/signs 0
Coagulation parameters slightly abnormal: PT < 20 sec; PTT < 50 sec; platelets 100,000 – 150,000/mL; or 1
fibrinogen 155 – 150 mcg/mL
Coagulation parameters abnormal: PT < 20 – 50 sec; PTT < 50 – 75 sec; platelets 50,000 – 100,000/mL; or 2
fibrinogen 50 – 100 mcg/mL
Coagulation parameters abnormal: PT < 50 – 100 sec; PTT < 75 – 100 sec; platelets 20,000 – 50,000/mL; or 3
Coagulation parameters markedly abnormal, with serious bleeding or the threat of spontaneous bleeding; 4
unmeasurable PT or PTT; platelets < 20,000/mL; undetectable fibrinogen; or severe abnormalities of other
laboratory values
No symptoms/signs 0
Moderate apprehension, headache, weakness, dizziness, chills, paresthesia, confusion, or fasciculation in the 2
area of the bite
Figure 2. Snakebite treatment protocol. SSS = Snakebite Severity Scale; ICU = intensive care unit.
METHODS single emergency medicine residency-trained doctor of
pharmacy, using a standardized data collection tool.
Study Design
Patients treated prior to June 21, 2012 are referred to as
This was a single-center retrospective evaluation of the ‘‘pre-protocol group.’’ Patients treated on or after
snakebite treatment protocol. Patients treated for June 21, 2012 are referred to as the ‘‘post-protocol
snakebite from January 2010 to November 2014 were group.’’ Protocol violations, defined as any deviation
included. SSS protocol was implemented as a process from the local protocol (Figure 2), were excluded from
improvement project in June 2012, and the evaluation the ‘‘post-protocol’’ group. Documentation of baseline
period provided approximately equal time periods prior SSS was required prior to all initial hospital FabAV
to and after protocol implementation. This evaluation was administration; however, subsequent doses of FabAV
granted institutional review board approval. may have been administered without documented SSS at
the provider discretion. Repeat loading doses of FabAV
Study Setting and Population without documented SSS in the EMR were considered
protocol violation and excluded from analysis.
Our hospital is a 716-bed academic medical center that
serves as an adult Level I and pediatric Level I trauma Study Protocol
center. Patients with a trauma registry diagnosis of
‘‘snakebite’’ were included in the evaluation. Patients The primary outcome was difference in total FabAV vials
with known noncrotaline snakebites were excluded (e.g., used for treatment between the pre-protocol and
coral snakebites). Medical records were reviewed by a postprotocol groups. ‘‘In-hospital treatment’’ includes
Resource Utilization After Snakebite Severity Score Treatment Algorithm 859
FabAV vials received in the ED and during the in-patient 24 interquartile range) vs. 12 (10–16 interquartile range),
stay. ‘‘Total treatment’’ includes FabAV vials received p = 0.006 (Table 3). This decreased utilization correlates
during prehospital and in-hospital treatment. Secondary to an approximate $13,200 savings per patient, $52,800
outcomes included total cost of FabAV, hospital and ICU (33,000–79,200) vs. $39,600 (33,000–52800), p <
length of stay (LOS), total opioid use, blood product 0.0001. Hospital and ICU LOS, opioid use, incidence of
transfusions, need for surgical intervention, need for blood product transfusion, need for surgical interven-
intubation, and allergic reaction incidence. LOS was Table 2. Baseline Characteristics
analyzed as ICU LOS and as total LOS. Total LOS Pre-protocol (n Post-protocol
included the ED LOS and hospital LOS. Opiate usage = 88) (n = 58)
Characteristic
was converted to intravenous morphine equivalents (10-
Male gender, n (%) 57 (64.8) 43 (74.1)
mg i.v. morphine = 1.5 mg i.v. hydromorphone = 100 mg
Age, years: median (IQR) 36 (21–51) 40 (24–52)
i.v. fentanyl) (10). Allergic reactions were defined as any
Race, ethnicity: n (%) White,
incident labeled as an allergic reaction in the EMR that Hispanic 43 (48.9) 30 (51.7)
caused discontinuation of therapy. FabAV costs were White, non-Hispanic 42 (47.7) 27 (46.6)
calculated using AWPat the time of writing this Baseline SSS, median (IQR) 3 (2–4) 3 (2–4)
manuscript. Bite site, n (%)* Lower
extremity 46 (52.3) 21 (36.2)
Data Analysis Hand 38 (43.2) 37 (63.8)
Upper extremity 4 (4.6) 0 (0)
Data were analyzed using JMP 11.0.0 (Copyright 2013, Received antivenin, n (%) 80 (90.9) 47 (81.0)
SAS Institute, Cary, NC). Continuous variables were IQR = interquartile range; SSS = snakebite severity score. There was no
tested for normality and reported as mean 6 standard statistically significant difference between groups for any baseline
deviation, and median and interquartile range characteristic. * p = 0.05.
appropriately. The c2 or Fisher’s exact test were used to
compare nominal data. Alpha level of # 0.05 was used to
determine statistical significance for all comparisons. tion, and need for intubation were not different between
groups. Rates of allergic reactions were low overall (8/
RESULTS 146 patients, 5.6%) and similar between groups: 3.5% vs.
There were 182 patients who met criteria identified in the 5.6% for the pre- and post-protocol groups, p = 0.72.
trauma registry. Six patients were excluded due to bites DISCUSSION
by coral snakes. Three patients were excluded due to
miscoding. Twenty-seven were excluded for protocol Our institution developed a protocol that required
violation. Reasons for protocol violation were repeat objective SSS documentation in the EMR, with dosing
loading dose without documented increase in SSS (15/ 27 recommendations as a solution for excessive use of
patients, 56%), incomplete maintenance courses (6/ 27 FabAV. This study evaluated protocol modification on
patients, 22%) and prolonged maintenance courses (6/27 FabAV utilization. We were able to demonstrate a
patients, 22%). In total, 146 patients were analyzed, 88 in statistically significant difference in total FabAV vials
the pre-protocol and 58 in the post-protocol groups. per patient between pre- and post-protocol groups.
Demographics, bite location, baseline SSS, and FabAV acquisition cost throughout the study period was
percentage of patients treated with FabAV are unavailable to the authors. Applying the current AWP
summarized in Table 2. Most patients were White and decreased usage amounts to an estimated savings of
male, with a median age of 38 years. Twenty-four of 146 $13,200 per patient (9). Absence of difference observed
patients (16%) were < 18 years old. Approximately half in LOS, opioid utilization, and other resource utilization
of snakebites occurred on a hand or upper extremity, and implies the decrease in FabAV treatment was not
the other half occurred on a lower extremity. Eighty associated with poorer outcomes.
patients (91%) in the pre-protocol and 47 (81%) in the Our protocol differed from the UTA via SSS use to
postprotocol group received FabAV. Rattlesnakes were objectively assess envenomation control. The SSS was
the predominant species reported (Figure 3). developed and validated by Dart et al. to have high
The decrease in median total number of FabAV vials correlation to physician assessment of envenomation
administered per patient between the pre-protocol and severity at baseline and at the point of worst condition (5).
post-protocol group was statistically significant; 16 (10– In addition, the SSS had high sensitivity for detecting
860 A. L. Fowler et al.
Finally, a small but significant portion of patients in per-protocol population; therefore, our outcomes may not
our study were treated for copperhead (Agkistrodon be reproduced in a real-world setting.
contortrix) envenomation. Whereas some institutions
utilize a supportive-care-only treatment approach without CONCLUSIONS
FabAV due to the generally less severe symptoms of
envenomation, our protocol left that decision up to the Incorporation of an objective SSS into a protocol for
provider assessing the patient. In some cases of crotaline snakebite management significantly decreased
copperhead envenomation, patients with low SSS scores antivenin therapy cost in snakebite patients. No increase
at baseline or reassessment did not complete the in hospital or ICU LOS, opioid use, blood product
maintenance
Table 3. FabAV Utilization Outcomes in Pre- and Post-protocol Groups*
Outcome Pre-protocol (n = 80) Post-protocol (n = 47) p Value
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ARTICLE SUMMARY
1. Why is this topic important?CroFab is expensive!
2. What does this study attempt to show?
The Snakebite Severity Scale can facilitate objective
assessment of envenomation control, and communication
thereof among providers, which leads to decreased
resource utilization.
3. What are the key findings?
There was decreased resource utilization with this
strategy.
4. How is patient care impacted?
There was no difference observed in efficacy outcomes,
and it was cheaper for the patient and the health system.