Clinical trial NCT01826851
Conditions: Coronary Artery Disease Pain, Postoperative
Keywords: Pain management Anesthetic, local Nerve blockade Coronary Artery Bypass Surgery Analgesics, opioid Postoperative complications Bupivacaine
Sponsor: Peter A Knight
Start date: 2013-03-01; Completion date: 2017-06-01
Enrollment: 79 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Exparel is a new local analgesic (numbing medication) that is intended to be longer acting than currently available local analgesics. The purpose of this study is to determine whether use of Exparel to numb the nerves along the breastbone after open heart surgery, will decrease pain and pain medication use after surgery.

Detailed description:
This is a Phase 2, single-institution, randomized, double-blind, parallel-group, placebo-controlled trial of patients undergoing a median sternotomy for primary cardiopulmonary bypass grafting (CABG) surgery.

78 subjects (39 per treatment arm) will be randomized in a 1:1 ratio to receive a single-dose, parasternal nerve block with either 266 mg Exparel or placebo (0.9% normal saline solution). The nerve blocks will be performed under direct visualization at the end of surgery, just prior to sternal closure.

Arms: arm 1: 266 mg Exparel, single-dose injection. arm 2: 0.9% Normal saline, single-dose injection.
Interventions: intervention 1: Exparel intervention 2: Placebo
Intervention descriptions: intervention 1: Patients in this group will receive 266 mg Exparel diluted with 0.9% normal saline to a total volume of 50 mL and administered via parasternal intercostal nerve block prior to sternal closure.

Post-operatively, patients will receive IV fentanyl as needed in the ICU while still intubated. A fentanyl PCA pump will be set up post-extubation as soon as possible and prior to the patient leaving the ICU. intervention 2: Patients in this group will receive 50 mL of 0.9% normal saline as a parasternal intercostal nerve block prior to sternal closure.

Post-surgical pain management will be the same as for the Exparel group.

Protocol documents:
Prot_SAP_000.pdf: 
Parasternal intercostal nerve block in cardiac surgery patients 
Peter A. Knight, MD 
 
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Parasternal Intercostal Nerve Block in Post-Cardiac Surgery Patients: A randomized, 
controlled trial of extended-release liposomal bupivacaine (Exparel®) versus placebo 
Principal Investigator:  Peter A. Knight, MD 
Co-Investigator:  Candice Y. Lee, MD 
 
 
I. PURPOSE OF THE STUDY AND BACKGROUND  
 
Purpose of the study. 
 
The aim of this study is to examine the effect of parasternal intercostal nerve blocks with extended-release 
liposome bupivacaine (Exparel®) on pain control in patients undergoing non-emergent cardiac surgery in a 
prospective randomized controlled trial.  
 
Background. 
 
Inadequate post-operative pain control is a significant problem faced by many patients undergoing cardiac, 
thoracic and abdominal surgery. Barriers to adequate pain control include unwillingness or inability of the 
patient to request for pain medication, inability of nursing to reach the patient in a timely manner and 
hesitance of health care providers to prescribe and reluctance of nurses to administer pain medication1. Poorly 
controlled pain has been shown to lead to various physiologic changes including tachycardia and 
hypertension, which causes increased myocardial oxygen demand. In addition, inadequate pain control results 
in splinting and decreased mobilization, increased morbidity and longer lengths of stay1,2.  
 
Opioids along with non-opioid and nonsteroidal anti-inflammatory agents are the mainstays of treatment for 
post-operative pain in adult cardiac patients. However, the doses of opioid often required can result in 
respiratory depression, delay of extubation, nausea, vomiting, delirium, slowing of gastrointestinal motility 
and hypotension from peripheral vasodilatation2,3. For these reasons, a better method of pain management 
would be valuable. Neuraxial anesthesia (e.g. thoracic epidural anesthesia, spinal anesthesia and paravertebral 
blocks) has shown benefits, yet remains controversial and not widely accepted in cardiac surgery due to 
concerns regarding associated hypotension and paresthesias, as well as potential development of epidural 
abscess or epidural hematoma following anticoagulation3,4.  
 
Parasternal intercostal blocks using local anesthetics have been shown to provide improved post-operative 
pain control and decreased opiate requirements with less potential complications5-8. The sensory innervation 
of the thorax is provided by the 2nd through 6th intercostal nerves. The intercostal nerves terminate in anterior 
cutaneous branches, which divide into medial and lateral branches, providing innervation to the anterior chest 
wall (Fig.1). A parasternal intercostal nerve block targets the anterior intercostal nerves just lateral to the 
sternum (Fig. 2a). Local anesthetic is injected along the undersurface of each rib, infiltrating the space where 
the intercostal nerve travels (Fig. 2b). By doing this prior to sternal closure, the surgeon is able to perform the 
block under direct visualization of the nerves and rib interspaces.  
 
 


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Reproduced from. Gray, Henry. Diagram of the course and branches of a typical intercostal nerve.  
1918. Illustration. Anatomy of the Human Body, 20th ed. By Henry Gray. Philadelphia, PA :  
Lea & Fbiger, 1918. 
 
Figure 1. Saggital view of intercostal space. The intercostal nerve gives off the lateral  
and anterior cutaneous nerves. The anterior cutaneous nerve penetrates through the  
intercostal muscles just lateral to the sternum before dividing into medial and lateral  
branches. These branches supply the anterior chest wall. 
 
 
 
 
Images adapted from: (a) Singer, Raymond L. “Median sternotomy.” Illustration. 12 Sept. 2012. 
http://www.heartlungdoc.com/heart/bypass/coronary_images/Sternotomy%20Diagram.jpg. 
Accessed 12 Sept. 2012. (b) “Intercostal nerve block.” Illustration.  
http://www.advancedorthopain.com/pain-procedures/images/interc1.jpg. Accessed 21 Sept. 2012. 
 
Figure 2. Parasternal intercostal nerve block. (a) Target injection sites are marked (X).  
Each intercostal space was infiltrated, 2 cm lateral to the sternal border, as well as the  
deep subcutaneous space around the mediastinal tubes. (b) Local anesthetic is injected  
along the undersurface of each rib, where the neurovascular bundle travels. 


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In a randomized-controlled trial (RCT) comparing parasternal nerve blocks using ropivacaine vs. placebo, 
Barr et al.5 showed a 30-50% reduction in pain scores and total opiate use. The differences between placebo 
and ropivacaine group were greatest over the first 12 hours post-op and subsequently diminished over the 
next 12 hours of observation5. These benefits were extended over 72 hours with the addition of continuous 
local infusion of ropivacaine6. Thus demonstrating that the efficacy of a parasternal nerve block is limited by 
the duration of action of the local anesthetic used. Bupivacaine is another long-acting local anesthetic (amide-
type local anesthetic) that is routinely used for postsurgical anesthesia, yet the maximum duration of this drug 
is only 6-12 hours. We hypothesize that use of a longer-acting local anesthetic will potentiate the benefits of 
improved pain control and reduced opioid requirements. 
 
Exparel® is a long-acting, extended-release liposome injection of bupivacaine that has been FDA-approved 
for “single-dose infiltration into the surgical site to produce postsurgical anesthesia”. Exparel® is a liquid 
suspension of spherical, microsomal liposomes (DepoFoam® drug delivery system) containing multiple 
aqueous chambers of encapsulated bupivacaine8-10 (Fig. 3). Bupivacaine is gradually released from the 
liposomes by diffusion as the unprotonated (uncharged) form of bupivacaine. This formulation allows for 
sustained release of bupivacaine at the site of injection without exposing patients to toxic plasma 
concentrations10-11. In clinical trials, Depofoam® bupivacaine has shown duration of action up to 72 to 96 
hours, while peak plasma bupivacaine concentration (0.4 to 1.4 µg/ml) remained well below the reported 
toxic plasma concentration (2-4 µg/ml)11-14. Randomized clinical trials (RCT) comparing Exparel to 
bupivacaine and placebo in various surgeries (e.g. hemorrhoidectomy, bunionectomy, inguinal hernia repair, 
total knee replacement) have shown improved outcomes of pain control and decreased narcotic requirements.  
In RCTs with patients undergoing hemorrhoidectomies, benefits from Exparel® were more substantial from 
12-72 hours with a 47% reduction in cumulative pain score and 66% relative reduction in opioid 
consumption compared to bupivacaine12-13.  
 
 
 
 
 
 
 
Figure 3. Cross-sectional diagram  
of DepoFoam® drug delivery system  
containing aqueous chambers filled with  
Bupivacaine.  
 
 
 
 
 
 
 
                        
Reproduced from Chahar P, Cummings KC. Liposomal bupivacaine: a review of a new 
        
bupivacaine formulation. J Pain Research. 2012. 
 
To compare differences in pain control, we will use a number of validated pain assessment tools. These 
include the adult nonverbal pain scale (NVPS), numerical rating scale (NRS) and brief pain inventory (BPI) 
(see Appendix II and III). The NVPS has been adopted by the cardiovascular ICU (CVICU) for assessing 
pain in critically-ill, intubated patients. It includes assessments of the patient’s face, body movements, muscle 
tension and vital signs to determine a total score ranging from 0 to 10. It has been shown to exhibit high 
reliability and inter-rater agreement, as well as increase patient and staff satisfaction15-16. The NRS is an 11-
point scale ranging from 0, “no pain”, to 10, “the worst possible pain”, that is used by nursing staff for 


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assessing and documenting pain in extubated, alert patients. The scale has shown high sensitivity and 
simplicity17. Moreover it is interval and allows for parametric analysis. The BPI consists of four questions 
rating pain severity and seven questions regarding impact of pain on daily function, allowing calculation of 
pain severity and interference indices for comparison. Studies have shown that BPI scores correlate with the 
number of days from surgery and decreasing analgesic requirements18-20. 
 
Exparel® is not currently FDA-approved for peripheral nerve blocks. There are two ongoing clinical trials 
studying the use of Exparel® for femoral nerve blocks21-22. However, Exparel® has not previously been 
studied for our specific application. Thus, we are conducting this study to evaluate the efficacy and safety of 
Exparel® in parasternal nerve blocks in cardiac surgery patients. Successful use of Exparel® for parasternal 
intercostal nerve blocks may revolutionize the management of post-cardiac surgery pain. Optimal pain 
control and reduced opioid doses would enable earlier extubation and mobilization, less opioid-associated 
morbidity and shorter ICU and total hospital lengths of stay. 
 
Hypothesis: We hypothesize that administration of Exparel® in parasternal nerve blocks will provide 
improved pain control and decreased narcotic use in the adult post-operative cardiac surgery patient. 
 
Primary aim: To determine if there is a statistically significant improvement in analgesia and decreased 
opioid requirements in the post-operative period.  
 
Secondary aim: To look at differences in LOS (ICU and hospital), time to return of bowel function, and 
time to return to work or daily activities. We will also look at incidence of complications related to 
inadequate pain control and the incidence of adverse events. 
 
II. CHARACTERISTICS OF THE RESEARCH POPULATION  
Number of subjects.  
 
The study will include 78 patients, 39 patients in the study drug arm and 39 patients in the control arm. Since 
there are two primary outcomes, we set the type I error at 0.025 for the power analysis. Based on results from 
a prior study by Barr et al.5, we assumed a baseline Numerical Rating Scale (NRS) score for pain of 53.2 with 
standard deviation of 24.1 and a baseline cumulative morphine requirement over 24 hours of 23.2 mg with 
standard deviation of 8.3 mg. The proposed sample size was calculated to achieve 86% power to detect a 
30% decrease in mean NRS scores at the 2.5% level of type I error (two-sided). This sample size also 
provides for a 98% power to detect a 30% decrease in total opioid consumption over the first 24 hours post-
operatively. Note that we assumed the standard deviation decreases accordingly. A 5% drop out rate was 
included into the sample size calculation. 
 
Gender of Subjects.  
 
The study will include male subjects and non-pregnant female subjects. 
 
 
Age of Subjects.  
 
Adults (age ≥ 18 years old) will be included. Exparel® is currently only approved in patients ≥ 18 years old. 
 
Racial and Ethnic Origin.  
 
Subjects of all racial and ethnic origins will be included in the study. 
 


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Inclusion Criteria.  
 
We will include adult patients (≥ 18 year old) undergoing non-emergent coronary artery bypass grafting 
surgery (on and off pump) requiring a median sternotomy.  
 
Exclusion Criteria.  
 
• 
Concomitant cardiac procedures (e.g. aortic valve repair/replacement, mitral valve repair/replacement, 
aortic root replacements) 
• 
Redo sternotomy. 
• 
< 50 kg (Exparel® is currently only approved in patients > 50 kg). 
• 
Pregnant or nursing 
• 
History of alcohol, narcotic or illicit drug abuse 
• 
Participation in another study evaluating investigational medications within the past 30 days 
• 
Taking narcotic analgesics within 3 days pre-operatively or perioperative stress-dose steroids. 
• 
Chronic non-cardiac pain (e.g. lower back pain, fibromyalgia) requiring narcotic analgesics. 
• Pre-operative mild liver insufficiency as defined by LFTs (i.e. ALT, AST) ≥ 1.5 times the upper 
limit of normal (ULN: ALT: 0-35 U/L, AST: 0-35 U/L, Alk Phos 35-105 U/L, Total bilirubin: 0-
1.2 mg/dL) 
• Pre-operative mild renal insufficiency (Cr ≥ 1.5 mg/dL) 
• 
Allergy to amide-type anesthetics 
• 
Recurrent ventricular arrhythmias, low cardiac output requiring inotrope and/or intra-aortic balloon pump 
support, LVEF < 30% at time of pre-operative screening/evaluation. 
• 
Unable to provide informed consent or unable to understand how to use pain rating scales. 
• 
Inability to understand or operate the patient-controlled analgesia (PCA) machine. 
 
Withdrawal Criteria. 
 
Patients meeting these intra-operative and post-operative criteria will be withdrawn from the study because of 
the likelihood that these characteristics will independently affect primary and secondary study outcomes. 
However, primary and secondary outcomes will still be collected for these patients and results included in an 
“intention-to-treat” analysis. 
 
• 
Post-operative intubation longer than 16 hours. 
• 
Cardiopulmonary bypass time > 3 hours or aortic cross-clamp time > 120 minutes. 
• 
Return to OR during hospital admission. 
 
Vulnerable Subjects.  
 
No vulnerable subjects will be included in this study. Only patients deemed competent to voluntarily consent 
to participation in this study will be included. 
 
 
  
III. METHODS AND PROCEDURES  
Methods and Procedures.  
Refer to Appendix I for overview of Study Schedule. 
 


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Patient enrollment 
 
Screening procedures will be performed in the outpatient clinic, inpatient floor or cardiac cath lab. During the 
screening visit, medical/surgical history, vital sign measurements, and routine clinical laboratory tests, which 
are normally obtained in all cardiac surgery patients (complete metabolic panel, CBC, INR/PTT). If the 
patient meets eligibility criteria and is willing to participate, then informed consent will be obtained. 
Consenting patients will also undergo drug/alcohol screening and forced vital capacity (FVC) measurement 
prior to surgery. The patients will be trained on the pain assessment tools used during the study, including the 
adult NVPS and NRS (see Appendix II). 
 
Prior to the planned operation, patients will be administered the Brief Pain Inventory to establish baseline 
pain scores (see Appendix III). The patient will also receive a sheet reviewing the NVPS and NRS pain 
assessment scales and be asked to rate their pain on the NRS scale. They will also be instructed on how to use 
the PCA pump prior to surgery.  
 
On the day of surgery, the subjects’ history, physical and labs will be reviewed by research staff to confirm 
study eligibility. They will also be instructed on how to use the incentive spirometer and their peak 
inspiratory capacity (IC) will be measured. 
 
Randomization and Blinding 
 
Patients will be randomized on the day of surgery to either placebo or treatment group. The subjects will be 
randomized in blocks of 4 to ensure a 1:1 ratio of placebo to treatment groups.  
• 
Placebo: 0.9% normal saline 
• 
Treatment group: 0.53% Exparel® 
 
A randomization sheet will be generated by the study pharmacist, listing the randomization schedule in 
sequence for each block. The study pharmacist will have control of the randomization sheet. At the time of 
randomization, he will go to the next available row to determine which medication to disperse. The 
randomization sheet will document each subject’s number, initials, date of surgery and study arm (active or 
placebo).  
 
The study pharmacist will hold the key identifying which study group corresponds with which letter. In order 
to maintain blinding of the study investigators, the pharmacist will not reveal the subject’s group assignment 
and data collection will be done according to the subject number. At quarterly intervals during the trial, the 
study pharmacist will reveal the blinding to the Independent Data/Safety Monitor (DSM) only. This will 
enable the Independent DSM to capture for any alarming trends in adverse events or serious adverse events 
as they are occurring. At completion of data collection and analysis for the entire study, the pharmacist will 
provide the study investigators with a copy of the report revealing which subject belonged to which study 
group. 
 
The subjects will be blinded to their study arm and remain blinded for the entire duration of this study. 
Subjects who wish to know which drug they received (Exparel® or placebo), may contact the PI or co-PI and 
they will be informed of their study group following completion the study.  
 
The study investigators, surgeon administering the medications, operating room staff and ICU/floor staff will 
all remain blinded. Only the pharmacist who will prepare and dispense the medication will be unblinded.  
 
 
 
 


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Anesthetic Regimen 
 
A standard anesthetic regimen to promote early extubation will be used, per our institutions protocols. The 
regimen will include: 
• 
Pre-induction with midazolam. 
• 
Induction with midazolam, fentanyl/sufentanyl, vecuronium/rocuronium, and isoflurane. 
• 
Maintenance of intra-operative anesthesia with isoflurance and vecuronium/rocuronium.  
 
Intraoperative monitoring will include standard ASA monitor, an arterial catheter and a central venous 
catheter. Pulmonary arterial catheters and transesophageal echocardiography will be used per institutional 
standards.  
 
Parasternal intercostal nerve block 
 
The parasternal blocks will be performed by a blinded surgeon at the end of surgery, just prior to sternal 
closure.  
 
The medication will be prepared and dispersed by the study pharmacist in a concealed vial. The contents of 
the vial will be drawn up into two sheathed sterile 30 cc syringes by the operating room staff. Due to the 
distinct visual characteristics of normal saline (transparent) compared to Exparel® (translucent), sheathed 
syringes will be used to maintain blinding of the surgeon and operating room staff.  
 
The components of a parasternal nerve block include anesthetizing the anterior cutaneous branches of 
intercostal nerves two through six and the deep subcutaneous layers around the mediastinal drain sites (Fig. 
2). First, sequential intercostal blocks will be performed with 4 mL per intercostal space across 5 intercostal 
spaces bilaterally. Then 10 mL will be injected in the superficial to deep subcutaneous tissue surrounding 
mediastinal drains. A total of 50 mL of either 0.9% normal saline or 50 mL of 0.53% Exparel® will be used 
for the parasternal block. 
 
Cardiac and Neurologic Monitoring 
 
Continuous electrocardiogram (ECG) and vital sign (heart rate, blood pressure, respiratory rate) monitoring 
will be performed following administration of Exparel®, per standard protocol. Electrocardiogram tracing and 
vital signs will be documented pre-injection, during injection, post-injection, and at 1 hour and 2 hour post 
injection. Continuous ECG monitoring will be maintained for at least 48 hours post dose. Vital signs will be 
measured and recorded at time 0, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours post dose. 
 
Neurologic assessments will include evaluation for signs of lethargy, restlessness, anxiety, dizziness, tinnitus, 
blurred vision, tremors and convulsions. Patients will be assessed to the extent possible while still intubated 
and recovering from anesthesia. The assessments will be performed upon the patient’s initial arrival to the 
ICU (prior to initiation of continuous sedation) and at 2, 4, 8, 12, 24, 36 and 48 hours post dose.  
 
If a subject exhibits signs of suspected bupivacaine toxicity (e.g. cardiotoxic and/or neurotoxic signs or 
symptoms), then a blood sample will be drawn as soon as possible to determine plasma bupivacaine levels. 
Cardiovascular system reactions may include atrioventricular block , ventricular arrhythmias and/or cardiac 
arrest. Central nervous system reactions may include lethargy, restlessness, anxiety, dizziness, tinnitus, 
blurred vision, tremors and/or convulsions. 
 
Post-operative pain control 
 
Patients will be treated with fentanyl boluses during the immediate post-operative period and while intubated 


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in the ICU, until they are able to use the PCA. Pain will be evaluated using the adult NVPS (see Appendix II) 
and medication will be administered for NVPS score ≥ 4. Per routine cardiovascular ICU protocol, patients 
will receive Indomethacin 25 mg every 8 hours for three doses if they meet the following criteria: (1) Cr < 
1.5 and (2) age < 75.  
 
The patients will be extubated per the standard cardiovascular ICU protocol (see Appendix IV). Following 
extubation, pain will be assessed using the NRS (see Appendix II) and pain regimen will be adjusted for NRS 
score ≥  4. All patients will receive either fentanyl IV or hydromorphone IV (if fentanyl is poorly tolerated or 
patient is allergic to fentanyl) via PCA device following extubation. The PCA will be continued for the first 
48 hrs postoperatively.  
 
The initial PCA orders will be written by a study team member. If the PCA requires dose adjustment or 
medication change, then the cardiovascular ICU or floor providers will modify the order per the protocol 
below. This is a safety mechanism, in case a study team member is unavailable at the time. 
 
The PCA will be set accordingly (see Appendix V): 
 
• 
A fentanyl PCA will be set up with the following specifications: 
o Loading dose: 1 mcg/kg IV bolus fentanyl divided into 2 doses given 10 minutes apart 
o Bolus dose: 10 mcg IV bolus fentanyl with a lockout interval of 15 minutes and maximum 1 hr limit 
of 80 mcg. The incremental bolus dose of fentanyl will be increased by 25-50% if analgesia is 
inadequate (NRS ≥ 4).  
o If the patient experiences undue side effects from fentanyl PCA (see below) and pain is still 
inadequately controlled at current dosage, then the patient will be switched over to a dilaudid PCA. 
However, if pain is controlled with the fentanyl PCA bolus, but the patient is experiencing undue side 
effects, then the following steps will be taken:  
1. Decrease the PCA bolus dose to 7.5 mcg IV bolus with a lockout interval of 15 minutes. 
2. If the patient still does not tolerate the fentanyl PCA well, then decrease the PCA bolus dose 
to 5.5 mcg IV bolus with a lockout interval of 15 minutes. 
3. If the patient still does not tolerate the fentanyl PCA well, then decrease the PCA bolus dose 
to 4.0 mcg IV bolus with a lockout interval of 15 minutes. 
4. If patient continues to not tolerate the fentanyl PCA well, then switch over to a dilaudid 
PCA. 
 
• 
If the patient is allergic to fentanyl or continues to poorly tolerate fentanyl (despite dose adjustments), 
then the patient will be switched over to a dilaudid PCA: 
o Loading dose = 0.02 mg/kg IV bolus hydromorphone divided into 2 doses given 10 minutes apart,  
o Bolus dose = 0.2 mg IV bolus hydromorphone with a lockout interval of 15 minutes and maximum 1 
hr limit of 1.6 mg. The incremental bolus dose of hydromorphone will be increased by 25-50% if 
analgesia is inadequate (NRS ≥ 4). 
 
• 
“Poor tolerance” and/or undue side effects of the narcotic may include: 
o Excessive nausea/vomiting refractory to antiemetics. 
o Itching/rash deemed related to narcotic and refractory to Benadryl. 
o Altered mental status or feeling “high” from narcotic bolus. 
 
• 
The PCA dose may be titrated up or down to attain adequate anesthesia and minimize side effects from 
the narcotics. 
• 
Naloxone may be used for respiratory depression (respiratory rate < 8 breaths per minute), over-sedation 
or muscle rigidity secondary to opioid overdose. The PCA bolus dose will be decreased by 25-50% if this 
occurs. 


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Following discontinuation of the PCA, patients will be transitioned to Percocet 5/325 mg 1-2 tabs PO every 4 
hours as needed or Hydrocodone-Acetaminophen 5/325 mg 1-2 tabs PO every 6 hours as needed. 
 
Rescue pain medication:  
• 
A dose of Toradol 15 mg IV or Tramadol 50-100 mg PO will be administered as rescue medication if 
patient is still reporting inadequate analgesia (NRS ≥ 4), but has already met the 1 hour maximum dose of 
fentanyl or dilaudid. 
• 
Once the patient has been transitioned to PO pain medications, a dose of dilaudid 0.5 mg IV or morphine 
2 mg IV may be administered as rescue medication if the patient is still reporting inadequate analgesia 
(NRS ≥ 4), but cannot receive additional narcotics (i.e. Percocet or Hydrocodone-Acetaminophen) for 
that time period. 
 
Standardized bowel regimen 
 
Bowel regimens will be standardized to control for differences in prescribed stool softeners and laxatives. 
 
All patients will receive Colace 1 tab twice daily, Dulcolax 1 tab oral every morning and Senna 1 tab nightly 
once they are able to tolerate PO medications. If patients do not have a bowel movement by post-operative 
day 2 (POD #2), the bowel regiment will be increased until the patient has a bowel movement. The order of 
escalation of prescribed medications will be as follows: 
• 
POD #2 AM: Dulcolax suppository + Milk of Magnesia  
• 
POD #2 PM: Lactulose oral or Miralax 
• 
POD #3 AM: Lactulose oral or Miralax (whichever he/she did not receive on POD #2)  
• 
POD #3 PM: Enema (soapsuds, fleets, mineral oil, etc.) 
 
Follow-up 
 
The subjects will be seen by their primary care physician within 7-10 days per standard URMC protocol. 
They will return to clinic for a post-operative visit approximately 30 days from discharge. During this visit, 
they will be administered a brief questionnaire regarding presence/quality of continued pain following 
discharge (BPI-SF, see Appendix III). They will also be asked to rate the quality of their pain control during 
their hospitalization and recall their time to return to work or daily activities. During this visit, they will also 
be debriefed about the study. 
 
In addition, in order to assess the success of maintenance of the blind, we will ask the subjects to: (1) guess 
which treatment (Exparel® or placebo) they think they received in the study, (2) express their degree of 
certainty regarding their guess, and (3) explain their reasons for their guess. 
 
Measurements/Data collection. 
 
Pain assessment: 
 
The adult NVPS will be used to assess pain while patient is intubated in the ICU. This scale is used routinely 
in intubated and nonverbal critically ill patients in the Cardiovascular ICU (CVICU). The NVPS will be 
performed by a blinded care provider (e.g. nurse or nurse manager) who is trained on how to use the scale. 
Time 0 will be designated as the time the patient leaves the OR. The NVPS will be performed every 2 hrs for 
the first 4 hrs and then every 4 hrs following until the patient is extubated. 
 
The numerical rating scale (NRS) ranging from 0 (no pain) to 10 (worst pain ever) will be used to assess pain 


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once the patient is extubated and alert. The scale will be administered every 4 hrs for the first 72 hrs post-op.  
 
Cumulate pain scores at time points at 2, 4, 8, 12, 24, 36, 48, 60 and 72 hrs will be compared. 
 
 
Opioid requirements: 
 
All narcotics will be converted to fentanyl equivalents (see Appendix VI) in order to calculate total morphine 
requirements for each interval. Cumulate morphine equivalents used at time intervals 2, 4, 8, 12, 24, 36, 48, 
60 and 72 hours will be calculated. 
 
Secondary outcomes: 
 
“ICU length of stay” will be calculated as the time the patient leaves the OR to the time that the patient is 
deemed appropriate for transfer out of the ICU by the treating physician and nursing staff, in hours. 
 
“Hospital length of stay” will be calculated as the time the patient leaves the OR to the time of discharge, in 
days.  
 
“Time to extubation” will be calculated as time the patient leaves the OR to the time of extubation, in hours. 
 
“Time to return of bowel function” will be calculated as the time the patient leaves the OR to the time of first 
recorded bowel movement, in days. 
 
Other variables:  
 
Splinting can occur from inadequately controlled pain, resulting in the subject avoiding deep inspiration. The 
degree of splinting will be measured by a change in bedside inspiratory capacity (IC) at post-operative day 1-
2 from preoperative IC. 
 
Adverse events will be recorded: 
• 
Adverse cardiac events: angina, myocardial infarction, new cardiac arrhythmia 
• 
Neurologic: transient ischemic attack (TIA), stroke (CVA) 
• 
Gastrointestinal: constipation, ileus, bowel obstruction 
• 
Pulmonary: Pneumonia 
• 
Renal: renal insufficiency 
• 
Wound infection, wound dehiscence 
 
Assessment of the blind 
 
Subject responses at follow-up regarding speculation about the treatments received will be 
compared to each subjects actual group assignment in order to determine adequacy of the blind. 
 
Data Analysis.  
 
Data Analysis 
• 
Patient demographics/Pre-op characteristics: 
o Age, sex, race, Body surface area (BSA)/BMI 
o Co-morbid diseases: Diabetes mellitus, COPD, smoking, hypertension, coronary artery disease 
o Left ventricular ejection fraction (%) 


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o Creatinine (Cr), Cr clearance 
o Functional status: New York Heart Association (NYHA) class, American Society of 
Anesthesiologists (ASA) classification 
• 
Intra-operative characteristics: 
o Operation type: CABG (on/off bypass), AVR, MV repair/replacement, Maze, Other (i.e. TV 
repair/replacement, ASD closure) 
o Internal mammary artery (IMA) harvested (one or two) 
o Cardiopulmonary bypass time (min) 
o Aortic cross-clamp time (min) 
o Intraoperative fentanyl (µg), intraoperative versed (mg) 
• 
Pain assessment: 
o Calculate mean area under the curve (AUC) for adult NVPS scores over the time intervals “0-2”, 
“0-4”, “0-8” and “0-12” hours. 
o Calculate mean AUC for NRS scores over the time intervals “0-12”, “0-24”, “0-36”, “0-48”, “0-
60” and “0-72” hours. 
• 
Opioid requirement: 
o Calculate mean cumulative fentanyl equivalent use for time intervals “0-2”, “0-4”, “0-8”, “0-12”, 
“0-24”, “0-36”, “0-48”, “0-60” and “0-72” hours.  
o Use of breakthrough pain medication (e.g. Toradol or Tramadol) 
• 
ICU length of stay: 
o Calculate mean lengths of stay (hours) for placebo and Exparel® groups. 
• 
Hospital length of stay: 
o Calculate mean lengths of stay (days) for placebo and Exparel® groups. 
• 
Time to extubation: 
o Calculate mean time to extubation (hours) for placebo and Exparel® groups. 
• 
Time to return of bowel function: 
o Calculate mean time to return of bowel function for placebo and Exparel® groups. 
• 
Splinting 
o Mean change in IC from pre-operative to POD #1-2 in both treatment arms. 
• 
Assessment of blind 
o Calculate the percentage of correctly guessed treatment assignments. 
 
Statistical analysis 
 
Descriptive statistics will be reported for each group. Means with standard deviation and 95% confidence 
intervals of the means will be reported for continuous variables and frequency and proportion distribution 
will be reported for categorical outcomes. 
 
Student t-test (for normally distributed continuous variables) and Wilcoxon rank sum tests (for non-normally 
distributed variables) will be used to compare continuous outcomes such as AUC for adult NVPS/ NRS and 
opioid requirements between the two groups. For categorical outcomes, chi-square tests will be used to 
compare differences between the two groups. If some cell counts are small and the asymptotic tests are not 
reliable, then exact methods will be used. A general linear regression model for NRS scores will be applied to 
show the main effect for the treatment group, adjusting for covariates. Regression analysis will also be 
applied to opioid requirements. For the binary outcome of whether a patient has reached his/her maximum 
allowed dose of opioid, logistic regression models will be applied. For the opioid requirement outcome, 
patients who have reached their maximum allowed dose of opioid will be treated as censored and a Tobit 
regression model will be applied. Since there are two primary outcomes, a type I error of 2.5% will be used. 
All the tests will be two-sided. 
 


Parasternal intercostal nerve block in cardiac surgery patients 
Peter A. Knight, MD 
 
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Survival analyses will be applied for time to event data, such as the lengths of stay and mean time to return of 
bowel function. Logrank tests will be applied for simple comparisons between the two groups. Cox 
proportional hazards models will be used to facilitate the inclusion of covariates in the regression analysis. 
Note that although no censoring of subjects are expected in the study (i.e. the lengths of stay and mean time 
to return of bowel function will be observed for each patient) and a general linear regression analysis may be 
applicable, our survival analysis approach enables us to estimate the survival curves and read the different 
rates at different time points from the curves.  
 
Since variables such as NRS are measured repeatedly over the 72-hr time period, we may refine our analysis 
by using all of the measures instead of using the simple summarizing index, AUC. Methods for longitudinal 
data will be applied to deal with the correlation among repeated measures in the same patient. The two most 
popular approaches for longitudinal data modeling are the generalized estimating equations (GEE) approach 
and the mixed-effects model (MM) approach.  MM explicitly models between- and within-subject variation 
using random effects, and thus has the advantage of being able to separate between-subject variability from 
the total variability of responses. However, it requires parametric assumptions on observed and latent 
variables, which render inference vulnerable to departures from a normal distribution. An alternative 
approach to these models is the GEE approach. GEE ignores between-subject variability in model 
specification, but accounts for such variability during model estimation in order to ensure inference validity; 
therefore, GEE can provide robust estimates for between-group differences, as it does not require any 
assumption of the distribution. However, GEE is limited in that it requires the missing completely at random 
(MCAR) assumption, which may be violated. We will examine the nature of the missing data and use a 
weighted GEE (WGEE) approach as needed to address potential informative dropout. Our hypotheses 
concern between-group differences, so both parametric and semi-parametric approaches will be used. Both 
approaches will be used in the analysis and if discrepancies in MM and GEE (or WGEE) analyses occur, 
GEE (or WGEE) will be recommended, as the latter semi-parametric approach generally provides more 
robust inference. 
 
All analyses will be performed using the latest version of SAS, which includes procedures for all of the 
analyses proposed, including Tobit regression, survival analysis, linear mixed model, and GEE (or WGEE) 
models. A statistician will be involved in reviewing the final analyses and confirming statistical soundness.  
 
Data Safety Monitoring. 
 
Data Safety Monitoring Plan 
Dr. Stephen Breneman will serve as our independent DSM. He is not directly involved in data collection or 
patient interaction and will be used to avoid conflict of interest. The DSM will be unblinded, so that he can 
identify any alarming trends in adverse events or serious adverse events that may warrant modification or 
stopping of the study. The independent DSM will conduct periodic unblinded assessments of the aggregate 
data at 25% (20 patients), 50% (39 patients), 75% (59 patients) and 100% (78 patients) study enrollment. If 
enrollment is slow, then the independent DSM will review all aggregate adverse events at least yearly and 
review completed electronic adverse event case report forms (stored in RedCAP) at least quarterly during 
throughout the year.  
Dr. Candice Lee will serve as the Clinical Monitor. The Clinical Monitor will review all adverse events as 
they occur to make sure that they fall within reason of the study (expected possible adverse events). The 
Clinical Monitor will contact the DSM if there are concerns regarding a greater than expected number of 
adverse events or serious adverse events. All serious adverse events will be reported to the DSM within 24 
hours of identification of the event’s occurrence. The DSM will review these events in an unblinded fashion. 
If there is an alarming trend with multiple occurrences of serious adverse events that are determined to be 
significant enough to warrant modification or stopping of the trial, then the DSM will notify the PI.  
 


Parasternal intercostal nerve block in cardiac surgery patients 
Peter A. Knight, MD 
 
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The study investigator-sponsor is responsible for ensuring that all adverse and unexpected events related to 
study participation are reported in a timely fashion to the FDA and institution IRB. 
 
Self-audit 
 
An internal self-auditing of the blinded data will be conducted by the PI and co-PI. The data evaluated by the 
PI and co-PI during self-audits will be in the blinded form. Subject groups will only be identified by the 
arbitrary letter assigned to them by the study pharmacist in order to protect the true identity of their group 
(placebo or Exparel®). An initial self-audit will be conducted after completion of the 1st patient participation. 
During this audit, the PI and co-PI will review and discuss:  
• 
abnormal laboratory data 
• 
cumulative pain scores 
• 
cumulative opioid use 
• 
secondary outcomes  
• 
adverse events 
• 
signed informed consents 
• 
any need for revision of study methods and procedures or data collection forms  
 
Also reviewed during self-audits will be any feedback from involved departments (including pharmacy, 
anesthesia and nursing) regarding adverse events or concerns related to the subjects’ participation. These 
departments may contact the PI or co-PI with any concerns at any time during the study via telephone or 
email. 
 
A repeat self-audit will be conducted after completion of the 3rd patient participation to evaluate effectiveness 
of any changes made to the study protocol and/or data collection forms. Another self-audit will occur 
following 50% completion of subject participation (39 patients).  
 
Indications for termination of study 
The study will be terminated if an overwhelming amount of serious adverse events deemed related to therapy 
(e.g. significant new cardiac arrhythmias, CNS reactions, wound infection/dehiscence or severe allergic 
reactions) occur in either the Exparel® group or the placebo group. 
 
Data Storage and Confidentiality.  
 
Data collection will be entered and stored in the Research Electronic Data Capture (REDCap) system, which 
is a password-protected web application for building and managing online surveys and databases. REDCap 
allows database creation and storage of collected data in a secure manner. A comprehensive REDCap 
database will be created by the PI, co-PI and study coordinator. Only the PI and co-PI will have full 
administrative access to the database; meaning that they can add users, restrict levels of user access, export 
data and change data collection forms. The co-PI and trained study investigators will be in charge of entering 
patient data into the developed data collection forms. Each patient will be assigned a unique identification 
number (UID) upon initial entry into the REDCap database. Limited access to the REDCap database will be 
granted to the study statisticians and Medical/Safety Monitor. These persons will be allowed read-only access 
with all patient identifiers blocked (subjects identifiable only by their assigned UID). A printed key linking 
the patient medical record number (MRN) and UID, as well as any questionnaires including patient 
identifiers will be kept in a locked cabinet in Dr. Knight’s office. Only Dr. Knight and the co-PI will have 
access to the file. All printed data collection sheets will contain only the subject’s UID. 
 
The database will include data collection sheets that will store demographic information and clinical 
outcomes for each subject, including the following information: age at time of surgery, sex, race, 


Parasternal intercostal nerve block in cardiac surgery patients 
Peter A. Knight, MD 
 
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comorbidities (diabetes mellitus, COPD, smoker), left ventricular ejection fraction (%), baseline pain 
assessment score, surgical procedure performed, intraoperative measures (aortic cross-clamp time, LIMA 
harvest, cardiopulmonary bypass time, amount of crystalloid/blood products/cell saver received), total 
intraoperative opiate and benzodiazepines administered. Subjects’ NVPS and NRS pain scores, opiate 
requirements, length of stay, time to first bowel movement and any adverse events will also be stored on data 
collection sheets.  
 
At completion of data collection and entry into the database, all identifiers linking patient to UID will be 
destroyed and only the key will remain. The key will be destroyed following completion of this study. Study 
records will be maintained in a secured location for 3 years following closing of the study. No identifiers will 
be released in reported results or publications. 
 
IV. RISK/BENEFIT ASSESSMENT  
Risk Category: This study constitutes a greater than minimal risk to the patient.  
 
Potential physical harm arises from the possible side effects of Exparel®. Neurologic and cardiac adverse 
reactions that have been reported with Exparel® administration include dizziness (6.2%), headache (3.8%), 
somnolence (2.1%), hypoesthesia (1.5%), lethargy (1.3%), tachycardia (3.9%) and bradycardia (1.6%). High 
levels of bupivacaine in the plasma result from accidental overdose, unintended intravascular injection or 
accumulation of the drug in the plasma secondary to decreased hepatic metabolic degradation or decreased 
plasma protein binding capacity due to acidosis5. Clinical trials of Exparel® reveal a good safety profile5-7. 
Side effects that have been reported in clinical trials are represented in the following table. 
  
Table 1: Adverse reactions reported with use of Exparel® 
Information reproduced from: Exparel Prescribing Information. 23 Jan. 2012. Pacira Pharms, Inc. San Diego, CA.  
 
All parasternal intercostal nerve blocks will be performed by a cardiac surgeon familiar with the study 
protocol and experienced in performing the procedure. The benefit of performing parasternal blocks prior to 
sternal closure is the ability to directly visualize and confirm appropriate placement of the needle tip. The 
syringe will be aspirated prior to injection to avoid intravascular injection of the drug. Hemodynamics and 
electrocardiography tracings will be monitored closely for arrhythmias and hypotension following 
administration of the drug. 
 
PCA’s are not routinely used after cardiac surgery, but are often used after other major surgeries including 
abdominal and orthopedic procedures. The risks of PCA are related to the adverse effects of opioid use, 
which may include: constipation, nausea/vomiting, sedation, respiratory depression, pruritus, 
Incidence 
Adverse reaction 
Most common 
(≥ 10%) 
Nausea, constipation, vomiting 
Common 
(≥ 2 or ≤ 10%) 
Pyrexia, dizziness, peripheral edema, anemia, hypotension, pruritus, 
tachycardia, headache, insomnia, postoperative anemia, muscle spasm, 
hemorrhagic anemia, back pain, somnolence, procedural pain 
Less common/rare 
(< 2%) 
Chills, erythema, bradycardia, palpitations, supraventricular/ventricular 
extrasystoles, ventricular tachycardia, anxiety, urinary retention, pain, 
edema, tremor, postural dizziness, paresthesia, syncope, incision site 
edema, procedural hypertension/hypotension, procedural nausea, 
muscular weakness, neck pain, cold sweat, urticaria, confusional state, 
depression, agitation, hyperhidrosis, restlessness, blurred vision, 
tinnitus, hypoxia, apnea, urinary incontinence, drug hypersensitivity. 


Parasternal intercostal nerve block in cardiac surgery patients 
Peter A. Knight, MD 
 
Page 15 of 25 
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confusion/hallucination, urinary retention, sweating, miosis and myoclonic jerks. All patients will be 
monitored closely while using the PCA and if they start showing signs of opioid toxicity, then PCA dosing 
will be decreased or changed appropriately. If patients show signs of narcotic overdose (respiratory rate < 8 
breaths per minute, over-sedation, or muscle rigidity), then naloxone will be administered for opioid reversal.  
 
This study also constitutes a potential psychological stress arising from the blinding of subjects as to which 
research arm (placebo vs. Exparel®) they are assigned. There is also a risk of invasion of privacy because of 
the storage of identifiable clinical data. All clinical data will be in de-identified form. The key containing 
identifiers and linking medical record number will be kept secure and be accessible only to the PI and 
primary study coordinator. All clinical data released will be in de-identified form. 
 
Potential benefits to the subjects are that the parasternal intercostal nerve blocks with Exparel® may provide 
improved pain control. This would benefit the patients by leading to less discomfort post-operatively, less 
narcotic requirements, lower morbidity and quicker time to recovery. Patients randomized to the placebo 
group would receive no direct benefit from participating in this study. 
 
V. SUBJECT IDENTIFICATION, RECRUITMENT AND CONSENT/ASSENT   
Assessment for patient eligibility for the study will be performed by a qualified physician participating in the 
care of the patient who is familiar with the study and its objectives. Patients meeting eligibility criteria and 
none of the exclusion criteria will be recruited during their initial outpatient clinic visit prior to surgery.   
 
Capacity of the individual will be ascertained by the research personnel obtaining consent. The study, risks 
and benefits of participation will be described to the subjects by the PI, co-investigators or study personnel. 
Determination of capacity is based upon the potential subject’s ability to respond to the process 
appropriately. The person who obtains the consent will ensure that the subject is alert, able to communicate, 
able to understand information about the research, make a decision based upon the information and give 
informed consent. The research personnel obtaining consent will ask questions such as naming potential risks 
of participating in the study, summarizing the aim of the study, asking the subject to explain what he/she 
would do if he/she no longer wanted to participate, and asking the subject to explain what he/she would do if 
he/she experienced distress or discomfort during the study in order to assess the research subjects ability to 
comprehend and consent.  
 
Willing participants will be presented with a detailed consent form explaining the purpose and nature of the 
study. The consent form will be in the appropriate language for the patient. Consents will be obtained by an 
authorized study investigator with the use of a language or sign language interpreter if necessary. The 
investigator obtaining consent will explain to the patient that participation is not required and that refusal to 
participate will not alter the quality of their care.  
 
The consent form will be written in a language comprehensible by the lay public. Patients will be given 
adequate time to review the study with the surgeon and meet the PI if desired. All questions will be 
encouraged and answered. The consent form will contain contact information of the PI, participating 
surgeons, and primary study investigator who may be contacted if any further questions arise. 
 
Debriefing Procedures.  
 
In this study, it is necessary for the patients to be blinded to their treatment arm (placebo vs. Exparel®). 
Withholding this information is necessary in order minimize bias and control for a possible placebo effect. 
Following completion of the study, the subjects will be debriefed at their follow-up appointment, 
approximately 30 days following their surgery. During this debriefing, the patient’s study arm will not be 


Parasternal intercostal nerve block in cardiac surgery patients 
Peter A. Knight, MD 
 
Page 16 of 25 
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revealed. If the patient wishes to know their study group assignment, then they may be informed of their 
group assignment following completion of the entire study. They will have the opportunity to ask any 
questions and express any concerns regarding study participation. 
 
Documentation of Consent: Signed consent forms will be stored in the locked office of the co-PI, 
Candice Lee, MD.  
 
Costs to the Subject: There is no additional cost to the subjects for participating in this study. 
 
Payment for Participation: There are no incentives (monetary or otherwise) for participation in this 
research study. 
 
  
 
VI. CITED REFERENCES 
 
1. Warfield CA, Kahn CH. Acute Pain Management: Programs in US Hospitals and experiences and 
attitudes among US adults. Anesthesiology 1995;83:1090-4. 
2. Ashburn, MA, Caplan RA, Carr DB, et al. Practice guidelines for acute pain management in the 
perioperative setting: An updated report by the American Society of Anesthesiologists Task Force on 
Acute Pain Management. Anesthesiology 2004;100:1573-81. 
3. Olivier, JF. Neuraxial analgesia in cardiac surgery: a review of risks. Tech in Reg Anesth Pain Manag 
2008;12:26-31. 
4. Svircevic V, Nierich AP, Moon KGM, et al. Thoracic epidural anesthesia for cardiac surgery: A randomized trial. 
Anesthesiology 2011;114:262-70. 
5. Barr, AM, Tutungi E, Almeida AA. Parasternal intercostal block with ropivacaine for pain management 
after cardiac surgery: A double-blind, randomized, controlled trial. J Cardiothor Vasc Anesth 
2007;21:547-553. 
6. Dowling R, Thielmeier K, Ghaly A, et al. Improved pain control after cardiac surgery: Results of a 
randomized, double-blind, clinical trial. J Thor Cardiovasc Surg 2003;126:1271-8. 
7. McDonald SB, Jacobsohn E, Kopacz DJ, et al. Parasternal block and local anesthetic infiltration with 
levobupivacaine after cardiac surgery with desflurane: The effect on postoperative pain, pulmonary 
function, and tracheal extubation times. Anesth Analg 2005;100:25-32. 
8. Tokgöz O, Beyaz SG, Tanriverdi B. Effects of parasternal block and local anaesthetic infiltration by 
levobupivacaine on postoperative pain and pulmonary functions after off-pump coronary artery bypass 
graft surgery. Turkish J thorac Cardiovasc Surg 2011;19:24-9. 
9. Chahar P, Cummings KC III. Liposomal bupivacaine: a review of a new bupivacaine formulation. J Pain 
Research 2012;5:257-264. 
10. Mantipragada S. A lipid based depot (DepoFoam® technology) for sustained release drug delivery. 
Progress in Lipid Research 2002;41:392-406. 
11. Davidson EM, Barenholz Y, Cohen R, Haroutiunian S, Kagan L, Ginosar Y. High-dose bupivacaine 
remotely loaded into multivesicular liposomes demonstrates slow drug release without systemic toxic 
plasma concentrations after subcutaneous administration in humans. Anesth Analg 2010;110:1018-23. 
12. Gorfine SR, Onel E, Patou G, Krivokapic ZV. Bupivacaine extended-release liposome injection for 
prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: A multicenter, randomized, 
double-blind, placebo-controlled trial. Dis Colon Rectum 2011;54:1552-9. 


Parasternal intercostal nerve block in cardiac surgery patients 
Peter A. Knight, MD 
 
Page 17 of 25 
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IRB Approval Date 2/15/2018 
13. Haas E, Onel E, Miller H, Rugapathi M, White P. A double-blind, randomized, active-controlled study 
for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic 
formulation. Amer Surg 2012;78:574-81. 
14. Golf M, Daniels SE, Onel E. A Phase 3, randomized, placebo-controlled trial of DepoFoam® bupivacaine 
(extended-release bupivacaine local analgesic) in bunionectomy. Adv Ther 2011;28:776-788. 
15. Marmo L, Fowler S. Pain assessment tool in the critically ill post-open heart surgery patient population. 
Pain Management Nurs 2010;11:134-40. 
16. Topolovec-Vranic J, Canzian S, Innis J, Pollmann-Mudryj MA, McFarlan AW, Baker AJ. Patient 
satisfaction and documentation of pain assessments and management after implementing the adult 
nonverbal pain scale. AM J Crit Care 2010:19:345-53. 
17. Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin Nurs 
2005;14:798-804. 
18. Bequregard L, Pomp A, Choiniere M. Severity and impact of pain after day surgery. Can J Anesth 
1998;45:304-311. 
19. Zalon ML. Comparison of pain measures in surgical patients. J Nurs Meas 1999;7:135-152. 
20. Keller S, Bann CM, Dodd SL, Schein J, Mendoza TR, Cleeland CS. Validity of the brief pain inventory 
for use in documenting the outcomes of patients with noncancer pain. Clin J Pain 2004;20:309-318. 
21. University of California San Diego; Pacira Pharmaceuticals Inc. EXPAREL dose-response for single-
injection femoral nerve blocks. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of 
Medicine (US). 2000- [cited 2012 Oct 02]. Available from: 
http://clinicaltrials.gov/ct2/show/NCT01349140?term=exparel&rank=1 NLM Identifier: NCT01349140. 
22. Pacira Pharmaceuticals Inc. Femoral nerve block with liposome bupivacaine for postsurgical analgesia 
following total knee arthroplasty. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of 
Medicine (US). 2000- [cited 2012 Oct 02]. Available from: 
http://clinicaltrials.gov/ct2/show/NCT01683071?term=exparel&rank=6 NLM Identifier: NCT01683071. 
  
 
 


Parasternal intercostal nerve block in cardiac surgery patients 
Peter A. Knight, MD 
 
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IRB Approval Date 2/15/2018 
Appendix I: Study schedule and procedures 
 
Table 2: Study schedule and procedures 
Procedure 
  
  
  
  
After Study Drug Administration 
  
  
  
  
  
2-72 Hours 
Site 
Visit 
 Time post-
drug 
  
  
  
0  
2 
4 
8 
12 
24 
36 
48 
60 
72 
  
Study Day 
Day -30 
to -1 
Day -1 
to 1 
1 
1 
1 
1 
1 
1 
2 
2 
3 
3 
4 
30 
Time 
Window (±h) 
  
  
  
  
0.25 
0.25 
0.5 
0.5 
1 
2 
2 
4 
4 
96 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug screen 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Clinical labs¹ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Assess/confirm eligibility 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Medical history, demographics 
and baseline characteristics 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Train self-assessments 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy test (women of 
childbearing potential) 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Physical examination 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Randomize subject & prepare 
study drug 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Vital signs²  
X 
X 
  
continuous monitoring in CVICU 
 X 
X 
X 
X 
X 
X 
X 
ECG  
X 
 
 
Continuous monitoring 
 
 
 
Neurological assessment 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Inspiratory capacity 
 
X3 
 
 
 
 
 
 
X3 
X3 
X3 
 
 
 
Study drug administration 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
NVPS rating4 
  
  
  
1h 
X 
X 
X5 
X5 
  
  
  
  
  
  
NRS rating4 
  
 X 
  
  
  
  
 X5 
X5 
X 
X 
X 
X 
X 
  
PCA 
  
  
  
  
  
  
X  
X 
X 
X 
X 
  
  
  


Parasternal intercostal nerve block in cardiac surgery patients 
Peter A. Knight, MD 
 
Page 19 of 25 
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IRB Approval Date 2/15/2018 
Table 2: Study Schedule and Procedures (Cont.) 
Procedure 
 
 
 
 
After Study Drug Administration 
 
 
 
 
 
2-72 Hours 
Site 
Visit 
Time post-
drug 
 
 
 
0 
2 
4 
8 
12 
24 
36 
48 
60 
72 
 
Study Day 
Day -30 
to -1 
Day -1 
to 1 
1 
1 
1 
1 
1 
1 
2 
2 
3 
3 
4 
30 
Time Window 
(±h) 
 
 
 
 
0.25 
0.25 
0.5 
0.5 
1 
2 
2 
4 
4 
96 
Oral narcotics 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Subject's satisfaction with 
postoperative analgesia 
  
  
  
  
  
  
  
  
X 
  
  
  
X 
X 
Brief Pain Inventory 
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
Record occurrence and 
duration of nausea/vomiting 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Record date/time of each 
bowel movement 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Record date/time of each 
rescue pain medication dose 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Subject productivity (date 
subject returned to work or 
normal daily activities) 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Concomitant medications6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Record AEs and SAEs 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Clinical labs will include Complete Metabolic Panel, CBC and INR/PTT. 
2 Temperature, heart rate, blood pressure, oxygen saturation will be monitored continuously in the cardiovascular ICU (CVICU) and at the time points listed. 
3 Inspiratory capacity (IC) will be measured using the handheld spirometer at baseline (pre-op) and then once between POD #1-2.  
4 Pain will be assessed with the NVPS or NRS scores at the end of anesthetic and before the first dose of rescue pain medication. 
5 Pain will be assessed with NVPS if the patient is still intubated and/or sedated. Pain will be assessed with the NRS score if the patient is extubated and 
alert/responsive. 
6 All medications that the subject used within 3 days prior to surgery will be recorded; including medication name, dose and date last taken. 


Parasternal intercostal nerve block in cardiac surgery patients 
Peter A. Knight, MD 
 
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Appendix II: Pain assessment tools 
 
Adult Nonverbal Pain Scale (NVPS) 
 
Table 4: Revised Adult Nonverbal Pain Scale 
 
0 
1 
2 
Score 
1. Face 
No particular 
expression or smile 
Occasional grimace, 
tearing, frown or 
wrinkled forehead 
Frequent grimace, 
tearing, frown or 
wrinkled forehead 
 
2. Activity 
(movement) 
Lying quietly, normal 
position 
Seeking attention 
through movement of 
slow cautious 
movements 
Restless activity 
and/or withdrawal 
reflexes 
 
3. Guarding 
Lying quietly, no 
position of hands 
over areas of body 
Splinting areas of 
body, tense 
Rigid, stiff 
 
4. Physiologic I  
(vital signs) 
Stable vital signs, no 
change in past 4 
hours 
Change over past 4 
hours in any of the 
following:  
SBP > 20 
HR > 20 
RR > 10 
Change over the past 
4 hours in any of the 
following: 
SBP > 30 
HR > 25 
RR > 20 
 
5. Respiratory 
Baseline RR/SpO2 
Compliant with 
ventilator 
RR > 10 above baseline 
or 5%↓ SpO2  
Mild asynchrony with 
ventilator 
RR > 20 above 
baseline or 
10%↓SpO2 
Severe asynchrony 
with ventilator 
 
Revised Nonverbal Pain Scale (NVPS) 
Total  
Abbreviations: HR, heart rate; RR, respiratory rate; SBP, systolic blood pressure; SpO2, oxygen saturation as measured 
by pulse oximetry. 
 
Referenced with permission from Strong Memorial Hospital, University of Rochester Medical Center, Rochester, NY. 
 
 
Numeric Rating Scale (NRS) 
 
   0  
   1  
    2  
     3       4        5        6         7          8           9          10  
When evaluating pain, the care provider is to explain to the patient that "0" represents "no pain" and that "10" 
represents the "worst possible pain". Patients are to indicate the number that best reflects the intensity of pain 
that they are currently experiencing. Any score ≥ 4 requires a pain management plan to be implemented. 
 
 Scores:  
1-3 = mild pain 
 
 
4-7 = moderate pain 
 
 
8-10 = severe pain 
 


Parasternal intercostal nerve block in cardiac surgery patients 
Peter A. Knight, MD 
 
Page 21 of 25 
RSRB 00044181 
IRB Approval Date 2/15/2018 
Appendix III: Brief Pain Inventory (Short Form) 


Parasternal intercostal nerve block in cardiac surgery patients 
Peter A. Knight, MD 
 
Page 22 of 25 
RSRB 00044181 
IRB Approval Date 2/15/2018 
 
Copyright 1991 Charles S. Cleeland, PhD 
Pain Research Group 
Reprinted with permission. 
 
 


Parasternal intercostal nerve block in cardiac surgery patients 
Peter A. Knight, MD 
 
Page 23 of 25 
RSRB 00044181 
IRB Approval Date 2/15/2018 
Appendix IV: Criteria for extubation 
URMC, Strong Memorial Hospital, Cardiovascular Intensive Care Unit  
Cardiac Surgery Practice Guideline 
Postoperative Cardiac Surgery Weaning From Mechanical Ventilation Guideline 
This guideline is not to be used for the post-operative Ventricular Assist Device or Heart Transplant 
patient. 
1. Criteria to initiate the Fast Track Protocol 
a. Chest tube drainage <100cc/hour 
b. Core temperature >or = 36.0° C 
c. Hemodynamic stability with no escalation of care  
i. Cardiac Index > 2.2  
ii. SBP 90-140 with or without inotropes or vasoactive medications 
iii. Heart Rate <120 bpm 
d. Satisfactory arterial blood gases (ABGs) on full ventilation 
i. PO2 >70 and PCO2 <45 on 40% FIO2, peep 5-8 
2. Extubation Criteria 
a. Awake without stimulation 
b. Adequate reversal of neuromuscular blockade (able to hold head off pillow for 3 seconds or 
more) 
c. Acceptable respiratory mechanics 
i. Tidal Volume >5mL/kg 
ii. Vital Capacity >10 – 15 mL/kg 
iii. Spontaneous respiratory rate <24 /min 
d. Acceptable arterial blood gases (ABGs) on 5 cm or less CPAP 
i. PO2 >70, PCO2 <50 on 40% FIO2, peep 5-8 
 
Guidelines are intended to be flexible.  They serve as reference points or recommendations, not rigid criteria.  
Guidelines should be followed in most cases, but there is an understanding that, depending on the patient, the 
setting, the circumstances, or other factors, guidelines can and should be tailored to fit individual needs. 
Referenced from Strong Memorial Hospital, University of Rochester Medical Center, Rochester, NY. 
 
 


Parasternal intercostal nerve block in cardiac surgery patients 
Peter A. Knight, MD 
 
Page 24 of 25 
RSRB 00044181 
IRB Approval Date 2/15/2018 
Appendix V: PCA Set-up Flow Chart
Poor pain control
(NRS >= 4)
Increase bolus dose by 
25-50%
Pain controlled
(NRS < 4)
Decrease bolus dose by 25%
(5.5 mcg IV Q 15 min)
Decrease bolus dose by 25%
(4.0 mcg IV Q 15 min)
Undue SE*, BUT
Pain controlled
(NRS < 4)
Poor pain control
(NRS >= 4)
Dilaudid PCA
Loading dose: 0.01 mg/kg IV Q 10 min x 2
Bolus dose: 0.2 mg IV Q 15 min
1 hr Max dose = 1.6 mg
Fentanyl PCA
Loading dose: 0.5 mcg/kg Q 10 min x 2
Bolus dose: 10 mcg Q 15 min
1 hr Max dose = 80 mcg
Continued Undue 
SE*
* Undue Side Effects (SE) Include:
- Excessive nausea/vomiting refractory to 
antiemetics.
- Itching/rask deemed related to narcotic and 
refractory to Benadryl.
- Altered mental status or feeling "high" from 
narcotic bolus.
PCA dose may be titrated up or down in order 
to obtain adequate anesthesia and minimize 
SE of narcotics.
Undue SE*
Poor pain control
(NRS >= 4)
Undue SE*, BUT
Pain controlled
(NRS < 4)
Decrease bolus dose by 25%
(7.5 mcg IV Q 15 min)
Undue SE*, BUT
Pain controlled
(NRS < 4)
Allergic to 
Fentanyl
Decrease PCA dose by 25%
(0.1 mcg IV Q 10 min)


Parasternal intercostal nerve block in cardiac surgery patients 
Peter A. Knight, MD 
 
Page 25 of 25 
RSRB 00044181 
IRB Approval Date 2/15/2018 
Appendix VI: Equianalgesic Table 
 
Table 5: Equianalgesic Table 
MEDICATION 
EQUIANALGESIC DOSE 
IM/IV 
PO 
Morphine 
10 mg 
30 mg 
Fentanyl 
100 mcg 
N/A 
Hydromorphone 
1.5 mg 
7.5 mg 
Oxycodone 
N/A 
20 mg 
Hydrocodone 
N/A 
30 mg 
Codeine 
130 mg 
200 mg 
Information adapted from: ViaHealth Pain Initiative 2010. Equianalgesic Table for Adults, pamphlet, ViaHealth, 
Rochester, NY.