Intravenous Lidocaine to Reduce Postoperative Opioid Consumption and Improve Recovery After Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis
Phase: PHASE4
Conditions: Systemic Lidocaine Improves Pain Control After Surgery by Attenuating the Systemic Inflammatory Response to Surgery
Sponsor: Washington University School of Medicine

Intravenous Lidocaine to Reduce Postoperative Opioid Consumption and Improve 
Recovery After Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis 
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TABLE OF CONTENTS 
A 
INTRODUCTION ............................................................................................................................... 2 
A1 
PRIMARY HYPOTHESIS ................................................................................................................... 2 
A2 
PURPOSE OF THE STUDY PROTOCOL .............................................................................................. 2 
B 
BACKGROUND .................................................................................................................................. 2 
B1 
RATIONALE FOR THIS STUDY ......................................................................................................... 2 
C 
STUDY OBJECTIVES........................................................................................................................ 9 
C1 
PRIMARY AIM ................................................................................................................................ 9 
C2 
SECONDARY AIM ........................................................................................................................... 9 
D 
INVESTIGATIONAL AGENT .......................................................................................................... 9 
D1 
CLINICAL DATA TO DATE .............................................................................................................. 9 
E 
STUDY DESIGN ................................................................................................................................10 
E1 
OVERVIEW OR DESIGN SUMMARY ................................................................................................10 
E2 
SUBJECT SELECTION AND WITHDRAWAL......................................................................................10 
2.a 
Inclusion Criteria ....................................................................................................................10 
2.a 
Exclusion Criteria ....................................................................................................................10 
2.b 
Subject Recruitment Plans and Consent Process ....................................................................11 
2.c 
Randomization Method and Blinding ......................................................................................11 
2.d 
Risks and Benefits ....................................................................................................................12 
E3 
STUDY DRUG ................................................................................................................................12 
3.a 
Description ..............................................................................................................................12 
3.b 
Treatment Regimen ..................................................................................................................12 
3.c 
Method for Assigning Subjects to Treatment Groups ..............................................................12 
3.d 
Blinding of Study Drug ............................................................................................................12 
F 
STUDY PROCEDURES ....................................................................................................................13 
F1 
SCREENING FOR ELIGIBILITY ........................................................................................................13 
F2 
SCHEDULE OF MEASUREMENTS ....................................................................................................13 
F3 
SAFETY AND ADVERSE EVENTS ....................................................................................................13 
F4 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT ..........................................................15 
G 
STATISTICAL PLAN ........................................................................................................................15 
G1 
SAMPLE SIZE DETERMINATION AND POWER .................................................................................15 
G2 
ANALYSIS PLAN............................................................................................................................15 
H 
DATA HANDLING AND RECORD KEEPING .............................................................................16 
H1 
CONFIDENTIALITY AND SECURITY ................................................................................................16 
H3 
CASE REPORT FORMS AND SOURCE DOCUMENTS .........................................................................17 
H4 
RECORDS RETENTION ...................................................................................................................17 
I 
STUDY MONITORING, AUDITING, AND INSPECTING ..........................................................17 
I1 
STUDY MONITORING PLAN ...............................................................................................................17 
J 
REFERENCES ...................................................................................................................................18 
 

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A Introduction 
 
A1 Primary Hypothesis 
We hypothesize the systemic infusion of lidocaine will improve pain control in 
patients undergoing posterior spinal fusion for adolescent idiopathic scoliosis, 
decreasing opiate consumption in the acute perioperative period. We further 
hypothesize that lidocaine infusion will attenuate the inflammatory response to 
injury and surgery, and that taken together decreased perioperative opiate 
consumption and decreased inflammation will lead to improved longer-term 
outcomes including decreased chronic opiate use and improved physical 
function.  
A2 Purpose of the Study Protocol 
To evaluate the efficacy of intravenous lidocaine to reduce opioid consumption, 
improve recovery, and reduce the systemic inflammatory response to surgery 
posterior spinal fusion for AIS (Adolescent Idiopathic Scoliosis). 
B Background 
 
B1 Rationale for this Study 
Opiate dependence is a serious complication of surgery. Systemic opioids are 
one of the most effective analgesics to treat severe pain after spine surgery. 
Despite their effectiveness for treating severe pain, administration of systemic 
opioids is associated with adverse effects including long-term dependency and 
overdose.1-3 In the last 20 years, opiate addiction the associated risk of drug 
overdose has become a crisis of public-health proportions, with overdose deaths 
exceeding those from both motor-vehicle collisions and firearms (Figure 1). 
Amongst the current epidemic of opioid use disorders (by prescription opioids 
and heroin), there is also an alarming growing public health problems in 
adolescents opioid dependency, which comes with devastating consequences. 
Early age onset of prescription opioid and heroin use has been associated with 
higher prevalence of dependency and increasing clinical severity.4 Opioid 
dependency following trauma relates to issues beyond pain severity, such as 
depression and anxiety.5  

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Preliminary data obtained in our institution has followed adult spinal deformity 
patients after complex reconstructions.  27% of opioid-naïve patients undergoing 
adult spinal deformity surgery required opioid medications at one-year followup 
and the majority (62%) of patients using opioids before surgery continued their 
use at one-year after surgery. These data demonstrate that a subset of spine 
surgery patients are introduced to opioids and become dependent, while also 
emphasizing the difficulty of cessation of chronic opioid use. Furthermore, we 
have collected health-related quality of life (HRQOL) data, a necessary 
component of value-driven healthcare. Our preliminary data shows that opioid 
dependent patients, on average, complain of worse pain function versus the 
opioid naïve at baseline and after surgical treatment. (Figure 2) These data 
support the need for non-opioid pain control methods to minimize long-term 
opioid use in trauma patients, as up to 30% of patients may become opioid 
dependent and incur the risks associated with this condition, including chronic 
pain complaints refractory to treatment. 
 
 
 
 
 

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Exposure to opioids in the perioperative period may affect recovery beyond the 
psychological effects of dependency. Opioids are immunosuppressive, both in-
vitro and in-vivo, to the innate and native immune system and can further 
exacerbate the immune dysfunction induced by trauma and surgery.6 Tissue 
damage, either from traumatic injury or surgery causes release of damage-
associated molecular patterns (DAMPS) that serve as danger signals to the 
immune system, signaling the need for an inflammatory response 7. When the 
acute inflammatory response is limited to injured tissue, inflammation can 
contribute to hemostasis, help to prevent infection, and facilitate tissue repair 
8,9. In the setting of major invasive surgery, the inflammatory response can 
become dysregulated and extend systemically, manifest as a massive activation 
of the innate immune system with an almost concomitant inhibition of adaptive 
immunity. These pathophysiologic responses frequently complicate the care of 
complex-spine patients. By example, surgery for acute spinal injuries in 
polytrauma patients causes an increase in circulating levels of the inflammatory 
cytokines IL-8 and IL-6 at 7 and 24 hours after injury respectively 10-12.  
Further, the dysregulation of immune response in these patients is frequently 
exacerbated by the fact that these patients often need ongoing critical care, 
which is itself associated with immune dysfunction 13. 
 
IV lidocaine is an effective adjunct for perioperative analgesia. Intravenous 
lidocaine is a nonopioid method of perioperative analgesia.14-16 It is an amide 
local anesthetic that works primarily through inhibition of nociceptive stimuli via 
sodium channel blockade. This is not the primary mode of action when given 
intravenously. This is because the concentrations achieved with low-dose 
intravenous administration are similar to systemic absorption with epidural 
delivery, approximately 1µM. These low concentrations would not be sufficient to 
block any substantial number of sodium channels throughout the body. 
Intravenous lidocaine likely has local and central actions, including inhibition of 
noxious stimuli and encouraging the release of endogenous opioids.17 As a non-
opioid analgesic, intravenous lidocaine is effective in reducing pain, opioid 
consumption, ileus, and hospital length of stay.18-20 
Intravenous lidocaine has been studied most extensively in abdominal 
surgeries.18,20-23 Koppert et al found a 35% reduction in morphine equivalent 
opioid consumption after major abdominal surgery.20 These authors also 
reported reduced pain complaints with activity, which supports our hypothesis 
that systemic lidocaine will improve recovery with faster rehabilitation. Similarly, 
Kuo et al found a 33% reduction in opioid requirements after major abdominal 
surgery with reduced ileus and a reduced mean length of stay.22 There has 
been only limited investigation into systemic lidocaine in orthopedic surgery.. 
Farag et al performed a randomized trial of intravenous lidocaine versus placebo 
in elective spine surgeries.19 Subjective pain complaints were less in the 
lidocaine cohort. It is important to note that nearly 50% of the patients in this 
study underwent cervical surgeries, distinctly less invasive than thoracolumbar 
surgery.. Thus, the efficacy of intravenous lidocaine in a population at highest 
risk for large opioid requirements has not been investigated. 
Systemic lidocaine has been safe in the studies performed21,24. Serum 
concentrations of lidocaine at commonly prescribed doses (2mg/kg bolus, 
2mg/kg/hr infusion) remain lower than toxic levels.25 Adverse events may 
include cardiac abnormalities, such as arrhythmias. Studies investigating 
lidocaine in cardiothoracic surgery, however, have not found evidence of an 
increased risk of arrhythmia in this high risk population.26-28 A systematic 

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review of studies involving intravenous lidocaine failed to find relevant adverse 
events attributed to the study drug.24 
 
Injury-induced Inflammation drives perioperative pain. Nociception is the 
neurologic response to tissue injury or damage and is mediated by specialized 
sensory neurons which convey the signal of tissue damage from the periphery 
through the spinal dorsal root ganglion to ascending fibers of the spinal cord that 
transmit these signals to the brain.  At each level (periphery, spinal cord and 
brain) the immune systems modulates the pain signal through both pro-
nociceptive and anti-nociceptive mediators. These mediators influence both the 
sensation of pain and the threshold for a pain response to stimulation. 
 
Peripheral nociceptors respond to injury both directly and indirectly. Outside 
of a normally tolerated thresholds, specialized sensory neurons response to 
thermal and mechanical stress to transduce a pain signal. In addition to a direct 
response to thermal or mechanical stimulation, nociceptors respond to 
neuroactive signalling molecules and inflammatory mediators produced by non-
neural cells such as glia and leukocyte. These signals can both amplify (pro-
nociceptive) or attenuate (anti-nociceptive) the response of sensory neurons 29. 
Pro-nociceptive mediators include the canonical inflammatory cytokines TNF-
alpha 30, IL-6 31 and IL-1-beta32, produced in response to inflammation by 
innate immune cells such as monocytes and macrophages. Nociceptors express 
cell surface receptors that can respond directly to these mediators, decreasing 
the threshold for activation resulting in a pro-nociceptive effect 33. Conversely, 
antiinflammatory mediators such as IL-10 can decrease sensory neuron 
activation, having an anti-nociceptive effect 29. The effect of these mediators 
can be to both increase the intensity of an otherwise low-amplitude pain signal or 
to decrease the threshold for a response. In addition, there are cohorts of 
neurons that are normally that are insensitive to mechanical or heat stimulation, 
but in response to inflammatory mediators these neurons become sensitized to 
noxious mechanical or thermal stimulation, and are thereby recruited as 
nociceptors 6,34. Thus inflammation both facilitates the activation of the normal 
complement of peripheral nociceptors, but also recruits novel nociceptors, further 
amplifying the pain signal.   
 
In patients undergoing major spine surgery, the dynamics of inflammation 
and pain are particularly complex.  Major surgery can cause dysregulated 
immune response resulting in a systemic inflammatory response, characterized 
in part by elevated levels of circulating inflammatory mediators 35. These 
circulating inflammatory mediators can interact with pain neural pathways across 
the anatomic spectrum from the peripheral nociceptors to ascending spinal 
tracts, broadly decreasing the threshold for activation of pain pathways, resulting 
in the syndrome of hyperalgesia whereby normally innocuous stimuli cause a 
pain response. In the setting of recovery from major spine surgery, hyperalgesia 
may exaggerate the pain response from minor injuries, exacerbating the 
challenge of pain control.   
 
Injury and surgery induce a strong immuno-inflammatory response. The 
dysregulated immune response to major surgery and the associated 
exaggerated systemic inflammatory response contribute to the challenge of pain 
control. At the biochemical level, surgery increases pain signaling at the local, 
regional and central levels signal transduction exacerbating the challenge of pain 
control. In addition, systemic inflammation contributes to hemodynamic 
instability, driving hypotension and compromising spinal cord perfusion. 
Unchecked, this immune dysfunction can lead to the persistent inflammation, 

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immunosuppression and catabolism syndrome (PICS) that underlies chronic 
pain and critical illness 13. Prior studies have demonstrated that 
immunophenotype correlates with clinical recovery from surgery, with immune 
metrics measured in the first 24 hours correlating with metrics of clinical function 
measured out to more than 30 days 36. 
 
To better understand the effect of spine surgery immunophenotype, we first 
sought to develop a practical, high resolution clinical immunophenotyping 
protocol. High-resolution clinical immunophenotyping has been limited by the 
logistics of performing flow-cytometric analysis.  Conventional tissue processing 
protocols require real-time sample processing, as both prolonged storage or 
cryopreservation can result in changes in cell number, cell morphology and cell-
surface marker expression 37,38. In the setting of a clinical trial were samples be 
acquired during evening or weekend hours, 24/7 laboratory staffing by research 
personnel is logistically prohibitive. To address this issue, we have developed 
and validated a protocol for cell preservation using a novel buffer/fixation system 
(Proteomic Stabilizer, Smart Tube Inc, San Carlos, CA) which allows for stable 
cryopreservation of peripheral blood samples, with reproducible flow-cytometric 
immunophenotyping at least up to 72 hours after freezing. We find that Smart 
Tube proteomic stabilizer provides excellent reproducible results as compared to 
gold-standard immediate processing of samples (see Figure 3).  
 
 
 
 
We have successfully applied this technology to more than 500 clinical samples 
as part of a Phase-2 randomized, controlled  trial (Tranexamic Acid Mechanisms 
and Pharmacokinetics In Traumatic Injury, ClinicalTrials.gov #NCT02545949), 
done in collaboration with the United States Department of Defense.   

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We then determined the effect of traumatic thoracic spine injury on 
immunophenotype. Using our established protocol our immunophenotyping 
protocol to measure cell surface marker expression on circulating leukocytes 
from n=4 patients suffering traumatic spine injuries (Figure 4). The initial blood 
sample was collected within 2 hours of injury, on presentation to the emergency 
department; subsequent blood samples were taken at 6 hours, 24 hours and 72 
hours. In these preliminary data, we find that trauma patients with a thoracic 
spine fracture have reproducible changes in the circulating leukocyte cohort 
within 6 hours of presentation, with a dramatic decrease in the number of 
circulating Natural Killer (NK cells) and a trend towards increased numbers of 
dendritic cells (DC). We also detected an increase in monocyte CD14 expression 
and a decrease in monocytes HLA-DR expression. These preliminary data 
demonstrate that technical and logistical feasibility of our immunophenotyping 
approach.  
 
 
 
 
 
 
 
 
 
Lidocaine is a potent immunomodulator. In addition to its well-described 
functions as a local anesthetic, lidocaine directly modulates the function innate 
immune cells including macrophages, monocytes and polymorph neutrophils 
(PMN). In a rabbit model of acid-induced acute lung injury, pretreatment with 
systemic lidocaine at clinically significant levels (2 mg/kg bolus +2 mg/kg/hr 
continuous infusion) resulted in decreased PMN accumulation in the lung after 
injury39; ex-vivo analysis of PMN isolated from the lungs of injured animals 
found that treatment with lidocaine reduced reactive oxygen species production, 

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which would correlate with decreased free-radical production with an associated 
decreased injury to the pulmonary vasculature. Similar results were reported by 
Takao et al, who reported that lidocaine infusion was associated attenuated the 
levels of the inflammatory cytokines TNF-alpha and IL-1beta in the BAL of 
rabbits with a hyperoxic lung injury16. Critically, study of PMN isolated from 
septic human patients demonstrate that lidocaine treatment can reduce PMN 
recruitment. These authors also demonstrate that lidocaine can interact directly 
with PMN, modulating integrin-mediated activation of protein-kinase C (PKC)-
theta.15 These data support those from Hollmann et al which demonstrate that 
lidocaine can attenuate PMN superoxide production, which is mediated in part by 
outside-in integrin signalling.40  Lidocaine modulates the systemic inflammatory 
response. Pretreatment with systemic lidocaine prior to endotoxin-induced acute 
lung injury (ALI) in rabbits resulted in decreased levels of inflammatory cytokines 
TNF-alpha and IL-1-beta in the broncheoalveolar lavage fluid.39 Similar results 
were reported for both hyperoxic and hydrochloric acid induced ALI.16,39 
Similarly, systemic infusion of lidocaine was found to ameliorate shock in a rabbit 
model of endotoxemia, and this was associated with a significant decrease in the 
circulating levels of TNF-alpha, IL-6 and IL-8.41 Analogous results were seen in 
both rodent and equine models of endotoxemia.41-44 
 
To demonstrate the effect of lidocaine on the immuno-inflammatory 
response, we measured cytokine production by human peripheral blood 
mononuclear cells in response to either LPS or T-cell receptor ligation with anti-
CD3/anti-CD28 antibody in the presence of increasing doses of lidocaine (Figure 
5). We found that lidocaine strongly inhibits cytokine production in response to 
both stimuli, demonstrating that lidocaine can attenuate both the innate and 
adaptive immune response at physiologically relevant doses. These preliminary 
data directly demonstrate the immunomodulatory effects of lidocaine on human 
leukocytes. 
 
 
 

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C Study Objectives 
 
C1 Primary Aims 
Specific Aim 1: 
a. To determine the effect of systemic lidocaine on postoperative opioid  
consumption following posterior spinal fusion surgery for AIS. 
 
Specific Aim 2:  Determine the effect of lidocaine infusion on the immuno-
inflammatory response following posterior spinal fusion for AIS. 
 
a. Determine changes in leukocyte frequencies and phenotype during and 
following surgery by flow cytometric immunophenotyping. 
b. Assess systemic cytokine responses during and following surgery with 
and without IV lidocaine treatment. 
c. Define surgery- and lidocaine-induced functional changes in immune cell 
populations by mass cytometry. 
 
C2 Secondary Aims 
 
To determine the effectiveness of systemic lidocaine to improve recovery after 
posterior spinal fusion for AIS. We hypothesize that patients receiving 
intravenous lidocaine will experience faster recovery from surgery. To test this 
hypothesis PROMIS-Computer Adaptive Tests (CAT) for Mobility (M) and Pain 
Interference (PI) will be compared between groups at enrollment, 6 weeks, 3 
months, 6 months, and 12 months after surgery. The Scoliosis Research Society 
22 (SRS-22) will also be completed at these time points. 
D Investigational Agent  
D1 Clinical Data to Date  
 
  
Lidocaine hydrochloride (2-Diethylamino-2’, 6’-acetoxylidide monohydrochloride) 
is an amide-type, short-acting local anesthetic and delivered as an aqueous 
solution for intravenous administration. It has a half-life of 1.5-2 hours. A 
traditional method of administration is via epidural delivery. Epidural lidocaine is 
effective and this effect is due, in part, to systemic absorption. Systemic 
(intravenous) administration of lidocaine is a Food and Drug Administration 
approved method of delivery. Low plasma levels are needed for effective use, 
0.5µg/mL to 5.0µg/mL. Given this low concentration required and the short half-
life, continuous infusion of lidocaine is thought to be generally safe with low risk 
of complication. 
 
The low plasma levels have not been associated with hemodynamic 
instability nor have they been associated with changes in cardiac contractility. No 
interactions with the autonomic nervous system have been reported and there 
are no known effects on sinoatrial conduction. Lidocaine is metabolized by the 
liver, with less than 10% excreted in urine. Complications are rare. Despite 
concerns for arrhythmias, intravenous lidocaine has been used in cardiothoracic 

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surgery without increased rates of cardiac complications. Give this volume of 
evidence, we feel that intravenous lidocaine in the setting of AIS surgery is safe. 
D2 Dose Rationale and Risk/Benefits  
There are no prior studies investigating the use of intravenous lidocaine for the 
management of pain associated with adolescent idiopathic scoliosis surgery. As 
such, the dosage chosen comes from prior work in abdominal surgery and 
elective spine surgery18,19,22. These studies have shown lidocaine to be 
effective in improving pain scores, reducing opioid consumption, and improving 
patient reported outcomes measures. Lidocaine will be given at the induction of 
anesthesia until 24 hours after arrival to the Post-Anesthesia Care Unit (PACU) 
or Pediatric Intensive Care Unit (PICU).  
A research pharmacist not involved in the care of the patient will deliver 
lidocaine, 8mg/mL, in D5W (Baxter International, Deerfield, IL, USA), or D5W 
(Baxter International) to the operating room for continuous infusion. A separate 
bag containing 1mg/kg of lidocaine in D5W, or an identical volume of plain D5W, 
will be delivered for bolus delivery. All solutions will be packaged identically, to 
avoid accidental unblinding. The study pharmacy will report both loading bolus 
volume and volume/hr rate for the infusion in the electronic medical record. The 
total volume of study drug/placebo administered will be recorded. 
E Study Design  
 
E1 Overview or Design Summary 
Anesthesia, other than the lidocaine, will be given as standard of care per physician 
discretion  
 
Study Drug: After a 1 mg/kg lidocaine bolus with induction, a lidocaine 1 mg/kg 
(IBW)/hr IV infusion with maximum dose of 200 mg/hr or D5W (placebo) at equal volume 
rate of administration will begin prior to skin incision and continue intraoperatively for 
duration of the case. Study drug will be discontinued upon 24 hours of stay in PICU or 
PACU postoperatively. Study drug will be dosed according to ideal body weight (IBW). 
Patient height, weight, age, and gender will be delivered to the study pharmacy prior to the 
day of surgery for calculation of IBW and dosing parameters. 
E2 Subject Selection and Withdrawal  
Study participants will be AIS patients recruited from Orthopaedic Spine clinics at 
Center of Advance Medicine Barnes Jewish and St. Louis Children’s hospitals. 
Given the single disease investigated, AIS, we anticipate that our results will be 
generalizable to AIS patients at other institutions. We will enroll 50 patients, 25 
per group, over two years. Approximately 60 AIS surgeries are performed per 
year at our institution.   
2.a 
Inclusion Criteria  
1. Adolescent idiopathic scoliosis indicated for posterior spinal fusion. 
2. Ages between 12 and <18 years of age.  
3. Parent/Guardian capable of providing informed consent for study participation. 
2.a 
Exclusion Criteria  
1. Age < 12 or > 17.9 years old.  

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2. Unable to obtain consent for the surgical intervention or study, or if mental 
capacity prohibits the ability to provide consent and complete patient-reported 
outcomes tools. 
3. Diagnosis of sepsis or infection 
4. Diagnosis of primary or metastatic malignancy. 
5. Participation in another clinical trial.  
6. Past or current diagnoses of a cardiac arrhythmia or first/second degree heart 
block. 
7. Past or current seizure disorders. 
8. Known allergy to bupivacaine. 
9. Significant liver disease 
10. Significant kidney disease 
11. Known pregnancy 
12. Known allergy to lidocaine and/or benzocaine 
13. Planned anterior approaches for treatment of scoliosis deformity. 
14. Limited English proficiency (e.g. unable to obtain informed consent for surgery 
without a translator) 
15. Ward of the State children 
2.b 
Subject Recruitment Plans and Consent Process 
Description of Recruitment Process 
1. Subject selection will be equitable. No patient will be included or excluded on 
the basis of gender, race, religion, national origin, or sexual orientation. Refusal 
to participate in the study will not affect the patient’s access to care or surgical 
priority.  
2. The research coordinator will identify all patients with AIS in the orthopedic 
clinics. An interview will determine study eligibility. 
3. Subjects will not be compensated for their participation. There will be no 
advertisement material. All follow-up care is according to standard of care, with 
no non-standard tests, imaging, or follow-up appointments. 
2.c 
Randomization Method and Blinding 
Patients consenting to randomization will be randomized 1:1 to the control or study 
group. A permuted randomized block approach1 with blocks of size 4, 6 and 8. 
Given the relatively large number of patients to be enrolled, no stratification will be 
performed. After 30 patients are enrolled, an interim analysis, without unblinding, of 
baseline covariates will be performed to ensure equal distribution between groups. 
If distribution is uneven for covariates concerning for confounding, then 
stratification by these covariates will be employed to ensure equal distribution with 
randomization. 
 
Patient loss to follow-up can affect the randomization balance and quality. 
Aims 1a and 2 are in-hospital studies and outcome data will be collected during the 
hospital stay. Loss-to-followup is not expected during the hospital stay. Aims 1b 
and 3 may be affected by loss-to-followup. All efforts will be made to collect follow-
up data. A scheduled spine clinic visit is the preferred method of data collection. If 
the patient will not attend clinic, then they will be contacted by mail, email, and/or 
phone. Surveys may be sent electronically for completion. At enrollment, the 
contact information for two family members not living with the patient will be 
obtained. These people will be contacted should contact with the patient be lost. 
Registered mail will be sent to the last known address, with a self-addressed, 
stamped return envelope to collect outcomes data. Administration of PROMIS-CAT 
and SRS are valid by telephone and email.47 

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2.d 
Risks and Benefits 
E3 Study Drug  
 
3.a 
Description 
Lidocaine hydrochloride (2-Diethylamino-2’, 6’-acetoxylidide monohydrochloride) is 
an amide-type, short-acting local anesthetic and delivered as an aqueous solution 
for intravenous administration. It has a half-life of 1.5-2 hours. A traditional method 
of administration is via epidural delivery. Epidural lidocaine is effective and this 
effect is due, in part, to systemic absorption. Systemic (intravenous) administration 
of lidocaine is a Food and Drug Administration approved method of delivery. Low 
plasma levels are needed for effective use, 0.5µg/mL to 5.0µg/mL. Given this low 
concentration required and the short half-life, continuous infusion of lidocaine is 
thought to be generally safe with low risk of complication. 
 
The low plasma levels have not been associated with hemodynamic 
instability nor have they been associated with changes in cardiac contractility. No 
interactions with the autonomic nervous system have been reported and there are 
no known effects on sinoatrial conduction. Lidocaine is metabolized by the liver, 
with less than 10% excreted in urine. Complications are rare. Despite concerns for 
arrhythmias, intravenous lidocaine has been used in cardiothoracic surgery without 
increased rates of cardiac complications. Give this volume of evidence, we feel that 
intravenous lidocaine in the setting of AIS surgery is safe. 
3.b 
Treatment Regimen 
After a 1mg/kg IBW lidocaine bolus with induction, a lidocaine 1 mg/kg/hr (IBW) IV 
infusion with maximum dose of 200 mg/hr or D5W (placebo) at equal volume rate 
of administration will begin prior to skin incision and continue intraoperatively for 
duration of the case. Study drug will be discontinued upon 24 hours of stay in 
either PACU or PICU postoperatively. 
 Method for Assigning Subjects to Treatment Groups  
 
Patients consenting to randomization will be randomized 1:1 to the control vs study 
groups. A permuted randomized block approach1 with blocks of size 4, 6 and 8. Given the 
relatively large number of patients to be enrolled, no stratification will be performed. After 
30 patients are enrolled, an interim analysis, without unblinding, of baseline covariates will 
be performed to ensure equal distribution between groups. If distribution is uneven for 
covariates concerning for confounding, then stratification by these covariates will be 
employed to ensure equal distribution with randomization. 
3.c 
Blinding of Study Drug  
This is a Phase IV, randomized, triple-blind, placebo-controlled trial with two study groups: 
postoperative standard of care with opioid patient controlled analgesia (PCA) and IV 
lidocaine infusion versus postoperative standard of care plus normal saline placebo. Block 
randomization into one of the two groups will be based on a random table generated using 
an R-program. Group 1 (Study) will receive intravenous lidocaine during and after 
posterior spinal fusion for AIS. Group 2 (Control) will receive saline placebo during and 
after surgery. 
 
 

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F Study Procedures  
 
F1 Screening for Eligibility 
The research coordinator will screen all new patients for enrollment qualifications 
according to inclusion and exclusion criteria. Eligible patients will be approached by the 
study coordinator to introduce the study and obtain consent prior to surgery.  
We will screen that the following tests to confirm study eligibility: 
1. Negative result of pregnancy test by urine hCG 
2. Normal CMP tests to assess liver and kidney function 
 
F2 Schedule of Measurements 
The research coordinator will screen all new patients with Adolescnet Idiopathic 
Scoliosis (AIS) for enrollment qualifications according to inclusion and exclusion criteria. 
Eligible patients will be approached by the study coordinator to introduce the study and 
obtain consent prior to surgery. 
Patients consenting to randomization will be randomized 1:1 to the standard of care or 
study intervention arms. A permuted randomized block approach1 with blocks of size 4, 6 
and 8. Group 1 (Study) will receive intravenous lidocaine during and after posterior spinal 
fusion for AIS. Group 2 (Control) will receive saline placebo during and after surgery. 
      After a 1mg/kg lidocaine bolus with induction, a lidocaine 1 mg/kg (IBW)/hr IV infusion 
with maximum dose of 200 mg/hr or D5W (placebo) at equal volume rate of administration 
will begin prior to skin incision and continue intraoperatively for duration of the case.  
Study drug will be discontinued upon 24 hours of stay in either PACU or PICU 
postoperatively. 
Both the leukocyte frequencies and leukocyte cell surface phenotype will be measured by 
flow cytometry. This approach will allow hypothesis-based assessment of pathways 
demonstrated to contribute to the postoperative immune phenotype, while also providing 
data for a discovery-driven analysis to define novel mechanisms. Patients will be identified 
based on inclusion/exclusion criteria as described above. Blood samples with following 
time points: immediately preoperatively, 4 hours and 8 hours post incision, day 1 post 
surgery, and day 2-3 post surgery. All blood samples will be collected into 6 ml EDTA-
containing vacutainers and three aliquots prepared for fixation by mixing 1.25 ml blood 
with 1.75 ml Proteomic Stabilizer (Smart Tube, Inc, San Carlos, CA). Following fixation, 
samples will be stored at -80 °C until flow cytometric analysis. For each patient and time 
point, one aliquot of the fixed and frozen blood will be used for immunophenotyping. The 
remaining aliquots will be used for mass cytometry as described and preserved as a 
“biobank” for potential future studies. 
We will analyze signaling events in all major leukocyte subsets and compare phospho-
signal median intensities between the different time points and treatment groups to define 
any immune modulatory effects of lidocaine during surgery.  
The primary outcome measure is total, in-hospital opioid consumption following 
surgery for AIS Opioid consumption will be measured in morphine-equivalent dosage 
(MED), to allow for the use of different opioid medications (e.g. fentanyl, hydromorphone, 
oxycodone) over the course of care.  
 
Secondary outcome measures to assess recovery are the Patient Reported 
Outcomes Measurement Information System (PROMIS) Mobility (M) and Pain Interference 
(PI) domains. PROMIS is a general measure of health administered over particular health 
domains. The SRS-22 will be used in assessing the quality of life in AIS patients. The 
SRS-22r includes 22 items distributed among five different factors (pain, self-

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image/appearance, function/activity, mental health, and satisfaction with management). 
Each component includes five items, except for the “satisfaction with management”, which 
only contains two items. Secondary measures to assess the anti-inflammatory effect of 
lidocaine will be serum levels of IL-10, IL-4 and IL-12.  
 
The anticipated outcome is decreased in-hospital opioid consumption for those 
patients treated with intravenous lidocaine. Other anticipated outcomes are improved 
recovery as measured by PROMIS-M and PROMIS-PI measures at 6 weeks, 3 months, 6 
months, and 12 months after surgery. We anticipate that the anti-inflammatory effect of 
lidocaine will reflect a smaller postoperative inflammatory response as measured by IL-10, 
IL-4, and IL-12. 
 
 
F3 Safety and Adverse Events  
Serum lidocaine levels will be drawn at 12 hours after incision and reviewed by 
an individual independent from the study team. Lidocaine toxicity will result in 
immediate cessation of study drug, unblinding, and reporting to the Medical 
Monitor and IRB. If intraoperative surgical, medical, or anesthetic complications 
occur, including cardiac arrhythmia, the study medication will be stopped and the 
patient withdrawn from the study. The patient will be analyzed in an intent-to-
treat analysis, though they will be excluded from as-treated analyses. After 
surgery, patients will be seen and examined twice daily with attention to 
postoperative complications. As the study-drug will have completed infusion, all 
complications will be recorded though patients will remain enrolled in the study 
and analyzed per-protocol. All adverse events will be recorded up to 12 weeks 
after surgery. These will be captured via interview at the visit or via telephone if a 
clinic visit is not possible. Readmission for any reason will be recoded and 
details of this hospitalization will be recorded. Any reason reasonably related to 
the research protocol will be reported to the Medical Monitor and the IRB. 
  
We believe there are minimal risks associated with participation in this clinical 
trial and with the study intervention (intravenous lidocaine). The most concerning 
serious adverse event that might be attributed to systemic lidocaine 
administration is cardiac arrhythmia/arrest. Therapeutic serum concentrations 
are far lower than toxic levels and we believe the risk of serious adverse events 
to be low. The intervention will not add time to the surgical intervention and, thus, 
does not pose additional risk from this perspective. All patients will receive 
standard of care treatment before, during, and after surgery and the study 
intervention will pose no risk to this. 
 
Safety measures to minimize/eliminate risks to human subjects and study 
personnel include the use of the Medical Monitor and immediate reporting of any 
adverse (expected or unexpected) to the project PI and project manager. If any 
intraoperative complications occur, such as but not limited to cardiac arrest or 
seizure, the study medication will not be administered and the patient will be 
excluded from the study. However, if one of these problems occurs after the 
application of the study medication the patient will be unblinded. The patient will 
be followed for the occurrence of further adverse events or complications.  
 
For any serious adverse event, the Medical Monitor at the enrollment site 
will perform a root cause analysis and will notify the project PI in the study 
medication is believed to be a potential cause of the adverse event. The Monitor 
may recommend stopping the study. Any serious adverse event will be reported 
to the PI and the IRB within 10 working days. 

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F4 Study Outcome Measurements and Ascertainment 
The primary outcome measure is total, in-hospital opioid consumption following 
surgery for thoracolumbar trauma. Opioid consumption will be measured in 
morphine-equivalent dosage (MED), to allow for the use of different opioid 
medications (e.g. fentanyl, hydromorphone, oxycodone) over the course of care.
 
Secondary outcome measures to assess recovery are the Patient Reported 
Outcomes Measurement Information System (PROMIS) Mobility (M) and Pain 
Interference (PI) domains. PROMIS is a general measure of health administered 
over particular health domains. This instrument has been tested extensively and 
is reliable and precise.45 Scores range from 0-100 and are normalized so that a 
score of 50 is the population mean, with 10 points representing a standard 
deviation is 10 points. For the Mobility domain larger scores represent more 
function; for the PI domain larger scores represent more pain. The instrument 
administered via computer-adaptive testing (CAT) to minimize question burden. 
The Scoliosis Research Society 22 (SRS-22) will be used in assessing the 
quality of life in AIS patients. The SRS-22r includes 22 items distributed among 
five different factors (pain, self-image/appearance, function/activity, mental 
health, and satisfaction with management). Each component includes five items, 
except for the “satisfaction with management”, which only contains two items. 
Secondary measures to assess the anti-inflammatory effect of lidocaine will be 
serum levels of IL-10, IL-4 and IL-12.  
 
The anticipated outcome is decreased in-hospital opioid consumption for 
those patients treated with intravenous lidocaine. Other anticipated outcomes 
are decreased opioid consumption at three-months after surgery, with improved 
recovery as measured by PROMIS-M and PROMIS-PI measures at 6 weeks, 3 
months, 6 months, and 12 months after surgery. We anticipate that the anti-
inflammatory effect of lidocaine will reflect a smaller postoperative inflammatory 
response as measured by IL-10, IL-4, and IL-12. 
 
G Statistical Plan  
 
G1  Sample Size Determination and Power 
The target sample size of 50 patients, 25 per group, is based upon a two-tail test 
at the 0.05 level of significance, with 80% power to detect an effect size of d=0.8. 
Prior data from our institution has shown an average postoperative morphine-
equivalent consumption of 149 mg with a standard deviation of 37 mg. The 
proposed effect size is equivalent to approximately a 20% reduction in 
postoperative morphine-equivalent opioid consumption. The primary outcome 
measure is the inpatient measure of postoperative opioid consumption. As such, 
loss-to-followup is not possible, though 25 per group accounts for 10% loss due 
to treatment noncompliance which is unlikely. 
G2 Analysis Plan 
General Analysis Strategy: Our approach to data analysis includes three 
consecutive stages. Most analyses will be performed using SAS software, which 

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has a wide range of statistical routines and offers great flexibility in data 
manipulation. 
 
Descriptive Analysis and Data Reduction: 
 
Quality control will be ongoing throughout the project, as part of data 
management procedures that monitor data quality at each site and overall. 
However, prior to analysis, the data will be fully examined to confirm data quality 
and make final corrections. After addressing data quality, each variable will be 
summarized via marginal distributions as well as by relevant separate and 
combined study factors [(e.g., treatment, crossover status, patient demographics 
(age, gender, race)], and clinical factors (e.g., curve type, curve magnitude, 
etc.)]. Distribution summaries for continuous variables will include means, 
medians, interquartile ranges, minima and maxima and standard deviations; 
those for categorical variables will include proportions and 95% confidence 
intervals. The amount and patterns of missing data will be examined early and 
regularly during data collection to detect possible problems with instrument 
completion. Prior to analysis the amount and patterns of missing data are also 
important to see whether adjustments will be needed at the Inferential Analysis 
Stage. Those who complete data collection will be compared with those who 
drop out before the end of follow-up to identify potential selection biases, causing 
the study pool to differ from the target population. Transformations will be 
employed as needed to produce variables that conform to the distributional 
assumptions underlying the regression models that will be used. 
 
After 10 patients have completed the study, immunophenotyping with flow 
and mass cytometry will be performed to confirm appropriate data are collected 
with the chosen panels. 
 
 
H Data Handling and Record Keeping  
 
H1 Confidentiality and Security 
The primary data will come from the information contained in the patient’s medical records 
related to their illness.  In order to extract the relevant information, study staff will review 
the data from their records and record it into a secure database.  Only the minimum 
necessary data will be looked at and recorded for the study.  Records will be stored behind 
secured firewalls maintained by Washington University and is compliant with FDA Code of 
Federal Regulations Title 2, Volume 1, CITE: 21CFR11 and include the use of: (1) 
uniqueness of individual log in with restricted access via a strong username and password 
policy, (2) ability for users to periodically modify identification codes or passwords, (3) 
secure, computer-generated time-stamped audit trails, (4) 128-bit Secure Socket Layer 
(SSL) encryption for transactional safeguarding (5) electronic de-authorization of lost, 
stolen, or missing user authorization codes. Only study staff will have password access. 
There will be no patient identifiers or information that could link the patient to any 
published material.   
 
Any paper records will be maintained in locked file cabinets in code-accessed suites. 

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H2 Case Report Forms and Source Documents 
Using the assigned patient ID code, the WU coordinator will enter all eCRF patient data 
into the study REDCap secure database. The eCRF will be completed by the principal 
investigator or his designee. If any entry on a source document requires a change, a 
single line will be drawn throughout the incorrect entry, and the correction will be entered 
in ink, initialed and dated. Whiteout, erasures, or obliteration on source data are not 
permitted. The primary data will come from the information contained in the patient’s 
medical records related to their illness. In order to extract the relevant information, study 
staff will review the data from their records and record it into a secure database. Only the 
minimum necessary data will be looked at and recorded for the study. 
H3 Records Retention 
We will retain identifiers indefinitely on patients who consent to participate in this study.  
This will be done to protect the integrity of our study and for potential use in future, IRB-
approved research. 
 
I Study Monitoring, Auditing, and Inspecting  
 
I1 
Study Monitoring Plan  
After the first 15 patients are enrolled, a group consisting of the Principal Investigator 
and an unengaged physician will review the AE/SAE data.  The data will be 
reviewed blinded. If intraoperative surgical, medical, or anesthetic complications 
occur, including cardiac arrhythmia, the study medication will be stopped and the 
patient withdrawn from the study. The patient will be analyzed in an intent-to-treat 
analysis, though they will be excluded from as-treated analyses. After surgery, 
patients will be seen and examined twice daily with attention to postoperative 
complications. As the study-drug will have completed infusion, all complications will 
be recorded though patients will remain enrolled in the study and analyzed per-
protocol.  
Special attention will be given if adverse events occur in a higher frequency than 
expected given patient age and health condition. Serious adverse events, or those 
that are life threatening, result in death, prolonged hospitalization, readmission, 
cause persistent disability or require urgent intervention to prevent permanent 
morbidity will be monitored for up to 30 days after the drug is administered.   If there 
appears to be an imbalance in AE/SAE, unblinding and analysis will ensue to 
determine if the study should continue.  Early termination will occur if SAEs are 
linked to the treatment arm. 
After 10 patients have completed the hospital phase of the study, flow and mass 
cytometry will be performed to ensure we are capturing cell types and signaling 
proteins as anticipated. 
All protocol violations and SAE’s will be reported to HRPO within the WU HRPO 
policies and procedures reporting guidelines 
SAEs will be tracked through resolution. 
 

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