A Prospective Comparison of Continuous Intravenous Lidocaine Infusion Versus Placebo for Rib Fracture Analgesia
Phase: PHASE4
Conditions: Rib Fractures
Sponsor: Stanford University

 
 
 
 
A Prospective Comparison of Continuous Intravenous Lidocaine Infusion 
Versus Placebo for Rib Fracture Analgesia 
Study Protocol and Statistical Analysis Plan 
NCT04140396 
October 22, 2019 
 
 

Title 
Continuous intravenous lidocaine infusion versus placebo for rib fracture analgesia 
 
Study personnel 
Lei Xu MD, Shruthi Basireddy, Ban Tsui MD (PI)  
 
Institutional funding 
None 
 
Additional sources of funding 
None 
 
Background & Preliminary Unpublished Data 
 
Thoracic traumas comprise 10-15% of all major traumas. The most common mechanism 
is blunt injury and the majority involves rib fractures. In fact, rib fractures are identified in 10-
40% of trauma patients and they are associated with significant morbidity, mortality, and long-
term disability (1). The majority of the morbidity stems from pulmonary complications such as 
ARDS, pneumonia, aspiration, empyema, etc. (2). Studies have examined the multitude of 
factors that influence mortality after traumatic rib fractures and they include number of rib 
fractures, pre-existing cardiopulmonary disease, increased age, and associated level of pain (3). 
Thus the cornerstones of clinical management for rib fractures centers on pulmonary hygiene and 
adequate analgesia.  
 
The current cornerstone of pain control for rib fractures is oral and intravenous opioids, 
especially in the form of patient-controlled analgesia (IV PCA). Opioids however are associated 
with multiple adverse effects including sedation, respiratory depression, cough suppression, and 
increased risk of delirium. In patients with multiple rib fractures, advanced age, or severe and 
difficult to control pain – systemic analgesia with opioids is often not sufficient and in these 
scenarios thoracic epidural anesthesia (TEA) has been the gold standard. Retrospective studies 
however have not shown significantly improved clinical outcomes in rib fracture patients who 
received TEA. One retrospective study by Yeh (4) compared outcomes in 187 patients admitted 
with rib fractures and noted no significant difference in the incidence of pulmonary 
complications between patients who received TEA versus those who did not. However patients 
who received TEA had a significantly longer hospital and ICU length of stay., Thoracic epidural 
anesthesia is also technically challenging and associated with unwanted side effects particularly 
hypotension, urinary retention, and unintentional motor blockade (5). In addition TEA is 
contraindicated in several situations (such as head trauma, spinal cord injury, anticoagulation, 
hemodynamic instability) and carries significant, albeit rare, complications (epidural hematoma 
etc). 
 
In the past few decades, intravenous lidocaine infusion (IVL) has emerged as a new tool 
in the arsenal of multimodal analgesia. Multiple randomized clinical trials have been performed 
analyzing the analgesic effects of intravenous lidocaine infusion and few adverse events have 
been reported, demonstrating that it is overall well tolerated. Furthermore studies have shown 
other beneficial effects of IVL such as it’s anti-inflammatory properties. In vitro studies of white 
blood cells incubated with lidocaine demonstrated decreased release of different cytokines such 
as leukotriene B4 (potent stimulation of neutrophil activity) and interleukin-1alpha. Furthermore, 
in animal models of hyperoxia-induced lung injury, intravenous lidocaine infusion decreased 

chemotactic/cytokine factors in bronchoalveolar lavage fluid and resulted in less neutrophil 
accumulation compared to placebo. (6). 
 
At our institution SHC, both IVL and TEA have been used as part of a regimen of 
multimodal analgesia for pain in rib fracture patients for which opioids fail to reduce pain scores 
to <=4 or have poor respiratory effort. A retrospective analysis performed by our colleagues at 
Stanford University in comparing patients who received IVL versus TEA demonstrated that there 
were no significant differences in pain scores (at 24 and 48hrs), hospital LOS, incentive 
spirometry volumes, or pulmonary complications (7). This retrospective analysis however is 
confounded by biases including the fact that patients considered for TEA are generally higher 
risk for complications. To this date, there have been no published randomized clinical trials 
(RCT) evaluating the effectiveness of IVL in management of traumatic rib fracture pain. We thus 
propose a novel RCT comparing treatment with IVL versus placebo in patients admitted for 
traumatic rib fractures in order to evaluate the clinical effectiveness of IVL on OME 
consumption, pain scores, incentive spirometry volumes, cough strength, and LOS. 
 
Hypothesis 
 
We hypothesize that continuous intravenous lidocaine infusion will provide improved 
pain control as demonstrated by decreased OME consumption at 24 and 48 hours compared to 
placebo in adult patients with acute traumatic rib fractures. 
 
Methods 
 
This study will include all adult patients admitted to Stanford Health Care with two or 
more acute traumatic rib fractures. This study will exclude patients with hemodynamically 
instability, mechanical ventilation, polytrauma (defined as bone or organ injury outside the 
thorax), pregnancy, incarceration, local anesthetic allergy or contraindications to lidocaine 
(Stokes-Adams syndrome, Wolff-Parkinson-White syndrome, or severe degrees of sinoatrial, 
atrioventricular, or intraventricular block) and chronic opioid use. 
 
All study patients will be started on the standard of care multimodal regimen at SHC 
being currently used by the trauma surgery admitting team for all adult patients admitted with rib 
fractures. This consists of: Acetaminophen 1g TID, opioid prn (PO oxycodone and IV 
hydromorphone), Celebrex 100mg PO BID (for those without contraindications), gabapentin 
100mg qHS (increased as tolerated to max 300mg PO q8h) and any baseline chronic 
outpatient analgesics. Patients will receive either a lidocaine infusion or a placebo infusion 
consisting of normal saline at 10mL/hour. All patients on study drug (IVL) will have lidocaine 
levels drawn q8h. In addition, all patients will have blood drawn for a panel of inflammatory 
biomarkers right before intervention initiation, at 24hours and at 48 hours. Patients, will be 
blinded to the treatment however nurses, treating clinicians, and research personnel will not as 
they will monitor lidocaine serum levels and adjust infusion doses accordingly. 
 
Patients will be systematically evaluated at 12-24 hours after initiation of the intervention 
for failure (defined as pain scores at rest of > 7, clinically significant side effects from opioids, or 
ICV of <=500cc with appropriate effort). For the patients on placebo arm who have “failed”  -
they will cross over to the IVL treatment arm.  For patients on the treatment IVL arm who have 
“failed” – their lidocaine level will first be checked. If it is subtherapeutic, the lidocaine infusion 
dose will be increased to achieve a therapeutic lidocaine level. If the lidocaine level is withinin 
the therapeutic window – these patients will get removed from the study and receive a consult to 

the Acute Pain Services for further pain management. Any patient who has clinically significant 
side effects of IVL will have the infusion stopped and be removed from the study. 
 
 
An IRB approval will be obtained and all patients will be randomized to either the 
placebo arm (control) or the intervention arm (IVL) within 16 hours of hospital admission. 
 
Data analysis and sample size calculation 
 
The primary end point for this study is oral morephine equivalents (OME) consumption 
at 24 hours of treatment. Secondary end points include OME at 48 hrs, pain scores at rest and 
with cough and deep inspiration, incentive spirometry volumes, PIC score, length of hospital 
stay, inflammatory biomarkers, and rates of pulmonary complications (including need for 
positive pressure ventilation, pneumonia, aspiration, supplemental oxygen). The PIC score will 
be calculated according to Figure 1 (See below). Pain will be scored on a Numeric Rating Scale 
(NRS) of 0-10, where 0 is no pain and 10 is the worst imaginable pain. There will also be 
subgroup analyses by geriatric status and >4 rib fractures. 
 Figure 1: PIC score as described by Witt 
and Bulger (8). PIC is a composite score comprising pain level, ICV, and cough strength. 
 
 
At our institution, preliminary retrospective data (unpublished) shows that continuous IV 
lidocaine infusion reduces OME consumption from average of 174 OME/24hr with standard 
deviation 190 OME/24hr (extrapolated from OME consumption during time period prior to 
initiation of IVL) to 85 OME/24hr with standard deviation of 68 OME/24hr. Since we do not 
have data on patients that were not treated with IVL, we assume that this clinically significant 
difference would not occur in the placebo group. Therefore, with a type 1 error rate of 0.05 and 
power of 80%, sample size estimation suggests 144 patients total – 72 per group, would be 
required to demonstrate significance. To compensate for dropouts and incomplete data, 80 
patients per group will be targeted for enrollment. 
 
 
In terms of statistical analysis, we plan to use the Mann-Whitney U test for all 
continuous, ordinal, and interval variables, to determine equality of means between two groups 
regardless of normality. We will use two-sided P values of < 0.05 as the cutoff for statistical 
significance. We will collaborate with a statistician to perform further in-depth analyses 
especially for the subgroup analyses.  
 

Intervention  
 
All adult patients admitted to SHC for acute traumatic rib fractures will have their MRN 
and last name paged to the research team upon admission by the treating physician team (trauma 
surgery). The trauma surgery team will discuss with the patient that there is a research study 
about pain management in patients with rib fractures and obtain permission for the research 
study team to contact the patient. Furthermore, the primary service (trauma surgery) will put all 
patients on the standard baseline multimodal regimen as described above. 
 
Potential study patients will have their charts reviewed and if deemed to fit the 
inclusion/exclusion criteria, the patient will be evaluated for informed consent by the research 
team within 16 hours of admission. If the patient provides consent, he or she will be immediately 
randomized to either the control arm (normal saline infusion) or the intervention arm (continuous 
intravenous lidocaine infusion initially at 1.0mg/kg/hr, also referred to as ‘study drug’). Patients 
will be blinded to the treatment. Patients on study drug (IVL) will have q8h lidocaine serum 
levels drawn. Treating clinicians will monitor serum lidocaine levels and adjust infusion dose 
with pharmacy.  
 
The length of study drug or placebo infusion will be approximately 72 hours and thus the 
study period (defined as the period of active participation by the study participant) will be 
approximately 3 days. At conclusion of the study period, the patient will no longer need to be 
blinded to treatment. At the conclusion of the study period it is up to the treating clinician to 
continue the intravenous lidocaine infusion if the patient is on the study drug arm.  
 
There will be no other changes to the trauma rib fracture protocol. 
 
The following describes the points of data collection: 
• Pain scores at rest will be collected by RNs via a Numeric Rating Scale as per SHC 
hospital inpatient ward protocol every 4 hours and upon arrival (NRS, 0-10, where 0 is no 
pain and 10 is the worst imaginable pain). 
• In addition to the pain scores pre-randomization, time 0 will be designated as prior to 
starting either the control or intervention treatment.  
• The research team will assess all patients for: NRS pain scores at rest/deep 
inspiration/deep cough, maximum ICV (of 3 attempts), cough strength, signs/symptoms 
of lidocaine toxicity. These measurements will be taken at time 0 and then daily up 
through day 3 of the study period. 
• Serum lidocaine levels will be drawn q8h for all patients on the study drug as per SHC 
protocol. 
• All patients will also get blood drawn for panel of inflammatory biomarkers at time 0, 24 
hours, and 48 hours. 
• Analgesic consumption will be recorded in the following increments (pre-intervention to 
time 0, time 0-24hr, 24-48hr, and 48-72hrs). 
• Electronic medical records will be analyzed for: demographic data, name, age, MRN, 
gender, weight, height, medical history, medication history, current medical 
conditions/diagnoses and medications while hospitalized, medical complications from rib 
fractures. 
 

Data safety monitoring plan 
 
Please see the “Methods” and “Intervention” sections for the summary of the protocol for 
this prospective study. No children or pregnant women will be enrolled in the study per 
inclusion/exclusion criteria as previously described. Patients who experience significant pain 
despite the described multimodal analgesic regimen and intervention will be removed from the 
study and considered for alternative treatments (such as thoracic epidural, etc) and acute pain 
service consult. Treating clinicians and research personnel will not be blinded to assignment. All 
patients on the study drug will have serum lidocaine levels monitored by treating clinicians. 
Furthermore, research personnel will assess for symptoms of lidocaine toxicity daily (in addition 
to clinician and RN assessments). Treating clinicians will work with pharmacy to adjust 
lidocaine infusion based on lidocaine levels (as per SHC protocol) and if a patient has signs of 
lidocaine toxicity, he/she will be considered for removal from the study immediately. 
 
This project is a multidisciplinary collaboration between the Anesthesiology and Surgery 
departments. The study personnel include the PI - Dr. Ban Tsui, a professor in the Department of 
Anesthesiology at Stanford University, the study primary investigator - Dr. Lei Xu, a regional 
anesthesiology fellow, and the clinical research coordinator Shruthi Basireddy. The collaborators 
included, Dr. Kristen Lea Staudmayer (Trauma lead), Assocate Professor, Department of 
General Surgery, and Einar Ottestad (Acute Pain lead), Clinical associate professor, Department 
of Anesthesiology. All study personnel will be monitoring this study throughout the collection of 
data for all patients enrolled. This includes ensuring the study is conducted according to the 
protocol, monitoring enrollment, collecting data in a confidential manner on password protected 
and encrypted software, and reporting adverse events promptly to the IRB and any other 
applicable agencies. We will be applying our GCP training to conduct this study and providing 
updates to the IRB as appropriate per guidelines. 
 
Significance 
 
The foundation of clinical management for rib fractures centers on pulmonary hygiene 
and adequate analgesia. The current mainstay of pain control for rib fractures across the United 
States is oral and intravenous opioids. Opioids however are associated with multiple adverse 
effects including sedation, respiratory depression, cough suppression, and increased risk of 
delirium. Furthermore, in patients with multiple rib fractures, advanced age, or severe and 
difficult to control pain – systemic analgesia with opioids is often not sufficient and in these 
scenarios thoracic epidural anesthesia (TEA) has been the gold standard. Epidurals however are 
invasive, have side effects (such as hypotension and urinary retention), and carry risk of serious 
complications (epidural hematoma, etc). Intravenous lidocaine infusions are an alternative non-
opioid and noninvasive method to reduce pain, and the retrospective study done by our 
colleagues at SHC (7) would suggest IVL to be similar to thoracic epidural in terms of 
decreasing pain from acute rib fractures. Retrospective studies however have inherent 
confounding factors and thus we are proposing this novel randomized clinical trial. This trial has 
the potential to not only demonstrate and measure the effectiveness of IVL in treating rib fracture 
pain, but if clinically significant results are found, it has the potential to change clinical practice 
across the United States. 
 

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