Conditions: Erector Spinae Plane Block Pain Control Post-Operative Pain, Chronic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 70
Healthy volunteers: no

Brief summary:
Interfascial plane blocks have been developed for analgesia, among which the erector spinae plane (ESP) has gained popularity. The ESP block has been hypothesized to provide truncal analgesia by spread of local anesthetic into the paravertebral space. Recent studies have contested this idea showing unreliability in the spread of the local anesthetic into the paravertebral space.

Detailed description:
Post-operative pain is a significant issue following open heart surgeries and poorly controlled pain can result in significant cardiorespiratory morbidity. Many patients suffer pain both at rest (49%) and on movement (62%) following open heart surgeries via sternotomy and adequate pain management requires closer re-assessment and treatment. The intensity of pain is noted to be higher in the first 48 hours post surgery and hence modalities to control pain may make the greatest difference in the first 2 days after surgery.

Enhanced recovery pathways utilizing multimodal analgesia have shown significant analgesic and opioid sparing benefit while minimizing ICU and length of hospital stays. Some multimodal regimens have also incorporated regional blocks but the optimal analgesic regimen remains elusive. The ESP block has been hypothesized to provide truncal anesthesia by spread of local anesthetic into the paravertebral space, but recent studies contest this idea. Bilateral paravertebral blocks can result in higher than acceptable levels of local anesthetic in both cardiac and non-cardiac surgical patients and this may be true following bilateral erector spinae plane (ESP) as well. Hence, the pharmacokinetic profile of administered local anesthetics is necessary given the lack of information about the local anesthetic systemic levels following bilateral ESP.

Arms:
arm 1: Bilateral ultrasound guided erector spinae plane catheter placement for the administration of lidocaine. Dose will be 2 mg/kg ideal body weight. Bolus will be divided equally between the two ESP catheters. This is followed by lidocaine infusion via ESP catheter at 2 mg/kg/hr for 48 hours after catheter placement. arm 2: Subject will receive a bolus of lidocaine at 2 mg/kg ideal body weight. This is followed by lidocaine infusion via intravenous route at 2 mg/kg/hr for 48 hours.

Interventions: intervention 1: Intravenous Administration of Lidocaine Post Cardiac Surgery intervention 2: Administration of Lidocaine Post Cardiac Surgery via ESP Catheter
Intervention descriptions: intervention 1: Lidocaine will be administered via intravenously. Initial dose will be at 2 mg/kg ideal body weight followed by dosing at 2 mg/kg/hr for 48 hours intervention 2: Lidocaine will be administered via ESP catheter. Initial dose will be at 2 mg/kg ideal body weight split between two catheters followed by dosing at 2 mg/kg/hr for 48 hours

Protocol document:
Prot_SAP_000.pdf: 
i:rsa\hso\webstuff\protocoloutline.doc (01/03) 
 
TITLE:  Randomized Clinical Trial Comparing Analgesia and Plasma 
Pharmacokinetics of Lidocaine administered by Erector Spinae Plane 
Blocks vs. Intravenous Routes Following Open Heart Surgery:  An 
Equivalence Study 
 
 
 
NCT Number:  NCT04995497 
 
 
 
 
 
 
Archit Sharma, MD 
 
 
Document Date:  April 13, 2022


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Protocol Outline 
 
Protocol Title:  Randomized Clinical Trial Comparing Analgesia and Plasma 
Pharmacokinetics of Lidocaine Administered by Erector Spinae Plane Blocks vs. 
Intravenous Routes Following Open Heart Surgery:  An Equivalence Study 
 
Protocol Version:  5 
Protocol Date:  April 13, 2022 
Principal Investigator:  Archit Sharma, MBBS 
Research Team: Rakesh Sondekoppam Vijayashankar, MD 
 
 
      Melinda Seering, MD 
 
 
      Mohammad Bashir, MD 
 
 
      Anthony Panos, MD 
 
 
      Sangini Punia, MD 
 
 
      Sharon Larson, DO 
 
 
      Arun Singhal, MD 
 
 
      Erik Campbell, MD 
 
 
      Erin Evans, MD 
 
 
      Jordan Miller, MD 
 
 
      Rofayda Gad, MD 
 
 
       
 
 
       
 
 
      Breethaa Janani Selvamani, MD 
 
 
      Jonathan Simmons, DO 
 
 
      Sally Smith, MD 
 
 
      Jenna Lizzo, MD 
 
 
      Zita Sibenaller, PhD 
 
 
      Alicia Walter, ADN 
 
 
      Lori Stout, RN 
 
 
      Spenser Pfannenstiel, BS 
 
 
       
 
 
I. 
Abstract 
Recently interfascial plane blocks have been developed for analgesia 
including erector spinae plane (ESP) block.  The ESP block has been 
hypothesized to provide truncal analgesia by spread of local anesthetic into 
the paravertebral space.  However, recent studies have shown that the spread 
of local anesthetic by this block procedure into the paravertebral space is 
unreliable.  It has been established that interfascial plane blocks can result in 
systemic levels of local anesthetic that can achieve therapeutic concentrations 
similar to those observed by intravenous infusions of local anesthetic and 
could likely be the mechanism of action of the ESP block.  Free and total 
plasma lidocaine levels will be measured until steady state levels are achieved 
with ESP blocks.  Additionally, the safety of the ESP block using doses of 
local anesthetic has not been rigorously evaluated   This study will evaluate 
both the analgesic efficacy and safety of ESP blocks in post-cardiac surgery 


i:rsa\hso\webstuff\protocoloutline.doc (01/03) 
patients in comparison to intravenously administered lidocaine.   
 
II. 
Background and Significance/Preliminary Studies 
Postoperative pain is a significant issue following open heart surgery and 
poorly controlled pain can result in significant cardio-respiratory morbidity.  
A significant number of patients suffer from pain issues both at rest (49%) and 
on movement (62%) following open heart surgery via sternotomy (1,2) and 
adequate pain management requires closer re-assessment and treatment.   The 
intensity of pain is noted to be higher in the first 48 hours post-surgery 
(3,4,5,6,7,8) and hence modalities to control pain may make the greatest 
difference in the first two days after surgery.   
 
Enhanced recovery pathways utilizing multimodal analgesia have shown 
significant analgesic and opioid sparing benefit while minimizing ICU and 
length of hospital stays (9,10). Some such multimodal analgesic regimens 
have also incorporated regional anesthesia, but the optimal analgesic regimen 
is still elusive. Central neuraxial blocks such as epidural, intrathecal and 
paravertebral blocks have been utilized for cardiac surgery associated pain but 
given not widely adapted to practice due to concerns of altered coagulation 
status and the possibility of neuraxial hematoma. Additionally, there is a lack 
of clear guidelines to provide deeper regional nerve blocks in this patient 
population. A variety of interfascial plane blocks have been developed, among 
which the erector spinae plain (ESP) block has gained popularity recently. 
Given the non-neuraxial and superficial location of the structures of interest, 
more healthcare providers are offering ESP to provide analgesia following 
open heart surgery. Early evidence available from a clinical trial comparing 
ESP to no block and non-standardized multimodal anesthesia has shown 
variable pain reduction but consistent opioid sparing effects (11,12). The ESP 
block has been hypothesized to provide truncal analgesia by spread of local 
anesthetic (LA) into the paravertebral space (PVS). However, recent 
anatomical studies have contested this idea, showing unreliable spread of LA 
to the PVS. It is also well known that bilateral paravertebral blocks can result 
in higher than acceptable systemic levels of LA both in cardiac (13,14) and 
non-cardiac surgical patients and this may be true following bilateral ESP as 
well. Hence, the pharmacokinetic profile of administered local anesthetics is 
necessary given the lack of information about the local anesthetic systemic 
levels following bilateral ESP. 
 
It is well known that interfascial plane blocks can result in systemic levels of 
LAs that achieve therapeutic concentrations (15) similar to that observed by 
intravenous infusions of LA (16,17). This is very likely the case for the ESP 
block, especially since the clinical and anatomical studies have conflicting 
findings regarding the loco-regional effects. Although intravenous lidocaine 
has shown some promise to prevent post-operative cognitive dysfunction 
(18,19), its effect on postoperative pain is not well studies. One study utilizing 
low dose lidocaine failed to show improvement in pain scores or opioid 
consumption, but the study did not utilize standardized multimodal analgesia 


i:rsa\hso\webstuff\protocoloutline.doc (01/03) 
regimen (20). It is currently unknown whether the analgesic benefits of 
interfascial plane blocks are due to the multimodal analgesic regimen, the 
loco-regional benefits of the blocks, the systemic levels of local anesthetics 
following the block performance or a combination of all. We hypothesize that 
the mechanism by which the ESP block produces analgesia in the background 
of multimodal analgesia is probably related to the systemic absorption of local 
anesthetics. In addition, the safety of the ESP block using high doses of LA in 
cardiac surgery patients has not been rigorously assessed. We propose a 
pragmatic study to address both unknowns, the mechanism and safety of ESP 
following cardiac surgery. 
 
III. 
Study Aims 
1.  The hypothesis of this study is that the analgesic effects of ESP can be 
attributed to its systemic distribution rather than its locoregional effects.  A 
finding that lidocaine administered by ESP block achieves plasma 
concentrations in the analgesic range (2-5 ug/ml) at steady state will support 
our hypothesis whereas inability to reach analgesic levels will suggest that 
systemic distribution of local anesthetic is not a significant contributing factor 
of analgesia. 
 
2.  Despite the use of clinically acceptable doses, plasma concentrations of 
local anesthetic have been known to reach toxic levels following bilateral 
paravertebral blocks.   This may also be true of ESP blocks.  This study will 
address this concern and help establish a safety profile for ESP blocks in the 
cardiac patient population. 
  
IV. 
Administrative Organization 
University of Iowa Hospitals and Clinics—CVICU and Laboratories 
 
V. 
Study Design 
i. 
Experimental design of the study (e.g., single-blind, double-blind):  
Randomized 
ii. 
Study population general description:  Adults undergoing elective cardiac 
surgery for coronary artery bypass graft (CABG) or valve surgery via 
sternotomy 
iii. 
Sample size determination and power analyses:  70 adult patients as 
determined using an online calculator available at: 
https://www.sealedenvelope.com/power/continuous-equivalence/ 
iv. 
Study outcomes/endpoints:   
1.  Arterial blood samples will be drawn and assessed for lidocaine 
concentrations 
2.  Pain scores will be collected from EPIC electronic medical record or 
directly from the subjects. 
3.  Opioid doses will be assessed and reported in morphine equivalents 
 
 


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VI. 
Study Procedures 
a. Subject selection procedures 
i. Inclusion:  Any patient >18 years and <81 years undergoing 
elective cardiac surgery for CABG or valve surgery via sternotomy 
and surgical procedure is not greater than 12 hours  
 
Exclusion:  Allergy to study medications; major livor or kidney 
dysfunction; BMI <20 or >50; revision surgery; Off-pump 
coronary artery bypass surgery; surgery via thoracotomy; narcotic 
dependent (opioid intake morphine equivalent > 10 mg/day for 
more than 3 months); other sources of chronic pain such as 
fibromyalgia; patients with associated significant central nervous 
system, liver, renal or respiratory disease; coexisting hematological 
disorder or deranged coagulation parameters; lack of informed 
consent; preoperative neurological deficits; and emergency surgery 
(E1, E2 and E3 classifications only). 
 
ii. Recruitment procedures 
 
1.  Where will recruitment occur?   Pre-surgical clinic or  
 
Day of Surgery Admissions (DOSA)  
2.  Where and when will consent be obtained? DOSA  
prior to surgery or in pre-surgical clinic 
3.  Who will obtain consent?  Anesthesia team 
  
 
 
4.  What is the advertising plan, if applicable?  N/A 
5.  What recruitment materials will be provided to the  
      potential participant (brochures/information   
      sheets/video presentation)?   None.   
 
iii. Screening procedures 
1.  What procedures are required for screening?  Prior  
to the surgical procedure, the anesthesia team will 
review eligibility criteria: Allergic to study 
medication; diagnosed with major liver or kidney 
dysfunction; any bleeding disorders; in females 
verify non-pregnant state. 
2.  What is the screening schedule (number of visits,  
 
length of visits)?  This will occur only on the day 
 
of surgery and will last approximately 30 minutes. 
   
 
3.  Which screening tests/procedures are part of   
 
 
 
 
standard care and which are for research  
 
 
 
 
purposes only?  All screening procedures listed  
 
 
 
above are part of standard of care. 
4.  What happens with screen failures (including any  
 
data gathered during screening)?  A screening  


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log will be maintained and will be destroyed at  
 
upon study completion. 
 
b.  Randomization procedures (if applicable) 
 
Participants will be randomized to IV or ESP groups using a 
computer-generated block randomization sequence and the 
allocation concealment will be ensured using a sealed envelope 
technique. The randomization sequence will be available with the 
PI and the research team.  
 
       
c.  Study Intervention 
iv. For Drug/device studies: 
                         1.  Active study agents:  Lidocaine 
                   2.  Placebo study agents:  None 
       3.  Blinding/labeling/preparation of agents:  Drug will be 
 
provided through the UIHC Investigational Drug Service 
                   4.  Storage:  Room temperature.  Protect from light. 
                   5.  Administration: Per study, either through ESP catheter or  
 
 
intravenously.  
                   6.  Toxicities and guidelines for adjustments:  Acute 
emergencies from local anesthetics are generally related to high plasma 
levels encountered during therapeutic use of local anesthetics or to 
unintended subarachnoid injection of local anesthetic solution. 
 
Management of Local Anesthetic Emergencies The first consideration is 
prevention best accomplished by careful and constant monitoring of 
cardiovascular and respiratory vital signs and the patient’s state of 
consciousness after each local anesthetic injection. At the first sign of 
change, oxygen should be administered.  
 
The first step in the management of convulsions, as well as 
underventilation or apnea due to unintended subarachnoid injection of 
drug solution, consists of immediate attention to the maintenance of a 
patent airway and assisted or controlled ventilation with oxygen and a 
delivery system capable of permitting immediate positive airway pressure 
by mask. Immediately after the institution of these ventilatory measures, 
the adequacy of the circulation should be evaluated, keeping in mind that 
drugs used to treat convulsions sometimes depress the circulation when 
administered intravenously. Should convulsions persist despite adequate 
respiratory support, and if the status of the circulation permits, small 
increments of an ultra-short acting barbiturate (such as thiopental or 
thiamylal) or a benzodiazepine (such as diazepam) may be administered 
intravenously. The clinician should be familiar, prior to the use of local 
anesthetics, with these anticonvulsant drugs. Supportive treatment of 


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circulatory depression may require administration of intravenous fluids 
and, when appropriate, a vasopressor as directed by the clinical 
situation (e.g., ephedrine).   
 
If not treated immediately, both convulsions and cardiovascular 
depression can result in hypoxia, acidosis, bradycardia, arrhythmias and 
cardiac arrest. Underventilation or apnea due to unintentional 
subarachnoid injection of local anesthetic solution may produce these 
same signs and also lead to cardiac arrest if ventilatory support is not 
instituted. If cardiac arrest should occur, standard cardiopulmonary 
resuscitative measures should be instituted. 
 
Endotracheal intubation, employing drugs and techniques familiar to the 
clinician, may be indicated, after initial administration of oxygen by mask, 
if difficulty is encountered in the maintenance of a patent airway or if 
prolonged ventilatory support (assisted or controlled) is indicated. 
 
 
     d.  Study Assessments and Activities 
 
 
i. 
Describe all study procedures, assessments, and subject activities 
Procedures Affecting Both Groups 
A.  Pre-Operative Phase (Standard of Care) 
•  Pre-operative fasting and carbohydrate treatment.  Patients are 
kept NPO for 8 hours before surgery except for an oral 
carbohydrate beverage given 2 - 4 hours before procedure. 
•  Pre-operative multimodal analgesic is initiated.  Gabapentin and 
acetaminophen will be given pre-operatively and continued 
postoperatively at regular intervals. 
 •  Anxiolytic medications.  Minimal anxiolytic medications given 
 before surgery including midazolam given by anesthesia provider. 
 
 B.  Intra-Operative Phase (Standard of Care - At discretion of  
  
Anesthesia Provider) 
 •  Intraoperative opioid administration.  Fentanyl IV given as 
 needed for pain but typically < 1 mg for procedure. 
 •  Hydromorphone 0.5 - 1 mg given near completion of procedure 
 •  Intraoperative multimodal analgesia.   If time since preoperative 
 acetaminophen dose significantly exceeds 6 hours, acetaminophen 
 1000 mg IV, or via NG route is considered 
 •  Postoperative sedation initiated.  Near the end of the procedure, 
 dexmedetomidine or propofol infusion is begun for postoperative 
 sedation in ICU while intubated 


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 •  All patients will receive dual post-operative nausea and vomiting 
 (PONV) prophylaxis in the form of ondansetron and 
 dexamethasone at appropriate time periods.  
 
 If the surgical procedure takes longer than 12 hours, the subject  
  
will be withdrawn from the study. 
 
 C.  Block Performance/Procedure  
•  Upon arrival to the CV-ICU, patients will be assessed for 
eligibility to extubate based on hemodynamic and pulmonary 
stability on a case-by-case basis with the aim to extubate as early 
as possible.  When appropriate, extubation will proceed following 
the CV-ICU Fast Track Extubation protocol that is already in 
place.  Extubation is not required prior to the administration of 
study drug via IV or ESP catheters route.  Participation in the study 
can proceed as long as after assessment by clinicians, the subject is 
extubated or ready to be extubated. 
 
 
 D.  Group ESP (Study Procedures) 
•  Bilateral ultrasound guided erector spinae plane (ESP) catheters 
will be inserted either pre- or post-operatively. 
 •  After confirming that there  are no contra-indications, the subject   
will receive lidocaine via ESP catheter.   
 •  Patients will receive lidocaine at a dose of 2 mg/kg ideal body 
 weight (IBW) as bolus divided equally between the two ESP 
 catheters. 
 •  Subjects will then lie in a supine position.  
•  Lidocaine infusion via ESP catheters either through 2 dedicated 
pumps or via a single pump and a y-connector at a rate of 2 
mg/kg/hour for approximately 48 hours. 
 
• Blood samples will be drawn at 5, 30, 60, 120 minutes, 6 and 24 
hours and assessed for lidocaine concentration. 
 •  Pain scores (resting and with movement/cough) will be collected 
 from bedside record and EPIC medical record.  Standard 
 assessment protocol already in place has this charted every 2 - 4 
 hours by ICU nursing staff. 
 •  All patients will receive continued oral multimodal analgesia 
 •  When not eligible to receive oral medications (e.g. NPO), pain 
analgesia will be provided through an IV route.  This can include an 
IV PCA pump using hydromorphone 0.2 mg with a lockout of 
 10 minutes and a maximum dose of 6 mg in 4 hours continued           
postoperatively.  
•  If oral medications are insufficient to provide pain relief, and the 
subjects are not receiving medications via PCA, pain medications 


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will be provided IV. 
•  Opioid doses (both oral and IV) will be 
assessed and reported in morphine equivalents. 
 
 E.  Group IV (Study Procedures) 
   
 •  Patients will receive lidocaine at a dose of 2 mg/kg ideal body 
 weight (IBW) through IV route. 
 •  Subjects will then lie in a supine position. 
  
 •  Lidocaine infusion via IV route at a rate of 2 mg/kg/hour for 
 approximately 48 hours. 
 •  Blood samples will be drawn at 5, 30, 60, 120 minutes, 6 and 24 
hours and assessed for lidocaine concentration. 
 •  Pain scores (resting and with movement/cough) will be collected 
 from bedside record and EPIC medical record.  Standard 
 assessment protocol already in place has this charted every 2 - 4 
 hours by ICU nursing staff 
 •  All patients will receive continued oral multimodal analgesia  
•  When not eligible to receive oral medications (e.g. NPO), pain 
analgesia will be provided through an IV route.  This can include an 
IV PCA pump using hydromorphone 0.2 mg with a lockout of 
 10 minutes and a maximum dose of 6 mg in 4 hours continued           
postoperatively.  
•  If oral medications are insufficient to provide pain relief, and the 
subjects are not receiving medications via PCA, pain medications 
will be provided IV. 
  
 •  Opioid doses (both oral and IV) will be assessed and reported in 
morphine equivalents. 
 
ii. 
Provide a schedule of all study assessments and subject 
activities, including a tabular representation or timeline as 
applicable 
 
 
 


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VII. 
Safety Monitoring Plan 
i. 
Definition of adverse events, serious adverse events:   
 
An adverse event (also referred to as an adverse experience) can be any 
unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease temporarily associated with the use of a drug, without 
any judgment about causality or relationship to the drug.   
 
An adverse event or suspected adverse reaction is considered "serious" if, 
in the view of either the investigator or sponsor, it results in any of the 
following outcomes: Death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or a congenital anomaly/birth defect. 
 
Any adverse experience that places the subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred, or 
it is suspected that the use or continued use of the product would result in 
the patient’s death. 
 
ii. 
What procedures will be used to monitor subject safety?   


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Careful and constant monitoring of cardiovascular and respiratory 
(adequacy of ventilation) vital signs and the patient’s state of 
consciousness should be accomplished. It should be kept in mind at such 
times that restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, 
depression or drowsiness may be early warning signs of central nervous 
system toxicity. 
 
For the purpose of being prepared to deal with the side effects of lidocaine 
(Bradyarrhythmia, hypotension, infusion site reactions), the blocks will 
only be performed in the Cardiac ICU, where pharmacological and non-
pharmacological measures are available to treat these side effects.  The 
foundation of local anesthetic toxicity is outlined in seizure management 
with pharmacological seizure management, advanced cardiac life support 
(ACLS) to support the heart and use of 20% lipid emulsion to reverse 
local anesthetic toxicity.  Oxygen can be provided for patients needing 
improved oxygenation and all the emergency medications, pharmacists 
and intensivists are readily available in the ICU. 
 
iii. 
Who (list names) will identify, document, and report adverse events?  
Nursing staff in the CVICU should report adverse events to Dr. Archit 
Sharma or Dr. Rakesh Sondekoppam within 12 hours of the event.   After 
the subject is stabilized this information will be reported to a member of 
Anesthesia Innovative Research Core who will report the event to the IRB. 
 
iv. 
What is the frequency for review of summarized safety information 
and who will perform the review (e.g., safety monitoring board)?   
 
No committee is currently in place for this pilot study. 
 
v. 
What are the stopping rules with regard to efficacy and safety?   
 
If an adverse/serious adverse event occurs, the study will be paused until 
careful evaluations is performed.   
 
VIII. Analysis Plan 
 
Study variables will be collected and tabulated. The continuous and discrete 
variables will be presented as mean and standard deviation after calculation 
and the categorical variables will be presented as frequencies. Normality of 
distribution will be assessed using Q-Q plots followed by Shapiro-Wilk test. 
Normally distributed data will be assessed using independent sample t-test and 
non-normally distributed data will be assessed using Mann-Whitney U-test. 
Categorical variables will be tested using chi-square tests or Fisher’s exact 
test. Tests for equivalence will be applied for the primary outcome measures 


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failing which, tests of superiority will be applied. P values <0.05 will be 
considered statistically significant. 
 
IX. 
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ICF_001.pdf: 
TITLE: Randomized Clinical Trial Comparing Analgesia and Plasma 
Pharmacokinetics of Lidocaine administered by Erector Spinae Plane Blocks vs. 
Intravenous Routes Following Open Heart Surgery: An Equivalence Study 
NCT Number: NCT04995497 
Archit Sharma, MD 
Document Date: March 2, 2022