Intraosseous vs. Intravenous Vancomycin Administration in Total Shoulder Arthroplasty: Changing the Paradigm
Phase: PHASE4
Conditions: Shoulder Injuries
Sponsor: The Methodist Hospital Research Institute

PROTOCOL TITLE: Intraosseous vs. Intravenous Vancomycin Administration in Total 
Shoulder Arthroplasty: Changing the Paradigm 
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PROTOCOL TITLE:  
Intraosseous vs. Intravenous Vancomycin Administration in Total Shoulder Arthroplasty: 
Changing the Paradigm  
 
PRINCIPAL INVESTIGATOR  
Patrick McCulloch, MD 
HMH Orthopedics & Sports Medicine  
 
CO-INVESTIGATORS/ COLLABORATORS: 
Kwan Park, MD / HMH Orthopedics & Sports Medicine  
Francesca Taraballi, PhD / Houston Methodist Research Institute 
 
SPONSOR / FUNDING AGENCY  
Houston Methodist Hospital 
 
VERSION NUMBER/DATE  
Version 3 – Aug. 31, 2023 
REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change 
(Yes/No) 
1 
3/7/23 
The addition of tissue types for sample collection  
Yes 
2 
6/1/23 
The removal of Kendra Ihaza from the study team, 
the addition of Blesson Varghese to the study 
team, clarification to the exclusion criteria  
No 
3 
8/31/23 
Update 1: Correction of Protocol and ICF version 
history. Version 2 of the Protocol and ICF were 
approved via Mod00006367 on 6/1/23 with 
updates to the protocol and ICF. The documents 
were updated and have been the only documents 
used to enroll subjects thus far. However, it was 
noticed that the version numbers were not 
updated on the documents at that time.  
 
Update 2: Clarification of inclusion criteria 
definition in protocol and screening document  
Change 1: Yes, the 
date 
 
Change 2: No 
 
 
 
 
 
 
 
 

PROTOCOL TITLE: Intraosseous vs. Intravenous Vancomycin Administration in Total 
Shoulder Arthroplasty: Changing the Paradigm 
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1. Purpose of the Study / Objectives  
 
The purpose of this study is to compare two different antibiotic regimens and techniques 
during total shoulder arthroplasty.  
 
Primary Objective: Comparable levels of vancomycin will be found in bone, soft tissue, 
and systemic samples between patient groups. 
 
Secondary Objective: Compare 30 day and 90 day post-operative complication rates 
(infection) between the control (standard IV administration of vancomycin) vs the 
interventional group (intraosseous administration of vancomycin). The investigators 
hypothesize that there will be no difference in complication (infection) rates between 
groups. 
2. Background 
 
Primary total shoulder arthroplasty (TSA) is a common orthopedic procedure whose 
volume is expected to rapidly increase over the next decade [3]. During TSA, surgeons 
can choose to utilize anatomic (aTSA) or reverse (RSA) to remove arthritic articular 
surfaces and insert metal & polyethylene components. Vancomycin is commonly used as 
a prophylactic antibiotic for total shoulder surgery in an attempt to protect against 
methicillin resistant staph aureus (MRSA). Recent literature has suggested that 
intraosseous (IO) infusions are capable of providing equivalent systemic values to those 
administered via intravenous (IV) access [3,4]. Because of these findings, some began to 
consider that IO infusions could be a better way to administer prophylactic surgical 
antibiotics. IO has also recently been shown to significantly reduce periprosthetic joint 
infection (PJI) in total knee arthroplasty (TKA) [9,10]. This difference is presumably due to 
the increased concentrations of vancomycin present in bone and soft tissue samples in IO 
treated patients compared to the standard of care intravenous (IV) vancomycin treated 
patients [11,12]. Additionally, research has shown significant vancomycin concentration 
differences present even with limited tourniquet use during TKA [13]. Furthermore, 
preliminary data on IO injections in total hip arthroplasty have also been shown to 
provide equal or superior vancomycin concentrations in both bone and soft tissue 
samples while maintaining significantly lower systemic vancomycin levels in the IO group 
when compared to the IV group. To date, no protocol exists for the use of IO in total 
shoulder arthroplasty.  
3. Study Design 
 
This study is a prospective, randomized, single-blinded, controlled trial. 20 patients in 
each treatment arm: 20 patients will be given IV vancomycin, 20 patients will be given IO 

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Shoulder Arthroplasty: Changing the Paradigm 
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vancomycin. This sample size is based on previous studies examining vancomycin 
concentration in tourniquetless primary total knee arthroplasty between IO vs IV [12,13].  
 
Once the participant has been enrolled, they will be randomized into either the control group or 
the experimental group by an excel-based software program prior to their procedure. 
 
 
Control – Standard IV administration of vancomycin 
 Patients will receive the Houston Methodist Hospital orthopedic surgeon’s standard of 
care pre-operative antibiotic regimen for primary total shoulder arthroplasty patients. 
This includes IV abx (typically ancef or cefepime and vancomycin) will be started in the 
pre-operative period approximately 1 hour prior to incision (vancomycin dose weight-
based at approximately 15mg/kg [6,7] generally 1000-1750mg in 500mL NS). 
 
Intervention – Intraosseous (IO) administration of vancomycin 
 IV antibiotics (per physician’s standard of care): Typically ancef or cefepime is started in 
pre-op within 1 hour of incision 
 IO vancomycin is administered in the OR after sterile prep and draping has occurred 
(500mg in 100-150mL NS). 
 Injection will take place into the proximal humerus  
 
 
All patients in both groups will be monitored during the surgery and immediately post-
operatively for adverse injection reactions (i.e. Red Man Syndrome) as this is the 
standard of care. 
 
All patients (IV and IO) will otherwise follow identical post-operative protocols (including 
post-operative antibiotic administration) 
 
Intra-Op Sample Collection 
Samples will be taken from the following locations at the following times: 
o Systemic Sample – Start of Case 
 A vancomycin blood level will be drawn by the anesthesiologist staff 
(CRNA, MD) at the start of skin incision prior to any other samples being 
taken. 
o Soft tissue sample – Deltoid muscle at Start 
 A small sample will be taken from the edge of the deltoid muscle 
o  Soft tissue sample – Biceps tendon 
 A portion of the excised biceps tendon will be sent. This sample will only 
be taken if it is readily available for the surgeon to gather. 
o Bone Sample – Bone from Humeral Head 

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 After the humeral neck is cut with the “cookie cutter” instrument a 
portion of humeral head/neck will be removed and placed in a separate 
specimen jar (remainder of head will be sent to pathology as usual). 
o Soft tissue sample – Synovium/Capsule 
 A small soft tissue sample will be taken from the synovium upon entering 
the shoulder joint.  
o Soft Tissue Sample – Labrum 
 A small soft tissue sample will be taken from the glenoid labrum. 
o Bone Sample- Glenoid reaming 
 Reaming fragments from the glenoid will be collected. 
o Soft tissue sample- Deltoid muscle at the End 
 A small sample of the deltoid muscle will again be taken prior to closure.  
o Systemic Sample 
 A vancomycin blood level will be drawn by the anesthesiologist staff 
(CRNA, MD) at the time of initiation of closure and should occur 
simultaneously with the final soft tissue sample collection above   
  
Data Variables to be Recorded 
Age (calculated from DOB), date of surgery, discharge date, sex, laterality, study group, 
pre-op creatinine, post-op creatinine, systemic vancomycin level at incision, soft tissue 
vancomycin level (synovium start and synovium end), humeral head bone sample 
vancomycin level, and systemic vancomycin level at initiation of wound closure. 
Additionally, adverse local/systemic reactions as determined from patient’s chart, 30-day 
complications, 90-day complications, cost, time from antibiotic administration to incision, 
operative time, and incision time.  
 
Statistical Plan and Power Analysis 
 
Not yet published data from 20 participants from a recent study in our lab utilizing IO 
vancomycin vs IV vancomycin in a primary total hip arthroplasty (THA). Our research team found 
that there were significant differences for serum vancomycin levels (ug/mL) at the start of the 
procedure: IO =0, IV = 28.0 ± 6.1, p<0.001; and at closure: IO = 5.8 ± 1.0, IV 21.0 ± 2.5, p<.001. A 
significant difference was also present for acetabular bone: IO = 130.9 ± 14.4, IV = 68.0 ± 7.9, 
p=0.001. IO also resulted in higher, but not statistically significant, tissue levels in all other 
samples: IM bone 59.4 ± 9.0 vs 33.9 ± 8.5 (p=.05), femoral head 41.5 ± 9.5 vs 20.9 ± 6.9 (p=0.1), 
and pulvinar soft tissue 71.8 ± 18.2 vs 61.6 ± 17.6 (p=0.7). 
 
Based on previous data from our laboratory using IO vancomycin in total hip arthroplasty along 
with other previous reports [11-13] using very similar procedures, for a minimum detectable 
difference between techniques (IO vs IV) of 30 μg/mL for surgical site bone concentrations of 
vancomycin with a power of 0.8 (α=0.05), a minimum total of 14 patients per group (total 28) 
will be required. Therefore, we will elect to recruit a total of 20 patients per group to account for 
potential dropouts. 

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Shoulder Arthroplasty: Changing the Paradigm 
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The statistical model for this investigation will be a mixed model analysis of covariance with 
repeated measures, co-varied on BMI, gender, length of surgical procedure, time of vancomycin 
administration, and amount of vancomycin administered. If none of the covariates are significant 
then two sample t-tests will be used to compare the concentration levels between the 2 groups 
at each sample point including bone, soft tissue, and systemic samples. We will not make any 
comparisons between different sample types only comparing groups within the same sample 
type.  Potential demographic differences between groups will be measured using two sample t-
tests for numerical data and Chi-Square tests (or Fischer’s exact tests in cases where sample 
sizes are <5). Additionally, 30-day and 90-day wound healing and potential infection 
complications will be analyzed by Chi-Square tests or in cases where sample sizes are <5 
Fischer’s exact tests will be used. 
 
4. Study Intervention  
 
All research procedures include the intra-operative sample collections (tissue, bone, and 
systemic blood sample). If the patient is randomized into the interventional group (IO 
injection of vancomycin) then instead of receiving pre-operative IV vancomycin they will 
receive it intraoperatively through IO injection. These are the only changes to the 
patient’s care during their hospital stay. All other pre-operative and post-operative care 
will be standard of care including pre-operative, peri-operative, and post-operative 
monitoring. There will be no additional study visits and the anticipated time the subject 
will be in the study is 90 days. The research anticipates it will take 1 year to enroll all 
study subjects and for investigators to complete primary analyses. The study will not 
require any additional research clinical visits and will not interfere with the patient’s 
normal postoperative standard of care.  
 
The estimated amount of time for each subject to participate in this project would be 
approximately 20 minutes for the informed consent process. All patients in both groups 
will be monitored during the surgery and post-operatively for adverse injection reactions 
(i.e. Red Man Syndrome) as this is the standard of care. Additionally, patient medical 
record (Epic) will be monitored for 90 days after their surgery for differences in rate of 
infection and/or wound complications. Patients will follow their normal standard of care 
postoperative clinic visits where the patient will be examined for signs of infection as is 
the standard of care.  
5. Drugs, Biologics, Devices  
 
1) The drug product (Vancomycin) is lawfully marketed in the United States. Vancomycin is 
a very commonly used antibiotic in orthopedic surgery. 

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Shoulder Arthroplasty: Changing the Paradigm 
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2) This investigation is not intended to be reported to the FDA as a well controlled study for 
a new indication and there is no intent to use it or support it for significant changes in 
labeling of the drug. 
3) This investigation is not intended to support a significant change in advertising for the 
drug. 
4) There is not a disproportionate increase in risk present for changing the route of 
administration in the interventional arm (IO injection). The cited studies in Section 2 of 
the protocol all used 500mg in normal saline as the normal dosage when utilizing IO 
injection in orthopedic surgery; this is a lower dosage than SOC. All of these studies have 
shown that there is either higher or equal tissue concentrations in the IO injection 
groups. 
5) This investigation is conducted in compliance with the requirements for review by an IRB 
with the requirements for informed consent. 
6. Collaborative / Multi-site Research 
 
N/A 
7. Data Privacy / Confidentiality  
 
Houston Methodist policies for Protected Health Information will be followed, including all 
requirements for physical and electronic data security, use of encrypted devices and HM 
password protected servers. All data for this study will be complete, accurate, original, and 
legible. All physical study data such as data recorded in the intra-operative sample collection 
sheet will be stored in a locked office cabinet of a qualified member of the research team. All 
electronic data will be password protected and only accessible by members of the research 
team. The data for this study will be maintained indefinitely. Any data that is published from 
this study will be completely de-identified including the removal of any PHI. 
 
The only PHI being used by the research team for this study are dates including discharge 
dates and birth date (to determine age at time of surgery) as well as MRNs. The use of 
identifiable data is necessary for the research team to confirm past medical history (example: 
Diabetes) for the inclusion/exclusion criteria. No PHI will ever be disclosed beyond Houston 
Methodist. This data will be stored along with other data recorded from Epic on password 
protected servers accessible only to qualified members of the research team. 
 
 
 
Identifier (or parts of)  
Recorded Disclosed 
Comment 
Names 
Yes 
No 
Recorded prior to any 
recruitment method. Needed 
so that qualified members of 
the research team can 

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Shoulder Arthroplasty: Changing the Paradigm 
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properly address the patient 
to inform them about the 
study. 
All elements of dates (except year) for dates 
directly related to an individual, including 
birth date, admission date, discharge date, 
date of death; and all ages over 89 and 
elements of dates (including year) indicative 
of such age 
Yes 
No 
Recording birth date to 
determine age at time of 
surgery. Recording surgery 
date of surgery as well. 
Phone numbers; Fax numbers 
Yes 
No 
For recruitment purposes. 
However, the informed 
consent for this study will 
only take place in person 
with a qualified member of 
the research team. 
Medical record numbers 
Yes 
No 
Necessary to confirm past 
medical history during the 
screening process. 
 
8. Data and Specimen Banking  
 
N/A 
9. Study Population  
 
We will enroll 40 patients.  
 
Inclusion Criteria 
 Patient is undergoing anatomic or reverse shoulder arthroplasty 
 Patient is able to give informed consent to participate on the study. LAR consents will 
not be utilized for this study 
 Age Range >18 
 
      Exclusion Criteria 
 Previous shoulder surgery if surgeon deems it will affect the study   
 BMI above 35  
 Contraindication to receiving vancomycin, cefepime, ancef, or other standard of care 
pre-operative antibiotic (allergy, medical issue, etc). 
 Inability to administer the IO infusion 
 Refusal to participate 
 Diabetes as defined as uncontrolled A1C > 7.5 and eGFR <59 

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Shoulder Arthroplasty: Changing the Paradigm 
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 Immunocompromised or immunosuppressed patients (HIV, Hep C, ESRD, dialysis, 
transplant, chemo/radiation treatment in last 6 months, medications) 
10. 
Screening and Recruitment S R 
 
 
Potential study patients will be identified by the research team prior to their surgery date by 
looking at Dr. McCulloch’s surgery schedules searching for primary total shoulder 
arthroplasty surgeries. The potential study patient’s medical records will then be viewed in 
Epic to identify and confirm inclusion and exclusion criteria including age >18, past surgical 
history on the operative shoulder, BMI level, any contraindication to receiving vancomycin, 
cefepime, or ancef such as allergy, diabetes, and immunocompromised or 
immunosuppressed status. If the patient meets the initial criteria to participate in the study 
then a qualified member of the research team will email or call the patient to inform them 
about the study and determine if they are interested in possibly participating. Alternatively, 
the recruitment process may also take place in clinic (6445 Main Street Houston, Texas 
77030) after the patient’s visit with their physician. In either scenario, meaning 
phone/email/or in person recruitment, potential study patients will be screened for inclusion 
and exclusion criteria prior to the informed consent. The informed consent will take place in 
person with a qualified member of the research team where the patient will be informed 
about all aspects of the research study to determine if they wish to participate. 
 
Sensitive information such as history of HIV will be asked during the screening process. 
Should a patient admit to that history and consequently be excluded from the study the 
screening document will immediately be disposed of in a HIPAA bin to later be shredded. Any 
data from that patient prior to inclusion in the study will be deleted except for their name 
and “EXCLUDED FROM PARTICIPATION” in the dataset. It is important to note that screening 
data will not be collected from email and will only be done either in person or over the 
phone. 
 
11. 
Withdrawal of Subjects 
 
Subject reserve the right to withdraw from the study at any given time. All risks will be 
outlined with the subject during the consent process (see Risks section for more details). The 
research team reserves the right to remove a subject from the study if they deem necessary 
for reasons such as but not limited to: the subject fails to comply with the study, the 
participant no longer meets inclusion criteria, the physician feels it unsafe for the participant 
to continue.   
12. 
Provisions to Protect the Privacy Interests of Subjects  
 

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Shoulder Arthroplasty: Changing the Paradigm 
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Only members of the research team will screen the patient data, speak with the patient and 
have access to their information. If requested, the team member providing the consent will 
cover each research team member and their role in the study with the subject. It will also be 
explained that all data is de-identified and stored on password protected servers only 
accessed by said team members.   
13. 
Risks to Subjects 
 
- 
Local tissue reaction to injection 
- 
Damage to the proximal humerus (i.e. fracture) – minimal  
- 
Hardware damage (i.e. needle breakage, etc). 
 
No patients develop a therapeutic level of vancomycin after a single dose (1g dose) so the 
risk for overdosing despite infusion times is minimal if not non-existent [14] 
 
Research has also shown that patients receiving rapid infusions of vancomycin in critically ill 
patients showed that even those who developed RedMan syndrome did not develop vital 
organ hypoperfusion and maintained hemodynamic pressure. RedMan was resolved with 
anti-histamine medications [15]. 
 
14. 
Potential Benefits  
 
Periprosthetic joint infection (PJI) is a devastating complication after total shoulder 
arthroplasty (TSA) with rates estimated between .4 to 2.9% [2-4]. PJI significantly increases 
the all-cause mortality rate of TSA patients when compared to comparable patient 
populations [5]. Additionally, PJI is a large economic burden for TSA patients [6]. Therefore, 
reducing the incidence of PJI in TSA is important. Intraosseous injections (IO) have recently 
been shown to significantly reduce PJI in total knee arthroplasty (TKA) [7,8]. The dose of 
vancomycin in IO administration is lower than that of IV administration (500mg in IO vs. 
1000-1750mg in IV). This may reduce the risk of systemic side effects such as PJI while 
providing equal or enhanced prophylaxis in TSA. 
 
15. 
Financial and Economic Issues  
 
The subject will not incur any costs nor will they receive payment for participation in this 
study. Patients will not be charged for systemic vancomycin level testing or for vancomycin 
concentration sampling of bone and soft tissue. These costs will be covered by the research 
team. 
16. 
Data Safety Plan  
 

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Shoulder Arthroplasty: Changing the Paradigm 
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All PHI and data will be de-identified and stored on a Houston Methodist password protected 
server only accessed by the approved study team members.  
 Each subject’s data will be evaluated at each study visit to examine both harms and 
benefits to ensure the subject remains safe 
 If at any point before or during the study a patient meets 1 or more of the exclusion 
criteria listed in section 9 of the protocol, they will be immediately suspended from 
the study  
 No adverse events are expected. However, if an unanticipated problem should occur 
it will be properly documented on either a deviation log or adverse event log with 
immediate reporting accordingly.  
 
17. 
Informed Consent Documentation and Process  
 
Once a subject has met all inclusion criteria and expressed interest in participating in the 
study, a research team member will cover the consent form with the patient in its entirety. 
This will be done in person at either the initial clinic visit or pre-op visit. All risks and potential 
side effects and benefits of participating in this study will be thoroughly explained until the 
subject fully comprehends all aspects of the study. They will then be asked to sign the 
consent form. It will be made known that the subject still reserves the right to withdraw from 
the study at any given point. The research team will not recruit from any vulnerable 
populations.   
 
18. 
Waiver of Informed Consent and /or Authorization  
 
Not applicable. Preliminary screening will only take place with patients seen within the 
Orthopedic Surgery department at Houston Methodist Hospital. There will be no waiver of 
informed consent for this study.  
 
19. 
References 
 
1. Strandberg G, Larsson A, Lipcsey M, Michalek J, Eriksson M. Intraosseous and intravenous 
administration of antibiotics yields comparable plasma concentrations during 
experimental septic shock. Acta Anaesthesiol Scand. 2015 Mar; 59(3): 346–353.  
 
2. Jaimovich DG, Kumar A, Francom S. Evaluation of intraosseous vs intravenous antibiotic 
levels in a porcine model. Am J Dis Child. 1991 Aug;145(8):946-9. 
 
3. Wagner ER, Farley KX, Higgins I, Wilson JM, Daly CA, Gottschalk MB. The incidence of 
shoulder arthroplasty: rise and future projections compared with hip and knee 

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Shoulder Arthroplasty: Changing the Paradigm 
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arthroplasty. J Shoulder Elbow Surg. 2020 Dec;29(12):2601-2609. doi: 
10.1016/j.jse.2020.03.049. Epub 2020 Jun 9. PMID: 33190759. 
 
4. Padegimas EM, Maltenfort M, Ramsey ML, Williams GR, Parvizi J, Namdari S. 
Periprosthetic shoulder infection in the United States: incidence and economic burden. J 
Shoulder Elbow Surg. 2015 May;24(5):741-6. doi: 10.1016/j.jse.2014.11.044. Epub 2015 
Jan 13. PMID: 25595360. 
 
5. Bonnevialle N, Dauzères F, Toulemonde J, Elia F, Laffosse JM, Mansat P. Periprosthetic 
shoulder infection: an overview. EFORT Open Rev. 2017 Apr 27;2(4):104-109. doi: 
10.1302/2058-5241.2.160023. PMID: 28507783; PMCID: PMC5420823. 
 
6. Kunutsor SK, Wylde V, Beswick AD, Whitehouse MR, Blom AW. One- and two-stage 
surgical revision of infected shoulder prostheses following arthroplasty surgery: A 
systematic review and meta-analysis. Sci Rep. 2019 Jan 18;9(1):232. doi: 
10.1038/s41598-018-36313-3. PMID: 30659227; PMCID: PMC6338765. 
 
7. Austin DC, Townsley SH, Rogers TH, Barlow JD, Morrey ME, Sperling JW, Sanchez-Sotelo J. 
Shoulder Periprosthetic Joint Infection and All-Cause Mortality: A Worrisome Association. 
JB JS Open Access. 2022 Feb 23;7(1):e21.00118. doi: 10.2106/JBJS.OA.21.00118. PMID: 
35224410; PMCID: PMC8865504. 
 
8. Chalmers PN, Kahn T, Broschinsky K, Ross H, Stertz I, Nelson R, Yoo M, Tashjian RZ. An 
analysis of costs associated with shoulder arthroplasty. J Shoulder Elbow Surg. 2019 
Jul;28(7):1334-1340. doi: 10.1016/j.jse.2018.11.065. Epub 2019 Mar 1. PMID: 30827836. 
 
9. Park KJ, Chapleau J, Sullivan TC, Clyburn TA, Incavo SJ. 2021 Chitranjan S. Ranawat Award: 
Intraosseous vancomycin reduces periprosthetic joint infection in primary total knee 
arthroplasty at 90-day follow-up. Bone Joint J. 2021 Jun;103-B(6 Supple A):13-17. doi: 
10.1302/0301-620X.103B6.BJJ-2020-2401.R1. PMID: 34053300. 
 
10. Parkinson B, McEwen P, Wilkinson M, Hazratwala K, Hellman J, Khan H, McLean A, 
Panwar Y, Doma K, Grant A. Intraosseous Regional Prophylactic Antibiotics Decrease the 
Risk of Prosthetic Joint Infection in Primary TKA: A Multicenter Study. Clin Orthop Relat 
Res. 2021 Nov 1;479(11):2504-2512. doi: 10.1097/CORR.0000000000001919. PMID: 
34397615; PMCID: PMC8509941. 
 
11. Young SW, Zhang M, Moore GA, Pitto RP, Clarke HD, Spangehl MJ. The John N. Insall 
Award: Higher Tissue Concentrations of Vancomycin Achieved With Intraosseous 
Regional Prophylaxis in Revision TKA: A Randomized Controlled Trial. Clin Orthop Relat 
Res. 2018 Jan;476(1):66-74. doi: 10.1007/s11999.0000000000000013. PMID: 29529618; 
PMCID: PMC5919223. 
 

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12. Young SW, Zhang M, Freeman JT, Mutu-Grigg J, Pavlou P, Moore GA. The Mark Coventry 
Award: Higher tissue concentrations of vancomycin with low-dose intraosseous regional 
versus systemic prophylaxis in TKA: a randomized trial. Clin Orthop Relat Res. 2014 
Jan;472(1):57-65. doi: 10.1007/s11999-013-3038-z. PMID: 23666589; PMCID: 
PMC3889447. 
 
13. Spangehl MJ, Clarke HD, Moore GA, Zhang M, Probst NE, Young SW. Higher Tissue 
Concentrations of Vancomycin Achieved With Low-Dose Intraosseous Injection Versus 
Intravenous Despite Limited Tourniquet Duration in Primary Total Knee Arthroplasty: A 
Randomized Trial. J Arthroplasty. 2022 May;37(5):857-863. doi: 
10.1016/j.arth.2022.01.057. Epub 2022 Jan 26. PMID: 35091036. 
 
14. Nunn, M. O., Corallo, C. E., Aubron, C., Poole, S., Dooley, M. J., & Cheng, A. C. (2011). 
Vancomycin Dosing: Assessment of Time to Therapeutic Concentration and Predictive 
Accuracy of Pharmacokinetic Modeling Software. Annals of Pharmacotherapy, 45(6), 
757–763. https://doi.org/10.1345/aph.1P634 
 
15.  STIER GR, McGORY RW, SPOTNITZ WD, SCHWENZER KJ. Hemodynamic effects of rapid 
vancomycin infusion incritically ill patients. Anesth Analg 1990;71:394-9.