The Journal of Emergency Medicine, Vol. 53, No. 6, pp.

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

RESOURCE UTILIZATION AFTER SNAKEBITE SEVERITY SCORE

IMPLEMENTATION INTO TREATMENT ALGORITHM OF CROTALINE BITE
Amanda L. Fowler, PHARMD,*†‡ Darrel W. Hughes, PHARMD,*†‡§ Mark T. Muir, MD,k

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
manifestations vary considerably among patients. Current
recommendations for treatment with Crotalidae polyvalent
immune Fab require assessment of envenomation control.
Determining control of envenomation, particularly when
patients are evaluated by different providers in separate clinical
settings, can be difficult. Objective: To determine if a difference
in total vials of Crotalidae antivenin therapy exists between pre-
protocol and post-Snakebite Severity Score (SSS) protocol.
Methods: Retrospective medical record review at an academic
medical and regional Level I trauma center. Resource utilization
in patients with a diagnosis of ‘‘snakebite’’ was compared
between patients treated pre- and post-SSS protocol
implementation. Results: One hundred forty-six patients were
included in the evaluation. One hundred twenty-seven (87.0%)
patients received
antivenin, n = 80 (90.9%) in the pre-protocol group and n = 47
(81.0%) in the post-protocol group. Median total number of
antivenin vials per patient was lower in the post-protocol group
than the pre-protocol group, 16 (10–24 interquartile range) vs.
12 (10–16 interquartile range), p = 0.006. This decreased
utilization correlates to an approximate $13,200 savings per
patient. Hospital and intensive care unit length of stay, opioid
use, incidence of blood product transfusion, need for surgical
intervention, or need for intubation were not different between
groups. Conclusions: A snakebite protocol with SSS utilization
to guide antivenin administration results in significantly
decreased antivenin therapy in snakebite patients without
increase in other health care utilization. 2017 Elsevier Inc. All
rights reserved.
, Keywords—snake bite; envenomation; antivenin; clinical
pharmacy; outcomes; pharmacoeconomics
Resource Utilization After Snakebite Severity Score Treatment Algorithm
Previous presentations of the work: Fowler AL, Hughes DW,
Muir MT, VanWert EM, Gamboa CD, Myers JG. Resource
Utilization after Snakebite Treatment Protocol Implementation.
Southwest Surgical Congress. Coronado, California – April
2016.
Fowler AL, Hughes DW, Muir MT, Myers JG. Resource
Utilization after Snakebite Treatment Protocol Implementation.
Alcalde Regional Residency Leadership Conference. San
Antonio, Texas – April 2015.
Reprint Address: Darrel W. Hughes, PHARMD, Department of Pharmacy, University Health System, 4502 Medical Drive, MS 102-1, San Antonio, TX
78229
RECEIVED: 10 February 2017; FINAL SUBMISSION RECEIVED: 4 July 2017;
ACCEPTED: 30 August 2017
854
rarely fatal, with fewer than three deaths due to snakebite
reported annually in Texas since 1987 (2–4). Crotaline
envenomation clinical manifestations vary considerably
among patients. Symptoms range from local to multi-
organ system derangements and life- or limbthreatening
medical emergencies (3–6). Patients should be monitored
for compartment syndrome development in affected
limbs (4). Consumptive coagulopathies may occur,
evidenced by a prolonged international normalized ratio,
prolonged activated partial thromboplastin time,
hypofibrinogenemia, and thrombocytopenia (3–6).
Additional systemic manifestations are listed in Table 1
(3–6).
Crotalidae polyvalent immune Fab (FabAV) is
antivenin for crotaline envenomation treatment (7). The
product is purified immunoglobulin G Fab particles from
sheep inoculated with venom from four common species
in the Crotalinae subfamily (7,8). The FabAV package
insert recommends an initial four- to six-vial loading dose
for patients with moderate or severe envenomation (7).
Envenomation control, defined as 1) swelling and
tenderness not progressing, 2) prothrombin time,
fibrinogen, and platelets either normal or clearly
improving, and 3) patient hemodynamic and neurologic
stability, should be assessed within 1 h of antivenin
infusion completion. Patients should receive subsequent
loading doses until envenomation control is
accomplished. Once envenomation control is established,
a maintenance phase of two vials every 6 h for three doses
is recommended (7).
Table 1. Crotaline Snakebite Symptoms (3–8)
855
INTRODUCTION
Approximately 7000 venomous snakebites occur in
the United States annually (1). Five venomous snakes are
indigenous to Texas; however, crotaline envenomation is
The Unified Treatment Algorithm (UTA) for crotaline
snakebite management in the United States provides a
treatment guideline for managing crotaline snakebite (6).
Similar to the FabAV package insert, UTA
recommendations require provider determination of
envenomation control to direct further treatment.
Objective envenomation control evaluation is a
significant challenge in snakebite management,
particularly when patients are assessed by different
providers in separate clinical settings (e.g., emergency
department [ED] and intensive care unit [ICU]). The
Snakebite Severity Score (SSS) is an objective symptom
severity scoring tool developed and validated by Dart et
al. for the evaluation of initial severity and crotaline
envenomation progression (5). Symptoms are scored in
six categories: cardiovascular, pulmonary,
gastrointestinal, local wound, hematologic, and
neurologic (Figure 1). Total scores range from 0 to 20;
higher scores indicate greater severity. Importantly, this
score has been validated only to detect symptom
progression in an individual patient and is not used for
inter-patient comparison (5). Therefore, the SSS may be
used to objectively assess envenomation control for an
individual patient; however, no particular score indicates
antivenin therapy initiation, which should remain the
judgement of a provider.
FabAV cost presents another challenge to health
systems. Averagewholesale price (AWP) was
approximately $3300 per vial in October 2016 (9). UTA
and package insert dosing recommendations suggest
four- to six-vial loading doses, or even eight to 12 vials
for patients in
856 A. L. Fowler et al.

System Symptom (6,7). If envenomation control is not achieved, additional

loading doses are recommended. In 2010 and 2011,
Local wound
FabAV represented the largest nonchemotherapeutic,
Pain Erythema
Edema inpatient drug expenditure for our hospital system.
Compartment syndrome An internal drug utilization evaluation of FabAV use
Coagulopathy Prolonged INR between June 2011 and May 2012 identified frequent
Prolonged aPTT repeat loading doses after transition of care from ED to
Hypofibrinogenemia ICU. A snakebite protocol, developed by a
Thrombocytopenia
multidisciplinary team and approved by the Pharmacy
Gastrointestinal Nausea Vomiting
Diarrhea
and Therapeutics committee, was implemented with the
goal of optimizing appropriate FabAV use (Figure 2).
Neurologic Headache The protocol follows the UTA except that it utilizes SSS
Malaise to objectively assess envenomation control. Baseline SSS
Paresthesia
documentation into the electronic medical record (EMR)
Fasciculation
Altered mental status
is required, and used as a reference point for all providers
Cardiovascular Tachycardia Hypotension through transitions of care (Figure 2).
Dysrhythmias The study purpose was to determine the effect of
objective SSS inclusion in our institutional snakebite
Respiratory Dyspnea
protocol on FabAV therapy cost for crotaline
Tachypnea
Respiratory distress envenomations. We hypothesized that a treatment
INR = international normalized ratio; aPTT = activated partial protocol that required documentation of SSS in the EMR
thromboplastin time. would decrease overall FabAV utilization and thereby
shock or with serious active bleeding, with a six-vial decrease cost.
maintenance phase to prevent recurrence or limb swelling
Criterion Points

Pulmonary system

No symptoms/signs 0

Dyspnea, minimal chest tightness, mild or vague discomfort, or respirations of 20 – 25 breaths/minute 1

Moderate respiratory distress (tachypnea, 26 – 40 breaths/minute, accessory muscle use) 2

Cyanosis, air hunger, extreme tachypnea, or respiratory insufficiency/failure 3

Cardiovascular system

No symptoms/signs 0

Tachycardia (100 – 125 beats/minute), palpitations, generalized weakness, benign dysrhythmia, or 1

hypertension

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 within 5 – 7.5 cm of bite site 1

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

Pain, tenesmus, or nausea 1

Vomiting or diarrhea 2

Repeated vomiting, diarrhea, hematemesis, or hematochezia 3

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

fibrinogen < 50 mcg/mL

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

Central nervous system

No symptoms/signs 0

Minimal apprehension, headache, weakness, dizziness, chills, or paresthesia 1

Moderate apprehension, headache, weakness, dizziness, chills, paresthesia, confusion, or fasciculation in the 2
area of the bite

Severe confusion, lethargy, seizures, coma, psychosis, or generalized fasciculation 3

PT = prothrombin time; PTT = partial thromboplastin time

Figure 1. The Snakebite Severity Scale (SSS) (5).

858
Figure 2. Snakebite treatment protocol. SSS = Snakebite Severity Scale; ICU = intensive care unit.
METHODS
Study Design
This was a single-center retrospective evaluation of
snakebite treatment protocol. Patients treated for
snakebite from January 2010 to November 2014 were
included. SSS protocol was implemented as a process
improvement project in June 2012, and the evaluation
period provided approximately equal time periods prior
to and after protocol implementation. This evaluation was
granted institutional review board approval.
Study Setting and Population
Our hospital is a 716-bed academic medical center that
serves as an adult Level I and pediatric Level I trauma
center. Patients with a trauma registry diagnosis of
‘‘snakebite’’ were included in the evaluation. Patients
with known noncrotaline snakebites were excluded (e.g.,
coral snakebites). Medical records were reviewed by a
A. L. Fowler et al.
single emergency medicine residency-trained doctor of
pharmacy, using a standardized data collection tool.
Patients treated prior to June 21, 2012 are referred to as
the ‘‘pre-protocol group.’’ Patients treated on or after
June 21, 2012 are referred to as the ‘‘post-protocol
group.’’ Protocol violations, defined as any deviation
from the local protocol (Figure 2), were excluded from
the ‘‘post-protocol’’ group. Documentation of baseline
SSS was required prior to all initial hospital FabAV
administration; however, subsequent doses of FabAV
may have been administered without documented SSS at
the provider discretion. Repeat loading doses of FabAV
without documented SSS in the EMR were considered
protocol violation and excluded from analysis.
Study Protocol
The primary outcome was difference in total FabAV vials
used for treatment between the pre-protocol and
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.

envenomation symptom worsening when assessed based

on physician consensus. Based on the work by Dart et al.,
we employed the SSS as an objective tool to detect
clinical worsening and trigger reloading of FabAV (5).
Dart et al. also demonstrated that baseline SSS highly
correlates with patient severity at presentation (5).
However, during protocol development, our
multidisciplinary team chose to not trigger initiation of
FabAV based on an SSS, but rather, physician discretion.
Figure 3. Snake species associated with bite.

Additionally, the UTA contains a treatment pathway

where patients could potentially receive a loading dose of
FabAV without a maintenance dose. Our protocol more
closely follows FabAV package insert recommendations
to follow all loading doses with maintenance. Weant et
al. developed a FabAV treatment protocol based on
envenomation severity defined using subjective criteria
and an SSS (11,12). Evaluation of their protocol showed
a statistically significant decrease in vials used per patient
and hospital LOS (12). Patient stratification by symptom
severity, exclusion of children, and population with
slightly lower baseline SSS are important differences in
the Weant study (12). Our protocol does not provide
guidance on FabAV initiation, only course of treatment
once begun.
Resource Utilization After Snakebite Severity Score Treatment Algorithm 861

Finally, a small but significant portion of patients in
our study were treated for copperhead (Agkistrodon
contortrix) envenomation. Whereas some institutions
utilize a supportive-care-only treatment approach without
FabAV due to the generally less severe symptoms of
envenomation, our protocol left that decision up to the
provider assessing the patient. In some cases of
copperhead envenomation, patients with low SSS scores
at baseline or reassessment did not complete the
maintenance
Table 3. FabAV Utilization Outcomes in Pre- and Post-protocol Groups*
Outcome
per-protocol population; therefore, our outcomes may not
be reproduced in a real-world setting.
CONCLUSIONS
Incorporation of an objective SSS into a protocol for
crotaline snakebite management significantly decreased
antivenin therapy cost in snakebite patients. No increase
in hospital or ICU LOS, opioid use, blood product
Pre-protocol (n = 80) Post-protocol (n = 47) p Value

Cost of total FabAV therapy $34,100 (22,000–51,700) $26,400 (22,000–35,200) 0.006

Number of FabAV vials used total 16 (10–24) 12 (10–16) 0.006
Number of FabAV vials used in-hospital 12 (6–22) 10 (6–12) 0.003
Number of FabAV vials used prehospital 4 (0–6) 4 (0–6) 0.51
Morphine equivalents, mg/kg/day 16 (4–52) 16 (2–40) 0.28
Length of stay, days ICU
1 (0–3) 1 (0–2) 0.63
Total 3 (2–4) 2 (1–3) 0.06
Procedure, n (%) 5 (6.3) 3 (6.4) 1.0
Debridement, n (%) 4 (5.0) 2 (4.3) 1.0
Fasciotomy, n (%) 1 (1.3) 0 (0) 1.0
Intubation, n (%) 1 (1.3) 1 (2.1) 1.0
Fresh frozen plasma, n (%) 2 (2.5) 1 (2.1) 0.71
Units 2 (1–2) 6 (4–7) 0.25
Platelets, n (%) 1 (1.3) 0 (0) 1.0
Units 2 –

Cryoprecipitate, n (%) 3 (3.8) 2 (4.3) 1.0

Units 5 (5–20) 25 (10–40) 0.37
FabAV = Crotalidae polyvalent immune Fab; ICU = intensive care unit.
* All data reported as median and interquartile range unless otherwise noted.
phase of therapy. Although previous literature suggests transfusion, surgical intervention, or intubation was
that copperhead envenomation is less severe, our baseline observed. Further investigation of SSS integration into
SSS for copperheads was not different than for the UTA is warranted.
rattlesnakes. Sensitivity analysis of our primary outcome,
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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.