Dexmedotomidine for Acute Pain Control in Patients With Multiple Rib Fractures
Phase: PHASE4
Conditions: Rib Fractures, Pain, Acute
Sponsor: University of California, Irvine

 
Scientific Review Form - revised 
04-26-13 
 
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INSTITUTIONAL REVIEW BOARD 
SCIENTIFIC CONSULTANT CHECKLIST 
 
Date: 
Thursday, 06/03/2021 
Date Review Due 
to HRP/IRB: 
Thursday, 06/24/2021 
HS# 2021-6525 
Study Title:  Dexmedotomidine for Acute Pain Control in Patients with Multiple Rib Fractures: A 
Randomized Controlled Trial 
 
Lead Researcher:  Jeffry Nahmias 
 
Department: Division of Trauma, Burns, Surgical Critical Care and Acute Care Surgery 
 
Hypothesis/Specific Aims/Research Variables 
1. Are the hypotheses clearly identified in the protocol narrative? 
 
Yes 
No 
Comments: 
We hypothesize that the addition of dexmedetomidine (precedex) to a multimodal pain regimen 
will decrease numerical pain scores (NPS) and opioid use in blunt trauma patients with 3 or 
more rib fractures. 
2. Are the specific aims (purpose) of the research justified by the hypotheses? 
Yes 
No 
Comments: 
The aim of this study is to evaluate the effectiveness of adding a dexmedetomidine (precedex) 
infusion to a multimodal pain regimen to treat multiple rib fractures. 
3. Are the primary outcome variable(s), secondary outcome variables, and predictors and/or comparison 
groups adequately described and appropriate based upon the hypotheses and aims?      
                                                                                                                                         
Yes 
No 
Comments: 
Primary outcomes: objective numerical pain scores (NPS) and oral morphine equivalent (OME) 
utilization 
 
Secondary Outcomes: Epidural use, incentive spirometry (IS), ICU LOS, Hospital LOS, 
Pulmonary complications (PNA, intubation), mortality, delirium, and adverse events 
 
 
Methodology/Study Design 
4. Is the methodology and study design appropriate to assess the hypotheses and the aims? 
 
                                                                                                                                    
 Yes 
 
No     
Comments: 

 
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This is a prospective, randomized, double-blinded, placebo-controlled trial. Patients will be 
identified as they present to the trauma bay and meet eligibility criteria. Following informed 
consent patients will be randomized to either the intervention or control arm. Randomization and 
allocation concealment will be managed by a nominated independent individual(s) not involved 
in patient care or data extraction/analysis. The consenting physician will contact the 
randomization individual by phone. They will use a random number generator to assign group in 
a 1:1 ratio and then maintain a password protected randomization database that is only 
accessible to the principal investigator and randomization individual(s).  
  
The intervention arm will receive an infusion of dexmedetomidine (precedex) at 0.4-0.6 
mcg/kg/h (Based off ideal body weight). The control arm will receive an infusion of normal 
saline. Medication distribution and management will be handled by the Investigational Drug 
Service (IDS) at UCI medical center. A pharmacist who does not participate in the rest of the 
study will encode the study drug accordingly. Dexmedetomidine is approved for ICU and 
procedural sedation, and its use in this study for analgesic is off-label. A base line pain 
assessment will be performed using a numerical pain score (NPS). Infusions will start within 12 
hours of arrival to the ICU and will continue for 24 hours. Infusion will stop once the patient is 
transferred out of the ICU or at 24 hours, whichever is first. In the scenario of possible adverse 
events (as listed below) the physician can hold or stop the study medication at their discretion. 
All enrolled patients will also receive a multimodal pain regimen with acetaminophen, NSAIDs, 
lidocaine patch, gabapentin, and muscle relaxants. For moderate and severe pain (5-10) patients 
will receive 5-10mg oxycodone every 4-6 hours upon request. Nursing staff will assess pain per 
the unit standard of care. NPS and opiate administration will be documented in the EMR by the 
nursing staff. All participants, providers, and staff will be blinded unless medical necessity 
requires patients to be unblinded.  
 
Data will be collected prospectively from the EMR by blinded researchers and entered 
into a REDCap database. Data collection will include demographics, mechanism of injury, 
injury severity score (ISS), imaging, pain scores, pain medications, incentive spirometry, 
pulmonary complications, ICU LOS, hospital LOS, discharge disposition, and any other 
clinically relevant data.  
1. Patient identification and consenting – The research staff will identify patients that meet 
eligibility criteria and screen their medical record for inclusion. There mental status, 
capacity, and physical status will be assessed. If they meet criteria the patient or their 
LAR will be approached for informed consent 
2. Randomization – patients will be randomized independently by a third party not involved 
in patient care or data extraction. Researchers and care providers will be blinded to which 
arm they are in for the duration of the trail.  
3. Baseline assessment of pain 
4. Treatment/Study medication - Infusion of either dexmedetomidine (precedex) or normal 
saline – administration of study medication will be handled/monitored by the IDS 
pharmacy. Starting infusion will be set at 0.4 mcg/kg/h. Infusion will continue for 24 
hours. If pain is uncontrolled (NPS>5) after 2 consecutive evaluations patients/care 
providers will have the option to increase infusion to 0.6 mcg/kg/h. 
- 
All patients will receive standard of care pain medications with acetaminophen, NSAIDs, 
lidocaine patch, and muscle relaxants. Unless there are contraindications. 
- 
Nursing staff will document pain scores per unit policy every 2-4 hours 
- 
Opiates will be offered every 4-6 hours for severe pain (NPS>7) 
5. Treatment ends – infusions will stop after 24 hours or when the patient is transferred out 

 
Scientific Review Form - revised 
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of the ICU 
6. Data extraction – data will be collected prospectively by our blinded researchers and 
entered into a REDCap database 
 
 
 
5. Are the stratification, randomization, and blinding scheme procedures appropriate?           
                                                                                                                            
 Yes  
 No  
 N/A 
 
Comments: 
 
6. Are the study endpoints and criteria for evaluation justified?                                 
 Yes 
 No 
Comments: 
Primary end points: 
1. Numerical pain score (NPS) – subjective assessment of patient’s pain on a scale of 0-
10 which is assessed and recorded by our nursing staff as part of standard of care and 
before any pain intervention. We will calculate as area under the curve for pain 
trajectory. 
2. Oral morphine equivalents (OME) – measured at 24 and 48 hours 
Secondary endpoints: 
Epidural use – patients that fail pain management will be offered an epidural 
ICU length of stay – number of days in the ICU 
Hospital length of stay – number of days admitted to the acute care hospital 
Respiratory complications – includes events such as unplanned intubation, pneumonia, 
pneumothorax 

 
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Incentive spirometry (IS) – measured in ml and assessed by nursing per unit policy 
Mortality – in-hospital mortality rate and 30-day mortality 
Incidence of delirium – CAM-ICU score at 24 and 48 hours 
Adverse events – rate of dvt, pe, cardiac events, infections, ICU re-admission, unplanned 
operation, etc 
Adverse events related to dexmedetomidine - Hypotension (SBP <90), Bradycardia (HR 
<55), 
 
Additional Hospital information collected – includes but not limited to 
Medical history and co-morbidities 
Demographics 
Initial trauma assessment and evaluation – injuries, Injury severity score, GCS, vitals, 
weight, and height 
Laboratory results – CBC, BMP, LFTs, PT/PTT, cultures 
Imaging results – x-rays, ultrasounds, and CT scans 
 
Statistical Considerations 
7. Are the statistical method(s) appropriate for the stated specific aims and hypotheses? 
                                                                                                                                     
 Yes     
 No    
Comments: 
The UCI Institute for Clinical and Translational Science Descriptive (ICTS) will be assisting 
with power analysis and final data analysis.  All descriptive statistics (mean + SD, median with 
IQR, or count with percentage) will be calculated for all demographic, clinical variables, 
medical interventions, and outcomes. Any associations between each continuous, binary, or 
categorical variables will be examined using a student t-test, Mann-Whitney U test, Pearson’s χ2, 
or Fisher’s exact t-test. 
 
Primary outcomes will be compared using chi-square or T-test 
Secondary outcomes (including differences in patient demographics) will be analyzed using a 
combination of t-test and chi-square where appropriate. 
 
8. Is the power / sample size appropriately justified? 
 
 
                                                                                                                            
 Yes   
 No   
 N/A 
Comments: 
N=40 
A significant reduction in NPS is defined as a 2-point reduction on a 0-10 scale. Based on prior 
patient pain data, for our target population, the between patient mean was 6.18 with a standard 
deviation of 2.01. Based off this assumption, our sample size was calculated at approximately 17 
patients per group for an 80% power at an alpha of 0.05. We plan to enroll 20 patients in each 
arm and to account for dropout rate, we set out to screen/consent 60 patients.  We plan to 
perform an interval analysis after one year to reassess sample size.  
 
 
SUMMARY 
Summarize the scientific concerns to be addressed by the Lead Researcher (LR). (These comments will 
be incorporated into the IRB memo sent to the Lead Researcher): 

 
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The investigators have provided adequate responses to the first statistical review therefore the statistical 
merit of this study is now acceptable. 
 
Study design 
• 
Pain treatment is tailored according to patient’s trauma severity. Even with randomization, the 
distribution of patients with more severe trauma could be uneven between the two study arms just 
by random chance due to the small sample size of patients. Would it be possible to consider 
block randomization in which patients are paired by similar trauma severity before they are 
randomized into experimental versus control arms? Block randomization would ensure that 
patients are equally distributed between the two arms by their trauma severity. 
• Responses: Thank you for the comment by the SRC, we agree that trauma 
severity is a potential confounder on pain. Most often, injury severity is estimated 
by the injury severity score (ISS). However, we are unable to obtain the ISS until 
many days after admission and thus would not be able to perform a block 
randomization. Furthermore, we have reviewed the literature and a similarly 
designed RCT on Ketamine had two groups with similar ISS just from normal 
randomization (Kugler 2019). To account for this concern, we would plan to add 
a sub-group analysis of ISS>15 and a separate analysis of ISS<15.   
• Added to the protocol narrative is the planned subgroup analysis 
 
Statistical methods 
• 
The primary outcome is the numeric pain score documented every 2 hours during the 24 hours of 
pain treatment. The investigators stated that they will ‘calculate the area under the pain trajectory’ 
for each patient. Please describe in detail how ‘the area under the pain trajectory’ is adjusted for a 
patient’s baseline pain and how ‘the area under the pain trajectory’ is calculated when opioid is 
given to a patient. 
• Responses: All NPS data will be collected by the nursing staff and recorded 
through the patient’s electronic medical record. Each patient’s encounter will be 
organized chronologically by time of pain score entry. We will denote time zero 
as the first pain score after initiation of the study medication. Each additional pain 
score will be recorded as the time elapsed since time zero, until the pre-
determined 24-hour cut-off. A 24-hour observation window was determined 
based off two reasons. One, we are interested in studying the acute pain period 
immediately after admission. Second, dexmedetomidine is only FDA approved 
for up to 24 hours of continuous use. The area under the pain trajectory curve will 
be calculated using the trapezoid rule with linear interpolation between time 
points. Giving us a time-weighted average of pain scores. 
• To account for baseline pain or medications received before time zero, we will 
record all documented NPS and medications received prior to the start of the 
study mediation (time zero). The baseline pain score will be calculated by the 
average NPS prior to time zero. In addition to total pain, we will record the total 
reduction in pain from baseline every 2 hours. 
• Perceived pain is a complex process, which is why a multimodal pain regimen is 
implemented. All patients will receive Gabapentin, Tylenol, lidocaine patches, 
and muscle relaxers. Additionally, opioids are offered for NPS >5. Pain 
medications of different mechanisms work in synergy, and we do not believe 
opioids will nullify the effect of dexmedetomidine. Since both groups are receiving 
opioids and we will be collecting opioid equivalent data we feel this would be 
sufficient to evaluate opioid use as adjusting for timing would be difficult and 

 
Scientific Review Form - revised 
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furthermore this was not done in a recent randomized controlled trial on this topic 
related to use of ketamine (Kugler 2019). 
• Our protocol narrative has been updated to reflect the above changes 
 
 
RECOMMENDATION 
 
  SCIENTIFIC MERIT OF THE STUDY IS ACCEPTABLE (No revisions are necessary prior to IRB 
review.) 
 
 MINOR CHANGES REQUIRED, READY FOR IRB REVIEW (Study requires minor revisions to 
adequately justify the scientific merit of the study. Recommend that the LR address these revisions). 
 
 SUBMISSION INCOMPLETE AND/OR SIGNIFICANT DEFICIENCIES NOTED ABOVE - NOT 
READY FOR IRB REVIEW (Study requires significant revisions and/or has major deficiencies.  
Revisions to documentation required to adequately address the scientific merit of the study.  
Revisions should be re-reviewed by Scientific Consultant prior to IRB review. Strongly recommend LR 
seek methodological/statistical consultation.)    
 
 
TUYEN HOANG, PhD 
 
6/16/2021 ______ 
Scientific Consultant’s signature 
Date 
*If submitted electronically, you may type your name in space above in substitution of hand signature