A Randomized, Controlled, Double-Blind Trial of 3 Local Anesthetics for Spinal Anesthesia in Primary Total Hip Arthroplasty to Compare the Percentage of Patients in Each Group With Early Ambulation
Phase: PHASE4
Conditions: Osteoarthritis, Hip
Sponsor: Thomas Jefferson University

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RESEARCH PROTOCOL TEMPLATE 
INVESTIGATOR INITIATED TREATMENT TRIALS 
 
 
Title of Project: A Randomized, Controlled, Double-Blind Trial of 3 Local Anesthetics for 
Spinal Anesthesia in Primary Total Hip Arthroplasty 
 
Principal Investigator: 
Eric Schwenk; MD; TJUH Anesthesiology  
 
Co-Investigators:  
Jaime Baratta; MD; TJUH Anesthesiology  
 
 
 
 
David Beausang; MD; TJUH Anesthesiology 
 
 
 
 
John Wenzel; MD; TJUH Anesthesiology 
 
 
 
 
Stephen Goldberg; MD; TJUH Anesthesiology 
 
 
 
 
Christopher Wahal; MD; TJUH Anesthesiology 
 
 
 
 
Alexander Grant; MD; TJUH Anesthesiology 
 
 
 
 
Jeffrey Mojica; DO; TJUH Anesthesiology 
 
 
 
 
Jordan Smoker, MD; TJUH Anesthesiology 
 
 
 
 
Andrew Mendelson, MD; TJUH Anesthesiology 
 
 
 
 
William Hozack; MD; TJUH Orthopedic Surgery 
 
 
 
 
Matthew Austin; MD; TJUH Orthopedic Surgery 
 
 
 
 
Scot Brown; MD; TJUH Orthopedic Surgery 
 
 
 
 
Vincent Kasper, MD; United Anesthesia Partners 
 
 
 
 
Alyson Nemeth, DPT 
 
 
 
 
Lianne Previti, DPT 
 
 
 
 
James Filer, DPT 
 
 
 
 
Kristen Stout, DPT 
 
NCT number: NCT03948386 
 
 
 
 
 
Abstract 
 
Hip replacements are commonly performed under spinal anesthesia. Compared 
to general anesthesia, spinal anesthesia may reduce operative time, cardiopulmonary 
complications, and the need for blood transfusion.1 Spinal anesthesia may also allow for 
earlier ambulation in the postoperative period. Ambulation is encouraged after hip 
surgery, as delays have been associated with delirium, pneumonia, and increased 
length of stay.2 Early ambulation may also lead to better functional recovery.3 Several 
spinal local anesthetics exist, each with its own unique pharmacologic properties. In this 
prospective randomized trial, we will determine if a short-acting spinal medication, 
mepivacaine, leads to earlier postoperative ambulation following primary hip 
replacement surgery compared to two other formulations of another long-acting spinal 
local anesthetic, bupivacaine.  
 
Note: The Research Plan, A through E, should not exceed 4 pages. 
 
A. Specific Aims 
State the hypothesis and specific aims.  List the long-term objectives and what 

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the proposed research will accomplish.  (Suggested length: a paragraph or two) 
 
The specific aims of this study are to compare isobaric bupivacaine, 
hyperbaric bupivacaine, and isobaric mepivacaine as spinal anesthetic agents in 
the following areas:  
1. Percentage of patients ambulating at 3 hours (primary outcome) 
2. Return of sensory and motor function of lower extremities, incidence of 
hypotension, urinary retention, transient neurological symptoms (TNS)  
3. Postoperative pain levels, opioid consumption, percentage of patients 
able to meet discharge criteria on same day, length of stay 
 
Hypothesis: we hypothesize that a greater percentage of patients will ambulate 
early in the mepivacaine group compared to the two bupivacaine groups and that 
the smallest percentage of patients will ambulate early in the isobaric 
bupivacaine group. 
 
B.  Background and Significance 
 
Mepivacaine has a shorter duration of action than bupivacaine. Although some 
early studies suggested that mepivacaine might cause temporary pain in the 
buttocks and thighs, also known as transient neurological symptoms (TNS), 
mepivacaine has been utilized safely as a spinal anesthetic4 and more recent 
studies have refuted that.5 Mepivacaine spinal anesthesia has been shown in 
retrospective studies to facilitate rapid recovery in total knee arthroplasty 
compared to hyperbaric bupivacaine5 but this study was limited because the time 
of evaluation was not controlled and differences in ambulation may have been 
missed as a result. Both hyperbaric and isobaric bupivacaine provide reliable 
anesthesia for a variety of surgeries and there appears to be no difference in the 
failure rate of the two drugs.6 Even when used in low doses, both provide 
adequate anesthesia for greater than 60 minutes, which is the expected surgical 
time for this study. We will be using “low-dose” bupivacaine for both bupivacaine 
groups in an effort to maximize chance of early ambulation. Early ambulation is 
known to facilitate better functional recovery and reduce the incidence of some 
postoperative complications after hip surgery. A shorter-acting spinal anesthetic 
like mepivacaine may facilitate earlier ambulation in the postoperative period 
after hip surgery. Shorter time to ambulation could lead to faster discharge, which 
is desirable by both patients and surgeons and could reduce healthcare costs. 
 
 
C.  Preliminary Studies/Progress Report   
Existing evidence is limited by its retrospective nature5 and the inherent 
confounders and lack of controlling that were present. A review comparing 
isobaric to hyperbaric bupivacaine found that both drugs provide safe anesthesia 
but that isobaric bupivacaine has a slower onset and longer duration.6 A 
prospective, randomized trial comparing two doses of isobaric mepivacaine for 
ambulatory surgery found that both groups of patients were suitable for same-

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day discharge and no patients experienced TNS.7 Two separate studies in 
patients having ambulatory surgery found that TNS was rare after spinal 
anesthesia with mepivacaine.8,9 However, none of these studies compared all 3 
local anesthetics in the same study and they did not study the total hip 
arthroplasty population. 
 
D.  Research Design and Methods 
Describe the research design and procedures to be used (what, when, how) 
Include the duration of participation and early termination criteria.  Provide a flow 
diagram or timetable.  Procedures, situations, or materials that may be 
hazardous to personnel and the relevant precautions, should be outlined here. 
(suggested length not more than 2 pages) 
 
This is a prospective, randomized, double-blind study comparing 3 
different local anesthetics for spinal anesthesia. All patients between the ages of 
18 and 85 years of age, American Society of Anesthesiologists (ASA) Physical 
Status 1-3, scheduled for elective total hip arthroplasty with one of three board-
certified orthopedic surgeons (Hozack, Austin, Brown) and who have no 
contraindications to spinal anesthesia are eligible. Eligible patients will be called 
the night before to discuss the purpose and description of the surgery. Those 
who express interest will be approached the morning of surgery to discuss in 
more detail and consent will be obtained. A computer-generated randomization 
sequence will be used to assign patients to one of the three groups. The group 
assignment will then be shared with the anesthesia team caring for the patient. 
The surgeon, patient, and study team doing post-op assessments will remain 
blinded. Spinal anesthesia will be performed with the patient in sitting position 
unless he or she cannot tolerate that, in which case the patient will be positioned 
in lateral position with surgical side up (isobaric mepivacaine or isobaric 
bupivacaine) or surgical side down (hyperbaric bupivacaine). Patients receiving 
isobaric drugs will sit for 3-5 minutes until T10 dermatome is blocked and 
patients receiving hyperbaric drug will be placed in Trendelenberg position until 
T10 level is achieved. 
 
Intraoperatively, blood pressure will be recorded per usual routine ASA 
standards, which is every 5 minutes at least. Sedation will be given at the 
discretion of the anesthesia team to maintain moderate sedation or less, defined 
as purposeful response to verbal or tactile stimulation, no need for airway 
intervention, and adequate spontaneous ventilation. Hypotension will be treated 
at the discretion of the intraoperative anesthesia team for blood pressure more 
than 20% lower than the preoperative reading. As per institutional protocol, all 
patients without contraindications or allergies receive acetaminophen and 
gabapentin preoperatively and for 24 hours postoperatively, except patients over 
75 years of age do not receive gabapentin. The surgical approach for two of the 
surgeons is direct anterior approach (Hozack and Brown) and lateral approach 
for Austin. Any spinal block that is deemed inadequate for surgery based on 
sensory or motor exam by the anesthesia team will be converted to general 
anesthesia.  

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Time 
Event 
Day before surgery 
Phone call to patient 
to explain study 
Day of surgery – 
preoperative period 
1. Enrollment of 
patients who express 
interest 
2. Randomization 
3. Spinal performed 
with assigned drug 
Day of surgery – 
intraoperative period 
1. All blood pressures 
recorded 
2. Surgeon (blinded) 
rates quality of 
surgical conditions 
Day of surgery – 
postoperative period 
1. Sensory (ice) and 
motor (thigh flexion, 
knee extension, and 
toe dorsiflexion) 
assessments every 30 
minutes in the 
Postanesthesia Care 
Unit (PACU) 
2. First ambulation 
assessment by 
physical therapist in 
PACU or on ward at 3-
3.5 hours after spinal 
placement. Tests will 
include Tinnetti and 
ambulation 
assessment. 
3. Assessment for 
urinary retention and 
transient neurological 
symptoms (TNS) in 
PACU and on ward 
4. Pain assessments 
using 11-point 
numerical rating scale 
every hour while in 
PACU and per routine 
once on medical floor. 
5. Second ambulation 

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assessment by 
physical therapist at 5-
5.5 hours if patient 
unable to walk at first 
assessment. 
Postoperative day 1 
1. Assessment for TNS 
2. Assessment of 
patient satisfaction 
with anesthesia 
Postoperative day 2 
Assessment for TNS in 
person if in hospital or 
by phone if at home 
90 days 
Query of Epic to 
determine if 90-day 
readmission occurred 
 
 
Postoperatively, patient sensory and motor assessments will occur every 30 
minutes until strength returns to 5/5 in hip flexion, knee extension, and toe dorsiflexion. 
The sensory dermatome where numbness is detected at that time will be noted. 
Patients will be asked on POD 0, 1, and 2 about presence of TNS as defined above: 
“Do you have any back pain that you didn’t have before surgery that goes into your 
buttocks, thighs, hips, or lower leg?” 
 
Urinary retention will be defined by inability to urinate within 8 hours OR a report 
of distended or painful bladder occurring on POD 0, either by patient report or on 
palpation by nursing. 
 
90-day readmissions will be queried in Epic. 
 
E.  Statistical Methods   
If not a pilot study, provide biostatistical design, power calculations determining 
the number of participants, and the proposed analysis. (suggested length: ½ 
page)  
 
The study was powered using estimates of the study’s primary endpoint which is 
the percent of patients successfully ambulating within a 3-hour window post-surgery.  
The time window is based on realistic expectations of when Physical Therapy 
assessments will be performed with a near 0 percent chance of missing first ambulation. 
The assumptions are also supported by available data in the literature on duration of 
spinal blocks as well as our clinical experience and time to postoperative ambulation for 
these surgical procedures.  We believe that it is reasonable to expect ambulation within 
3 hrs in 70% of patients for mepivacaine, 35% of patients for hyperbaric bupivacaine, 
and 25% of patients for isobaric bupivacaine. With a one-way ANOVA for 3 groups and 
alpha set at 0.05, the study will require 44 patients per group (N=132) to achieve 80% 
power to detect a statistically significant difference between the 3 groups in the percent 
of patients ambulating within 3 hours. Allowing for a 10% dropout and screen failure rate 
the study will require a total of 144 patients.   

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F.  Gender/Minority/Pediatric Inclusion for Research 
All protocols must include documentation of the inclusion of women and 
minorities in the research protocol. If women and minorities are not to be 
included, provide rationale for exclusion. 
 
Women and minorities will be included in this research protocol.  
 
G.  Human Subjects 
1.  Provide number, age range, and health status of the subject population.  List 
criteria for inclusion or exclusion.  
 
This study will include 144 subjects. Patients between the ages of 18 and 
85 will be included. ASA physical status 1, 2, and 3 will be included. 
Patients who have a contraindication to spinal anesthesia will be excluded 
as will patients with body mass index (BMI) greater or equal to 40 kg/m2. 
Patients with pre-existing neuropathy in the lower extremities will also be 
excluded and any patient deemed a poor study candidate by the attending 
anesthesiologist will be excluded at his or her discretion. Patients in 
wheelchairs and those who cannot ambulate 25 feet with or without an 
assist device will be excluded. Those who take greater than the equivalent 
of 25 mg IV morphine (oxycodone 30 mg) daily will be excluded.   
2.  Identify sources of research material in the form of specimens, records or 
data.  
 
All data will be from interviewing patients before and after surgery and 
from review of Epic record (TJUH) or Meditech record and paper records 
(ROSH) from their admission. Rothman databases may be accessed if 
data are missing from Epic.  
3.  Describe plans for recruitment and consent procedures to be followed. 
 
As described above, patients will be called the night before surgery to 
discuss purpose of study and determine if further steps and official 
consent should take place on the day of surgery. Patients expressing 
interest by phone and those who are not able to be contacted by phone 
but are eligible will be approached on the day of surgery to discuss the 
purpose, risks and benefits, and any questions. If available, family 
members will be involved in consent process as well. 
4.  Describe risks and assess likelihood and seriousness. 
 
One risk of the study is premature resolution of spinal block necessitating 
general anesthesia conversion (unlikely and moderate severity). The other 
main risk is that early ambulation could put patients at risk for falls, 
although this risk is minimized by having the physical therapist walk with 
the patient during this session and patients without adequate resolution of 
spinal level would not attempt ambulation at that time. 
5.  Describe procedures for protecting against or minimizing potential risks. 
 
Only patients who are undergoing primary unilateral hip arthroplasty with 
one of 3 surgeons with typical operating times of 60 minutes or less will be 
candidates. This minimizes risk of patients being enrolled whose surgeries 

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would outlast the spinal duration. The risk of falls is minimized by physical 
therapists walking with the patients. 
6.  Describe potential benefits and importance to the subjects and others.   
 
Patients who receive mepivacaine spinal anesthesia may be able to 
ambulate sooner after surgery. Early ambulation could theoretically lead to 
decreased hospital length of stay. A shorter duration of spinal anesthesia 
may also lead to less urinary retention and systemic hypotension.  
 
7.  Discuss why risks are reasonable in relation to benefits. 
There is always a risk of conversion to general anesthesia when spinal 
anesthesia is used. That risk may be greater in this study because low 
doses of bupivacaine are used or mepivacaine is used. However, data 
from existing studies as well as our clinical experience suggest that with 
the three surgeons in this study this risk should be low. This is weighed 
against the moderate to good probability that patients may ambulate 
sooner and therefore have a chance at earlier discharge, which would be 
a benefit. 
 
H.  Data and Safety Monitoring Plan   
 
All protocols that pose greater than minimal risk must have a Data and Safety 
Monitoring Plan (see DHSP policy G 616 “Independent Monitoring of 
Investigator-Initiated Clinical Trials.” 
 
 
Dr. Jordan Goldhammer will be the independent study monitor. Quarterly 
meetings in person or via telephone with the PI will take place and adverse 
events will be discussed. Any event determined to be severe will be addressed 
immediately. 
 
1.  Describe the Data and Safety Monitoring Plan (DSMP) 
a. reporting mechanisms for adverse events to the IRB, FDA, and NIH.  
 
 
b. adverse event (AE) grading  
 
 
c. plan for unanticipated AE reporting 
 
 
d. plan for annual reporting of AEs 
 
 
e. interim efficacy analysis where appropriate  
 
2.  If applicable, describe the Data and Safety Monitoring Board (DSMB) that will 
be responsible for monitoring the study.  Indicate Chair, members, areas of 
expertise, frequency of meetings, distribution of reports. 
 
 
N/A 
 
I.  Literature Cited 
List only literature cited within the text. (suggested length:  no more than 12 references)  
 
1. Basques BA, et al. General Compared with Spinal Anesthesia for Total Hip 
Arthroplasty. J Bone Joint Surg Am 2015; 97(6): 455-61. 

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2. Kamel HK, et al. Time to Ambulation After Hip Fracture Surgery: Relation to 
Hospitalization Outcomes. J Gerontol A Biol Sci Med Sci 2003; 58(11): 1042-5.  
3. Oldmeadow LB, et al. No Rest for the Wounded: Early Ambulation after Hip 
Surgery Accelerates Recovery. Anz J Surg 2006; 76(7): 607-11.  
4. Pawlowski J, et al. Anesthetic and Recovery Profiles of Lidocaine versus 
Mepivacaine for Spinal Anesthesia in Patients Undergoing Outpatient Orthopedic 
Arthroscopic Procedures. J Clin Anesth 2012; 24(2): 109-15.  
5. Mahan MC, et al. Mepivacaine Spinal Anesthesia Facilitates Rapid Recovery in 
Total Knee Arthroplasty Compared to Bupivacaine. J Arthroplasty 2018; 33(6): 
1699-1704. 
6. Uppal V, Retter S, Shanthanna H, Prabhakar C, McKeen DM. Hyperbaric Versus 
Isobaric Bupivacaine for Spinal Anesthesia: Systematic Review and Meta-
analysis for Adult Patients Undergoing Noncesarean Delivery Surgery. Anesth 
Analg 2017;125:1627-1637. 
 
7. Pawlowski J, Sukhani R, Pappas Al, et al. The Anesthetic and Recovery Profile 
of Two Doses (60 and 80 mg) of Plain Mepivacaine for Ambulatory Spinal 
Anesthesia. Anesth Analg 2000;91:580-584. 
8. Liguori GA, Zayas VM, Chisholm MF. Transient Neurologic Symptoms after 
Spinal Anesthesia with Mepivacaine and Lidocaine. Anesthesiology 1998;88:619-
623. 
9. YaDeau JT, Liguori GA, Zayas VM. The Incidence of Transient Neurologic 
Symptoms After Spinal Anesthesia with Mepivacaine. Anesth Analg 
2005;101:661-665. 
 
 
 
 
 
 
 
__________________________________________________ 
Principal Investigator/ Date   
  
 
 
 
Date  3/21/2019 
 
 
 
Version  
 
 
 
Research Protocol Template, 11/15/2010