Stellate Ganglion Blockade in COVID-19 Positive Patients
Phase: PHASE1
Conditions: COVID 19, ARDS
Sponsor: University of Nebraska

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 
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Stellate Ganglion Blockade in COVID-19 Positive Patients 
NCT04445337 
23 Nov 2020 
 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 
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Stellate Ganglion Blockade in COVID-19 
Positive Patients 
 
 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 
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Title Page …………………………………………………………………… 
 
Summary……………………………………………………………………. 
 
Section 1.0 
Objectives ……………………………………………………  
 
Section 2.0 
Introduction, which includes background data and future aims  
 
Section 3.0 
Eligibility criteria ……………………………………………... 
 
Section 4.0 
Randomization/registration procedures ……………………... 
Section 5.0 
Treatment plan or research design …………………………..... 
 
Section 6.0 
Measurement of effect …………………………..……………. 
 
Section 7.0 
Study parameters ……………………………...……………… 
 
Section 8.0 
Drug dosage………………………. ………………………….. 
 
Section 9.0  
Adverse event reporting guidelines ……………........................ 
 
Section 10.0 Biostatistic considerations including stopping criteria …….. 
 
Section 11.0  Records to be kept ………………………………………...…… 
 
Section 12.0 Patient consent form statement ……………………………….. 
 
Section 13.0    Study and Safety monitoring DSMB…………………………..  
Section 14.0 References ……………………………………………………. 
Appendix A.  ………………………………………………………………….. 
Appendix B.   ………………………………………………………………….
 
 
 
 
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SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 
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STELLATE GANGLION BLOCKAGE IN COVID-19 POSITIVE PATIENTS 
IRB#523-20-FB 
Principal Investigator: 
 
Michael Lankhorst, M.D.  
Assistant Professor 
Director of Pain Clinics 
Pain Medicine/Anesthesiology 
University of Nebraska Medical Center 
Supported by: 
 
Department of Anesthesiology 
University of Nebraska Medical Center 
 
UNMC Nebraska Neuroscience Alliance COVID-19 Rapid Response Grants 
 
NCT Number: 
04445337 
 
 
 
 
 
 
 
 
 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 
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Brief Summary:  
The proposed research plan will reflect the proof of concept of our modified stellate ganglion 
block in the human subject, following several key cardiac and pulmonary parameters leading to 
clinical benefit as well as the safety aspects of stellate ganglion blockade (SGB). Enrolling 
subjects will be enrolled from patients cared for in the COVID ICU/progressive care at Nebraska 
Medicine.   
Patient eligibility will be determined based on the following criteria;  Any patient between the ages 
of 40-75 with laboratory established COVID-19 infection (via rRT-PCR) requiring critical care in 
an intensive care unit, signs or symptoms consistent with ARDS, at least 2 of the following 
(respiratory rate ≥30 breaths per min, oxygen saturation at rest ≤ 93%, PaO2/FIO2 ≤ 200 mm Hg, 
bilateral infiltrates on chest radiograph or CT not due to cardiac failure, requiring non-invasive or 
invasive mechanical ventilation.)  Block randomization will be used to determine equal allocation 
to control (labs, nitric oxide levels +SOC) and intervention group (labs, nitric oxide levels, SGB 
procedure, perineural catheter 5 days). Once enrollment criteria are met, baseline assessments will 
be completed by the Acute Pain Service (APS).  They will place SGB and manage intervention 
group for 5 days. Data collection will be collected through Day 5 of hospital stay, discharge 
information will be documented, and survival at 90 days via telephone to complete SF 36 
questionnaire.  
 
Section 1.0 Objectives:  
 
To assess the safety, tolerance, oxygenation, lung and cardiac function, proinflammatory 
immune response and nitric oxide changes associated with the use of our modified SGB protocol 
in patients with ARDS due to COVID-19 disease. 
 
Secondary (to be confirmed at later trial phase): To determine the association of use of our 
modified SGB protocol in patients with ARDS due to COVID-19 disease on: incidence of 
cardiac arrhythmias associated with ARDS, need and duration of use of mechanical ventilation 
and extracorporeal membrane oxygenation (ECMO). 
 
Section 2.0 Introduction:  
The novel coronavirus, now officially designated as severe acute respiratory syndrome 
coronavirus-2 or SARS-CoV-2 was first identified in Wuhan, Hubei Province, China in 
December of 2019. Since its identification, Coronavirus disease 2019 (COVID-19) has evolved 
into an international public health emergency. As is common for the coronavirus family, (SARS-
CoV-1 and MERS), COVID-19 is associated with acute respiratory infection.  The mortality of 
COVID-19 infection is mostly due to complications related to pneumonia and ARDS 1. 
Strategies to mitigate ARDS and consequent multi-organ failure is in high demand. Currently, 
there are no FDA-approved treatments outside of supportive care for patients suffering from 
ARDS due to COVID-19. Unique to COVID-19 associated respiratory failure and ARDS is the 
early overproduction of proinflammatory cytokines. This exaggerated immune response or 
“cytokine storm,” is felt to lead to increased vascular hyperpermeability, multiorgan failure, and 
death.  Many ARDS/lung injury patients manifest refractory hypoxia, cardiac arrhythmias and 
acute myocardial damage10-13. Cardiovascular complications such as circulatory failure are 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 
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frequently associated with COVID-19 ARDS and are associated with a poor outcome14. Case 
series have noted cardiac arrhythmias, cardiomyopathy, and cardiac arrest as terminal events in 
Covid-1915-17. Stellate ganglia block (SGB) is a common clinical intervention to treat both 
sympathetic nervous system overstimulation and refractory cardiac arrhythmia. Traditional 
chemo-neuromodulation paradigms employ a single SGB strategy deriving short-term (lasting a 
few hours to one day) control of sympathetically mediated symptoms, e.g., cardiac arrhythmias 
are controlled by temporarily blocking stellate neuronal activity with local anesthetics18-20. Once 
the anesthetic effect is withdrawn, cardiac arrhythmias recur. We propose a modified SGB 
strategy utilizing a continuous infusion of medications instead of a bolus injection.  We expect to 
achieve a lasting chemo-neuromodulating effect in COVID-19 ARDS patients reducing overall 
inflammation, improving pulmonary function, and reducing cardiac complications.   
Preliminary Data: A notable innovation of our modified SGB approach is the addition of 
clonidine and dexamethasone to a local anesthetic (LA). The scientific rationale supporting 
this modification is derived from both the literature as well as work done here at UNMC by 
Dr. Hanjun Wang (Figure 1).  
 
 
 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 
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Recent animal studies from Dr. Wang’s lab suggest macrophage activation in stellate ganglia 
plays a critical role in mediating acute lung injury-caused cardiac arrhythmia (Figure 2).  
 
 
Additionally, systemic administration of an anti-inflammatory medicine, minocycline, can 
largely block macrophage activation and arrhythmias in a bleomycin-induced lung injury rat 
model (Figure 3).  

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 
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Dr. Wang’s findings support the novel concept that local delivery of anti-inflammatory/anti-
macrophage medicine to/around the stellate ganglia may be a promising new therapy for 
treatment of inflammation-augmented comorbidities (especially cardiac) in acute lung 
injury/ARDS patients. To test this hypothesis in humans, we propose addition of two 
medications to the LA-SGB.  Low dose dexamethasone will be added to ameliorate stellate 
ganglia inflammation directly. Additionally, based on Dr. Wang’s work, we will also add 
clonidine.  This additive is supported in that 1) clonidine selectively stimulates α2 adrenergic 
receptor and promotes the norepinephrine reuptake by cardiac sympathetic nerve endings 20-
22 ) clonidine has local anti-inflammatory effects via promoting apoptosis of leukocytes and 
switching pro-inflammatory macrophage to anti-inflammatory macrophage23. In addition to 
testing, the beneficial cardiac effects of our modified SGB approach, we also aim to examine 
if SGB could also improve lung damage/inflammation as well as respiratory function in 
COVID 19 patients. This work is also previously performed in animal models.  In septic rats, 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 
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SGB was able to attenuate sepsis related lung injury and decrease serum levels of TNF-alpha 
and IL-63.  In a direct lung injury model using rabbits, SGB showed decreased levels of TNF-
alpha, IL-6 and IL-10 as well as decreased postmortem acute lung injury4. Human studies in 
trauma patients revealed immunological findings of decreased pro inflammatory cytokine 
production, and no negative effect on cardiovascular or pulmonary parameters.2 Finally, in 
one small human study of patients undergoing one-lung ventilation, SGB was shown 
associated with increased plasma levels of nitric oxide and improved oxygenation5.   In 
animal models, SGB was shown to improve pulmonary hypertension via NO production; 
oxygenation was improved as well.6-7 Several studies show nitric oxide can directly inhibit 
RNA synthesis, viral protein accumulation and virus released from infected cells.  This was 
found in a variety of viruses, but specifically SARS.  Not only was replication of the virus 
reduced, by NO was found to block SARS binding to the receptor host.8-9 We expect that the 
modified SGB strategy will achieve prolonged anti-arrhythmia and anti-inflammatory effects 
in COVID patients.  
 
Study Rationale: 
Available research indicates that an exaggerated immune response plays a key role in the 
cardiopulmonary pathophysiology of COVID-19. Preliminary data from previous studies at 
UNMC suggest that acute lung injury initiates robust and sustained macrophage activation in 
thoracic dorsal root ganglia and in stellate ganglia, resulting in increased cardiac and 
pulmonary afferent and efferent neuronal sensitivity. In the current proposal, we plan to 
validate a novel therapeutic strategy to treat coronavirus-induced cardiopulmonary symptoms 
and complications by local delivery of bupivacaine, dexamethasone, and clonidine to the 
stellate ganglia.  Single injection and continuous infusion SGB have been safely 
utilized clinically and in many human studies.  
 
Section 3.0 Eligibility Criteria:  
 
Inclusion:  
• Subject admitted to COVID ICU/progressive care, age 40-75 years old 
 
Subjects must have + covid test with signs of impending respiratory compromise as identified 
by having at least 2 of the following:  
• Respiratory rate ≥30 breaths per min 
• Oxygen saturation at rest ≤ 93% 
• PaO2/FIO2 ≤ 200 mm Hg 
• bilateral infiltrates on chest radiograph or CT not due to cardiac failure 
• Requiring non-invasive or invasive mechanical ventilation.  
Any patient with a + covid test and any cardiac tachydysrhythmia (excluding sinus tachycardia) 
will be included regardless of respiratory status. (Note: The broader inclusion of patients who 
have cardiac tachydysrhythmia is based on our prior experience and other reported beneficial 
antiarrhythmic effects of SGB in this patient group.) 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 10 
 
 
 
Exclusion:  
• Hemodynamic instability (>2 vasopressors)  
• Heart rate < 60 beats per minute 
• Systolic Blood pressure of less than 80 mmHg 
• pre-hospital diagnosis of heart failure or fluid overload  
• anatomical inability to perform block  
• prior sympathectomy  
• Patient currently enrolled in another clinical trial for COVID-19 or respiratory 
distress/ARDs  
• Uncorrectable coagulopathy  
• ECMO already engaged  
• On Nitric Oxide  
• Pre-existing multi-organ failure (>2 organ systems)  
• Allergic to dexamethasone, clonidine, or bupivacaine.  
• If female, currently pregnant or breast-feeding.  
• Investigators determine the subject would be too unstable to participate in the study 
intervention.  
 
If a woman of childbearing age is enrolled as a subject and there has not been a pregnancy test 
during their current inpatient stay, a urine or blood pregnancy test will be performed. Pregnancy 
will not be allowed for this study as the drug is absorbed systemically and there are known risks 
to the fetus. 
 
 
Section 4.0 Registration Procedure:  
A prospective block randomized phase I/II two arm unblinded trial of a modified SGB protocol 
incorporated into Standard of Care vs UNMC standard of care Only for ARDS COVID-19 patients. 
Subjects and/or Legally Authorize Representative (LAR) will be approached while subject is in 
the ICU/progressive care. If subject is unable to participate in the consenting process, the LAR 
will be contact via telephone and/or video chat. Consents will be sent to LAR electronically. PI 
and/or Sub-I will be present for all consenting process regardless is the ICF process takes place 
in person or video digital presence. 
The randomization will be done by using Stratified Permuted Block Randomization in which 
sequential trial participants will be subdivided into the strata as indicated by their age-groups ie; 
40-59, 60-74, 75-85 years and thereafter allocated to study group via block randomization within 
the strata so that the balance between age groups between the two study groups stays close to 
equal throughout the trial.  
 
 
 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 11 
 
Section 5.0 Treatment Plan of Research Design:  
A prospective block randomized phase I/II two arm unblinded trial of a modified SGB protocol 
incorporated into Standard of Care vs UNMC standard of care Only for ARDS COVID-19 
patients. 
 
Sixteen subjects will be enrolled.  Eight in the control arm and eight in the intervention SGB arm.  
Subjects will be identified on the COVID unit. The study will be explained to the subject and if 
the subject wishes to voluntarily participate, the ICF will be signed. If the subject is unable to 
sign consent, the LAR consent will be utilized.  If LAR is not present, an electronic link to the 
consent will be sent to the LAR via email.  
 
The attending proceduralist will perform the SGB in the ICU/progressive care. ICU/progressive 
care nurse will provide patient monitoring and assistance during the procedure. Standard 
monitors and ACLS resuscitative equipment will be immediately available. A norepinephrine 
solution will be at bedside to treat potential hypotension associated with SGB. The SGB 
perineural catheter will be placed using standard sterile technique. Initial perineural bolus 
injection - clonidine 100 mcg, Decadron PF 5mg, and 0.25% bupivacaine 5 ml is delivered. A 
Cadd perineural infusion 0.2% bupivacaine will be initiated at 2ml/hr for 5 days. Acute pain 
service will discontinue infusion and remove the catheter after 5 days. 
 
All adverse events and serious adverse events related to the SGB. All other adverse and serious 
adverse events, including death will be reported per IRB requirements. Laboratory analysis will 
be obtained at baseline (prior to block, baseline) and on day 1, day 3, and day 5. Labs include a 
cytokine panel (TNF-beta, IL-6, and IL-1β), measurements of exhaled nitric oxide levels, and 
CRP (daily). Vital Parameter Analysis: Oxygenation, supplemental oxygen, type of respiratory 
support and need for mechanical ventilation, blood pressure i.e. hypotension requiring 
vasopressors and utilization of ECMO, heart rate, heart rhythm/new dysrhythmias, 
ICU/progressive care length of stay and discharge disposition will be collected from the EMR. 
 
Control group: There will be no sham procedure for the control group.  The control group will 
have nitric oxide levels performed once a day by a member of the research team. Lab draws will 
be drawn at the same frequency as the treatment group. 
Treatment group:  
The treatment group will have a SGB placed by the APS.   
 
Appendix A. Protocol for stellate ganglion blockade in COVID-19 patients.  
 
ICU/progressive care RN will follow Med-27 NM policy for peripheral nerve catheter 
management. APS will utilize a similarly established standard of care in managing the catheters 
daily, for 5 consecutive days. This includes daily rounding on the patient to assess for signs of 
infection, muscle weakness, voice hoarseness, hematoma, intravascular migration, local 
anesthetic systemic toxicity, correct medication verification, verification of pump setting, 
evaluation for Horner’s syndrome (expected), patient education, and proper dressing coverage. 
 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 12 
 
Horner's syndrome refers to a constellation of symptoms that are associated with a stellate 
ganglion block.  These include a decreased pupil size on the affected side, delayed reaction to 
light on the affected side, drooping eyelid and decreased sweating on the affected side.  
Increased temperature and vascular dilation are also noted on the affected side with stellate 
ganglion block.
 
 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 13 
 
Schedule of events: *treatment group only
Assessment 
Screening: 
Visit-1  
Baseline, 
Enrollment,  
Randomization
:  (Day 0) 
Treatment 
Day 1 
Treatment 
Day 2 
Treatment 
Day 3 
Treatment 
Day 4 
Treatment 
Day 5 
EOS  
Discharge 
from 
hospital 
Follow-up: 
Day 90 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
Informed Consent Form   
X 
  
  
  
  
  
 
  
  
Enrollment/Randomization 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
  
  
  
  
  
 
  
 
Eligibility 
X 
  
  
  
  
  
 
  
 
Medical History  
X 
  
  
  
  
  
 
  
  
Data Collection (Vitals ect) 
X 
X 
X 
X 
X 
X 
X 
X 
 
Acute Pain Service  
 
X* 
X* 
X* 
X*  
X* 
X* 
 
 
Stellate Ganglion Block  
 
X* 
  
  
  
  
 
  
  
CRP 
 
X 
X 
 X 
X  
X 
X 
  
 
TNF-Alpha 
 
X 
X 
 
X 
 
X 
 
 
IL-Beta 
 
X 
X 
 
X 
 
X 
  
 
IL-6 
 
X 
X 
 
X 
 
X 
 
 
Nitric Oxide Level 
 
X 
X 
X 
X 
X 
X 
 
 
Telephone Call  
 
 
 
 
 
 
 
 
X 
Concomitant Medications 
  
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events  
  
X 
X 
X 
X 
X 
X 
X 
X 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 14 
 
 
 
 
Section 6.0 Measurement of Effect: 
We will be taking measurement of the biomarkers indicative of oxygenation, lung and proinflammatory immune 
response and nitric oxide - specifically,  
a) differences in mean/median values for SGB vs SOC will be assessed at each of the study designated time 
points for all the continuous biomarker measures - by assessing magnitude of difference and its 95% confidence 
level and testing differences for statistical significance at each of the time points;  
b) Differences in mean/median values for SGB vs SOC will be assessed at treatment day 5 - adjusted for baseline 
levels  
c) Differences in changes from baseline levels for SGB vs SOC as measured by comparison in slope trends; 
d) Differences in frequency of adverse events for SGB vs SOC over the study period from treatment through 90 
day of follow up; 
Secondarily,  
e) Differences between SGB vs SOC in frequency and time to occurrence of cardiac arrhythmias; 
f) Differences between SGB vs SOC in frequency of need for and duration of use mechanical ventilation and/or 
extracorporeal membrane oxygenation (ECMO); 
g) Differences between SGB vs SOC in survival experience over treatment period through 90 -day discharge 
follow up  
Sample Size issues: 
For power computations we assume that SGB will particularly have an impact in reduction of inflammatory response 
as measured by IL-6. Looking at a meta-analyses of IL-6 values [Ulhaq ZS, Soraya GV. Interleukin-6 as a potential 
biomarker of COVID-19 progression. Med Mal Infect. 2020;50:382–383. doi: 10.1016/j.medmal.2020.04.002. 
2020/04/08] and picking the largest of studies of COVID patients [Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et 
al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis 2020, 
http://dx.doi.org/10.1093/cid/ciaa248 [pii: ciaa248].], we estimate the overall mean (SD) IL-6 for COVID-19 patients 
to be 21 pg/mL (30.1). Using these estimates we see that a sample of 16 patients equally randomized into SGB (n=8) 
and SoC (n=8) would provide sufficient power to observe magnitude of differences in mean of IL-6 from as small as 
about 50 pg/mL and larger with 80% power at the 5% significance level assuming 2-sided hypothesis testing. (see 
Power Figure). The study [Liu MH, Tian J, Su YP, Wang T, Xiang Q, Wen L. Cervical sympathetic block regulates 
early systemic inflammatory response in severe trauma patients. Med Sci Monitor. 2013;19:194–201.], indicates that 
SGB is capable of eliciting reductions of IL-6 between groups and from baseline of magnitudes of greater than 100 
pg/mL within 72hrs of first injection. 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 15 
 
 
 
 
Section 7.0 Study Parameters:  
  
Baseline Assessments   
• 
Current Fio2/PaO2 ratio   
• 
Current type of ventilation and oxygen use   
• 
Current production of nitric oxide via Niox   
• 
Current blood pressure and heart rate parameters   
• 
Labs: IL-1beta, TNF-alpha, IL-6, ABG, CRP  
• 
Chest x-ray   
• 
Need for mechanical ventilation or other support   
• 
Need for pressure support   
 
Day 1 Assessments     
• 
Vital Signs q 6 hours (0000,0600,1200, 1800)   
• 
FiO2   
• 
PaO2 if available   

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 16 
 
• 
Chest x-ray – if available   
• 
Heart rate and any arrhythmias noted via telemetry    
• 
Evidence of successful/ongoing block   
• 
Horner’s syndrome     
• 
Current rate of infusion   
• 
Concomitant Medications   
• 
Vasopressor use   
• 
Adverse Events   
• 
Labs: CRP, IL-1 beta, TNF-alpha, IL-6, ABG (if on vent)  
• 
Production of nitric oxide via Niox   
 
Day 2 Assessments   
• 
Vital Signs q 6 hours (0000,0600,1200, 1800)   
• 
FiO2   
• 
PaO2 if available   
• 
Chest x-ray- if available   
• 
Heart rate and any arrhythmias noted via telemetry   
• 
Blood gas if available   
• 
CRP  
• 
Evidence of successful/ongoing block   
• Horner’s syndrome     
• Current rate of infusion   
• Concomitant Medications   
• Vasopressor use   
• 
Adverse Events   
• 
Production of nitric oxide via Niox   
 
Day 3 Assessments   
• 
Vital Signs q 6 hours (0000,0600,1200, 1800)   
• 
FiO2   
• 
PaO2 if available   
• 
Chest x-ray – if available   
• 
Heart rate and any arrhythmias noted via telemetry    
• 
Evidence of successful/ongoing block   
• 
Horner’s syndrome   
• 
Current rate of infusion   
• 
Concomitant Medications   
• 
Vasopressor use   
• 
Adverse Events   
• 
Labs: Labs: IL-1beta, TNF-alpha, IL-6, ABG (if on vent), CRP   
• 
Production of nitric oxide via Niox   
 
Day 4 Assessments   
• 
Vital Signs q 6 hours (0000,0600,1200, 1800)   
• 
FiO2   
• 
PaO2 if available   
• 
Chest x-ray- if available   
• 
Heart rate and any arrhythmias noted via telemetry   
• 
Blood gas if available   
• 
CRP  

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 17 
 
• 
Evidence of successful/ongoing block   
• Horner’s syndrome     
• Current rate of infusion   
• Concomitant Medications   
• Vasopressor use  
• Production of nitric oxide via Niox    
• Adverse Events   
 
Day 5 Assessments   
• Vital Signs q 6 hours (0000,0600,1200, 1800)   
• FiO2   
• PaO2 if available   
• Chest x-ray-if available   
• Heart rate and any arrhythmias noted via telemetry   
• Evidence of successful/ongoing block   
• Horner’s syndrome     
• Current rate of infusion   
• Concomitant Medications   
• Vasopressor use   
• Adverse Events   
• Labs: Labs: IL-1beta, TNF-alpha, IL-6, ABG (if on vent), CRP   
• Production of nitric oxide via Niox    
 
Follow-up assessment Day 90   
• 
Survival status 
• 
SF 36   
• 
Adverse events   
• 
Ongoing issues/oxygen use/rehab   
  
 
Section 8.0 Drug Dosage: 
 
There will be no dosing adjustments to the continuous perineural catheter or initial bolus injection. The bosting of the 
block has been reduced to the minimum effective dose.  
 
SGB Drug doses:  
Initial perineural bolus injection will include clonidine 100 mcg, decadron PF 5mg, and 0.25% bupivacaine 5 ml.  
 
Perineural catheter:  
Infusion of 0.2% bupivacaine will be initiated at 2ml/hr for 5 days.  
 
All medications are FDA approved.  Standard orders for perineural blocks will be entered into the EMR system.  
Pharmacy responsible for ICU/progressive care will dispense orders for the medication used in the SGB.  Pharmacist in 
ICU/progressive care will fill Cadd pump infusion catheter once per day per standard procedure in the ICU/progressive 
care.   
 
Section 9.0 Adverse Event Reporting Guidelines:  
 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 18 
 
The initial procedure will be stopped and the patient will be withdrawn if any of the following occurs; vasopressor or 
unresponsive hypotension, intrathecal injection, pneumothorax, expanding hematoma, allergic reaction, or cardiac 
arrhythmias. For continuous infusions, the catheter will be removed and the patient will be withdrawn if any of the 
following occur: local systemic toxicity, seizure, catheter migration to intravascular or intrathecal space, expanding 
hematoma, vasopressor unresponsive hypotension, symptomatic bradycardia, insertion site infection. Any adverse 
events will be treated with Nebraska Medicine standard of care procedures. Subjects can also voluntarily withdraw at 
any time. The PI can also withdraw any subject that is not felt to be a suitable candidate for the study. 
 
Serious adverse events directly related to block will result in withdrawal. Directly block related serious adverse events 
include: local systemic toxicity, seizure, serious allergic reaction, expanding hematoma, or catheter migration to 
intravascular or intrathecal space, insertion site infection. As well, patients will be withdrawn if the patient develops 
medication unresponsive bradycardia or hypotension. This may not be directly related to block but discontinuation of 
infusion may facilitate resuscitation of patient. Expected complications may include voice hoarseness, ipsilateral eyelid 
drooping, mild pain at site of catheter, and blurred vision. Occurrence of expected complications will not result in 
withdrawal from study unless demanded by the patient. 
 
 
Section 10.0 Statistical Considerations:  
 
Statistical considerations for primary objective, the analysis would include means/medians (standard errors, IQRs) at 
each time point - and also represented by error bars - and comparisons using t test or the Mann-Whitney U test as 
appropriate. Multivariate analyses using Generalized estimating equations (GEE) and to compare longitudinal changes 
in the two groups adjusting for confounders and as well as ANCOVA based regression to measure before and after 
changes. Kaplan-Meier survival methods to measure time to defined thresholds and Cox regression to assess any 
impact of confounders.  
 
For safety - AE’s will be assessed by providing descriptive statistics related to their frequency (summarized by 
occurrence, percentage of occurrence, severity, seriousness, outcome, relation to treatment, start time summary, 
duration of AE analysis) as well as graphically via box plots and cumulative incidence plots indicative of distributions 
in the two trial groups. Non-parametric methods (e.g. Fisher Exact testing) will be used to statistically compare the 
period frequency of events between the two groups. In general, timely analysis, by creating summaries of adverse 
events and other safety measurements such as relevant vital signs, ECG, Laboratory abnormal findings will be done to 
keep a check on the increase in intensity of observations taken at baseline and/or new findings arisen after baseline.  
 
Secondary measures: 
Occurrence of cardiac arrhythmias, need for mechanical ventilation and/or ECMO as well as overall survival will be 
compared using time-to-event based methods (e.g. Kaplan-meier curves). The expectation is that any non-statistically 
significant but implied trends will be evaluated in larger phase IIb /III trial that will follow.  
 
Stopping Rules: 
We have computed stopping rules for safety, from a statistical standpoint, standpoint based on the known background 
rate to help support export opinion. The stopping rules for this study are based on the prospectively accumulated safety 
data collected from each individual patient and utilize the hypothesis testing approach.  The idea is to rule out an 
observed event rate that is higher than the background event rate and to stop the trial if an excessive event rate is 
observed. For our plan to enroll 16 subjects, we assume (based on literature) that the background rate for the known 
risk of our experimental intervention is 10%.   Based on this we have constructed a stopping rule plan (See Table 
below) based on the background rate of the main Serious Adverse Drug Reaction or Event SAE/ADR of 10%. 
 
Our DSMB is empowered to stop the trial whenever they deem fit to protect the safety of patients. However, based on 
our plan, the DSMB will consider adopting a stopping rule that evaluates the rate of SAE/ADR after 5 enrollments, 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 19 
 
and thereafter with each enrollment and SAE/ADR reported will require stopping/suspension of trial entry if the 
observed rate of SAE/ADR is sufficient to reject the null hypothesis that the true SAE/ADR proportion (P) is 10% or 
less in favor of the (one-sided) alternative hypothesis that the true SAE/ADR proportion is more than 10%. The table 
below depicts the stopping guidelines. Exact binomial methods are used to compute the p values and confidence limits. 
One-sided lower 90% confidence limit is calculated. 
Number of 
Subjects 
Enrolled in the 
Study 
Number of 
SAE/ADR Needed 
to Reject Null 
Hypothesis 
Observed 
Rate of 
SAE/ADR 
(%) 
One-
sided p 
values 
Lower 90% 
Confidence 
Limit 
~5 
2 
40% 
0.0815 
11.22% 
6-10 
3 
30% 
0.0702 
11.58% 
11-15 
4 
27% 
0.0556 
12.18% 
16-20 
5 
25% 
0.0432 
12.69% 
Thus, for instance, if 2+ SAE/ADR events are observed in less than and equal to 5 subjects enrolled, the lower 
confidence limit of 11.22% will exceed the 10% background rate. The stopping rule for safety will be triggered and the 
study should be suspended/stopped at the discretion of the DSMB. 
 
Section 11.0 Records to be kept: A list of all records, including flow sheets, data collection forms/instruments, summary 
and evaluation forms will be locked in the study coordinator’s office. The subject list will be maintained by the study 
coordinator. The data from the electronic medical record will be retrieved and entered into the REDCAP database by 
research personnel.   
 
Section 12.0 Patient Consent: The consent form must adhere to the guidelines established by the Institutional Review 
Board of the University of Nebraska Medical Center. The most current version of ICF will be located in the IRB 
application #523-20-FB.  Electronic versions of ICF will be used in the event a LAR is needed to sign consent.  
 
Subjects and/or LAR will be approached while subject is in the ICU/progressive care. If subject is unable to participate 
in the consenting process, the LAR will be contact via telephone and/or video chat. Consents will be sent to LAR 
electronically. PI and/or Sub-I will be present for all consenting process regardless is the ICF process takes place in 
person or video digital presence. 
 
The subject will be in the ICU/progressive care room. A one-on-one conversation will be had between the subject & 
PI/Sub-I, of approximately 30 minutes to review the ICF. Then the subject will be given time alone to read over consent 
and ask any additional questions. If the LAR is not present in the ICU/progressive care, the LAR will be spoken to over 
the telephone. An electronic ICF will be sent to the LAR prior to the phone conversation. The phone conversation will 
last approximately 30 minutes to review the ICF. The LAR will be instructed to hang up and read the ICF in its entirety. 
A return call will be placed to the LAR at a designated time. Additional questions will be answered before electronic 
signature is done by LAR. 
 
 
Section 13.0 Study and Safety monitoring DSMB  
  
A DSMB has been constituted that includes:  Dr. Robert Lobato, Dr. Madhuri Are, and Danstan Bagenda, Ph.D., 
whose responsibility will be to review continually the safety and efficacy data, as well as the other aspects of the trials 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 20 
 
conduct.  The DSMB has been charged with making recommendations regarding early suspension or termination of 
age trial if there is unexpected evidence of safety concerns or dramatic intervention effect.  With this particular phase, 
in addition to proper conduct of the trial as indicated in the protocol the DSMB will primarily  be concerned with 
monitoring  adverse effects and assessing any  potential adverse events with respect to patients  safety at all times  and 
advising study continuation.  The study PI will, nevertheless, still shoulder the responsibility of immediately reporting 
potential severe adverse effects to the DSMB and ultimately all SAEs to the IRB.  Weekly or  immediately - at the 
urgent  earliest opportunity-upon each potential SAE whichever occurs first, the DSMB will review the accumulating 
numbers and types of severe adverse-including  assessing there relatedness to study intervention and recommend any 
analyses by the study  biostatistician-pooled , by treatment group, or disaggregated as  may be requested,   for review  
against the specified stopping rules and to advise any concerns and  course of action with regard to  any individual  of 
collective  patient safety. The DSMB will be supported by Danstan Bagenda,  a trained Biostatistician with long 
experience working with NIH study  DSMBs for phase I, II and III clinical trials, and who, although a Co-I  with the 
study,  has no clinical responsibility  for care with any patients at  UNMC.   
 
Section 13.0 References 
1.Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in 
Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China [published online ahead of print, 2020 Mar 13]. 
JAMA Intern Med. 2020;180(7):1-11. doi:10.1001/jamainternmed.2020.0994 
 
2.Liu MH, Tian J, Su YP, Wang T, Xiang Q, Wen L. Cervical sympathetic block regulates early systemic 
inflammatory response in severe trauma patients. Med Sci Monit. 2013;19:194-201. Published 2013 Mar 15. 
doi:10.12659/MSM.883833 
 
3. Chen Y, Guo L, Lang H, et al. Effect of a Stellate Ganglion Block on Acute Lung Injury in Septic Rats. 
Inflammation. 2018;41(5):1601-1609. doi:10.1007/s10753-018-0803-x 
 
4. Liu Y, Tao T, Li W, Bo Y. Regulating autonomic nervous system homeostasis improves pulmonary function in 
rabbits with acute lung injury. BMC Pulm Med. 2017;17(1):98. Published 2017 Jul 3. doi:10.1186/s12890-017-0436-0 
 
5. Guo W, Jin XJ, Yu J, et al. Effects of stellate ganglion block on the peri-operative vasomotor cytokine content and 
intrapulmonary shunt in patients with esophagus cancer. Asian Pac J Cancer Prev. 2014;15(21):9505-9509. 
doi:10.7314/apjcp.2014.15.21.9505 
 
6.Na S, Kim OS, Ryoo S, et al. Cervical ganglion block attenuates the progression of pulmonary hypertension via 
nitric oxide and arginase pathways. Hypertension. 2014;63(2):309-315. 
doi:10.1161/HYPERTENSIONAHA.113.01979 
 
7. He,Shunhou, et al. "Effect of stellate block on vasomotor factor, vascular endothelialnitricoxidesynthase and 
pulmonary arterial pressure in rabbits with hypoxic pulmonary artery hypertension." Neural Regeneration Research 2.3 
(2007): 129-133. 
 
8. Åkerström, Sara, et al. "Dualeffect of nitric oxide on SARS-CoVreplication: viral RNA production and 
palmitoylation of the S protein are affected." Virology 395.1 (2009): 1-9. 
 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 21 
 
9. Keyaerts, Els, et al. "Inhibition of SARS-coronavirus infection in vitro by S-nitroso-N-acetylpenicillamine, a nitric 
oxide donor compound." International journal of infectious diseases 8.4 (2004): 223-226. 
 
10. Ferring M, Vincent JL. Is outcome from ARDS related to the severity of respiratory failure?. Eur Respir J. 
1997;10(6):1297-1300. doi:10.1183/09031936.97.10061297 
 
11. Amar D, Zhang H, Roistacher N. The incidence and outcome of ventricular arrhythmias after noncardiac thoracic 
surgery. Anesth Analg. 2002;95(3):. doi:10.1097/00000539-200209000-00006 
 
12. Dyszkiewicz W, Skrzypczak M. Atrial fibrillation after surgery of the lung: clinical analysis of risk factors. Eur J 
Cardiothorac Surg. 1998;13(6):625-628. doi:10.1016/s1010-7940(98)00084-0 
 
13.Shih HT, Webb CR, Conway WA, Peterson E, Tilley B, Goldstein S. Frequency and significance of cardiac 
arrhythmias in chronic obstructive lung disease. Chest. 1988;94(1):44-48. doi:10.1378/chest.94.1.44 
 
14. Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir 
Med. 2020;8(6):e46-e47. doi:10.1016/S2213-2600(20)30216-2 
 
15. Ruan Q, Yang K, Wang W, Jiang L, Song J. Correction to: Clinical predictors of mortality due to COVID-19 based 
on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46(6):1294-1297. 
doi:10.1007/s00134-020-06028-z 
 
16. Shi S, Qin M, Shen B, et al. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-
19 in Wuhan, China [published online ahead of print, 2020 Mar 25]. JAMA Cardiol. 2020;e200950. 
doi:10.1001/jamacardio.2020.0950 
 
17. Guo T, Fan Y, Chen M, et al. Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 
2019 (COVID-19) [published online ahead of print, 2020 Mar 27]. JAMA Cardiol. 2020;e201017. 
doi:10.1001/jamacardio.2020.1017 
 
18.Tian Y, Wittwer ED, Kapa S, et al. Effective Use of Percutaneous Stellate Ganglion Blockade in Patients With 
Electrical Storm. Circ Arrhythm Electrophysiol. 2019;12(9):e007118. doi:10.1161/CIRCEP.118.007118 
 
19.Hayase J, Patel J, Narayan SM, Krummen DE. Percutaneous stellate ganglion block suppressing VT and VF in a 
patient refractory to VT ablation. J Cardiovasc Electrophysiol. 2013;24(8):926-928. doi:10.1111/jce.12138 
 
20.Nademanee K, Taylor R, Bailey WE, Rieders DE, Kosar EM. Treating electrical storm : sympathetic blockade 
versus advanced cardiac life support-guided therapy. Circulation. 2000;102(7):742-747. doi:10.1161/01.cir.102.7.742 
 
21.Angus JA, Rajasekaran P, Wright CE. Novel technique to determine the pKA of clonidine at prejunctional α2-
adrenoceptors in cardiac and vascular sympathetic transmission. Eur J Pharmacol. 2017;800:81-95. 
doi:10.1016/j.ejphar.2017.02.030 
 
22.Akers WS, Shah SK, Flynn JD, Apparsundaram S. Effect of clonidine on cardiac norepinephrine spillover in 
isolated rat heart. J Cardiovasc Pharmacol. 2004;43(6):830-838. doi:10.1097/00005344-200406000-00013 
 
23.Romero-Sandoval EA, McCall C, Eisenach JC. Alpha2-adrenoceptor stimulation transforms immune responses in 
neuritis and blocks neuritis-induced pain. J Neurosci. 2005;25(39):8988-8994. doi:10.1523/JNEUROSCI.2995-
05.2005 
 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 22 
 
 
Appendix A.  
 
Protocol for stellate ganglion (SG) blockade in coronavirus disease (covid-19) 
patients  
Purpose:  
To prevent morbidity and mortality related to moderate to severe covid-19 infection.    
Responsibilities:  
The attending intensivists will determine if a covid-19 patient is displaying indications for stellate ganglion block.   
APS will be consulted to urgently place the stellate ganglion block.  
A left sided SGB continuous perineural catheter will be placed by either ultrasound guided or fluoroscopy guided technique 
at the discretion of the APS attending in consultation with the chronic pain attending.   
Procedure:  
The attending proceduralist and resident assistant will perform the SGB at bedside under the following conditions:  
1. 
The block will only be performed in the intensive care setting.   
2. 
Intensive care nurse will provide patient monitoring and assistance during the procedure.   
3. 
The proceduralist will exam and record pupillary size prior to procedure and 20 minutes post injection.  
4. 
For fluoroscopy guidance, the radiology technician will provide imaging assistance during the procedure.   
5. 
A Logiq R7 machine will be brought to the patient’s bedside by the APS attending for ultrasound guidance.  
6. 
All equipment will be decontaminated with bactericidal/virocidal wipes prior to exiting the patient’s room and 
immediately upon exiting the room.   
7. 
Personnel involved in the procedure will don and doff N-95 respirators, gowns, gloves, and faces shields and 
strictly adhere to Nebraska Medicine covid-19 isolation/precautions for this non-aerosol generating bedside 
procedure.  
8. 
Standard ASA monitors and ACLS resuscitative equipment will be immediately available.   
9. 
A norepinephrine solution will be ordered by proceduralist and at bedside in order to treat potential 
hypotension associated with SGB especially in a baseline unstable patient.   
10. 
Pain provider will also bring standard prn IV bolus vasopressors including phenylephrine and epinephrine.  
The SGB perineural catheter will be placed using standard sterile technique.   
1. 
Initial perineural bolus injection will include clonidine 100 mcg, decadron PF 5mg, and 0.25% bupivacaine 5 ml.   
2. 
A Cadd perineural infusion 0.2% bupivacaine will be initiated at 2ml/hr for 5 days.   
3. 
The proceduralist will stay at the patient’s bedside for 20 minutes to monitor for signs of cardiovascular 
instability of respiratory distress. Following this period, the patient may be returned to standard ICU/PROGRESSIVE 
CARE reassessment regimens.    
4. 
The patient will be monitored for neck hematoma formation by the nurse with neck soft tissue reassessment 
every 15 min for 1 hour.   
5. 
APS providers will round on the patient daily and provide standard perineural catheter maintenance as well as 
record of pupillary size.   
6. 
APS will discontinue and remove the catheter after 5 days have elapsed.   
  
 
 
 
 
 
 
 
 
 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 23 
 
Appendix. B 
SF-36 QUESTIONNAIRE 
 
Name: 
 
 
ID#:   
 
Ref. Dr:  
 
 
Age:   
 
Date: 
 
Gender: M / F 
 
Please answer the 36 questions of the Health Survey completely, honestly, and without interruptions. 
 
GENERAL HEALTH: 
In general, would you say your health is: 
  Excellent 
Very Good 
Good 
Fair 
Poor 
Compared to one year ago, how would you rate your health in general now? 
Much better now than one year ago 
Somewhat better now than one year ago 
About the same 
Somewhat worse now than one year ago 
Much worse than one year ago 
 
LIMITATIONS OF ACTIVITIES: 
The following items are about activities you might do during a typical day. Does your health now limit you in these 
activities? If so, how much? 
 
Vigorous activities, such as running, lifting heavy objects, participating in strenuous sports. 
Yes, Limited a lot 
Yes,  Limited a Little 
No, Not Limited at all 
Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or playing golf 
Yes, Limited a Lot 
Yes,  Limited a Little 
No, Not Limited at all 
Lifting or carrying groceries 
Yes, Limited a Lot 
Yes,  Limited a Little 
No, Not Limited at all 
Climbing several flights of stairs 
Yes, Limited a Lot 
Yes,  Limited a Little 
No, Not Limited at all 
Climbing one flight of stairs 
Yes, Limited a Lot 
Yes,  Limited a Little 
No, Not Limited at all 
Bending, kneeling, or stooping 
Yes, Limited a Lot 
Yes,  Limited a Little 
No, Not Limited at all 
Walking more than a mile 
Yes, Limited a Lot 
Yes,  Limited a Little 
No, Not Limited at all 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 24 
 
Walking several blocks 
Yes, Limited a Lot 
Yes,  Limited a Little 
No, Not Limited at all 
Walking one block 
       Yes,  Limited a Lot 
Yes,  Limited a Little 
No, Not Limited at all 
Bathing or dressing yourself 
Yes, Limited a Lot 
Yes,  Limited a Little 
No, Not Limited at all 
PHYSICAL HEALTH PROBLEMS: 
During the past 4 weeks, have you had any of  the following problems with your work or other regular daily 
activities as  a result of your physical health? 
 
Cut down the amount of time you spent on work or other activities 
Yes 
No 
Accomplished less than you would like 
Yes 
No 
Were limited in the kind of work or other activities 
Yes 
No 
Had difficulty performing the work or other activities (for example, it took extra effort) 
Yes 
No 
 
EMOTIONAL HEALTH PROBLEMS: 
During the past 4 weeks, have you had any of the following problems with your work or other regular daily 
activities as  a result of any emotional problems (such as feeling depressed or anxious)? 
 
Cut down the amount of time you spent on work or other activities 
Yes 
No 
Accomplished less than you would like 
Yes 
No 
Didn't do work or other activities as carefully as usual 
Yes 
No 
SOCIAL ACTIVITIES: 
Emotional problems interfered with your normal social activities with family, friends, neighbors, or groups? 
 
Not at all 
Slightly 
Moderately 
Severe 
Very Severe 
 
PAIN: 
How much bodily pain have you had during the past 4 weeks? 
 
None 
Very Mild 
Mild 
Moderate 
Severe 
Very Severe 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 25 
 
During the past 4 weeks, how much did pain interfere with your normal work (including both work outside the 
home and housework)? 
 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
ENERGY AND EMOTIONS: 
These questions are about how you feel and how things have been with you during the last 4 weeks. For each 
question, please give the answer that comes closest to the way you have been feeling. 
 
Did you feel full of pep? 
All of the time 
Most of the time 
A good Bit of the Time 
Some of the time 
A little bit of the time 
None of the Time 
 
Have you been a very nervous person? 
All of the time 
Most of the time 
A good Bit of the Time 
Some of the time 
A little bit of the time 
None of the Time 
 
Have you felt so down in the dumps that nothing could cheer you up? 
All of the time 
Most of the time 
A good Bit of the Time 
Some of the time 
A little bit of the time 
None of the Time 
 
Have you felt calm and peaceful? 
All of the time 
Most of the time 
A good Bit of the Time 
Some of the time 
A little bit of the time 
None of the Time 
 
Did you have a lot of energy? 
All of the time 
Most of the time 
A good Bit of the Time 
Some of the time 
A little bit of the time 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 26 
 
None of the Time 
 
Have you felt downhearted and blue? 
All of the time 
Most of the time 
A good Bit of the Time 
Some of the time 
A little bit of the time 
None of the Time 
 
Did you feel worn out? 
All of the time 
Most of the time 
A good Bit of the Time 
Some of the time 
A little bit of the time 
None of the Time 
 
Have you been a happy person? 
All of the time 
Most of the time 
A good Bit of the Time 
Some of the time 
A little bit of the time 
None of the Time 
 
Did you feel tired? 
All of the time 
Most of the time 
A good Bit of the Time 
Some of the time 
A little bit of the time 
None of the Time 
 
 
 
 
 
 
 
SOCIAL ACTIVITIES: 
During the past 4 weeks, how much of the time has your physical health or emotional problems interfered with 
your social activities (like visiting with friends, relatives, etc.)? 
 
All of the time 
Most of the time 
Some of the time 
A little bit of the time 

SGB IN COVID-19 VERSION 3.0 NOVEMBER 23, 2020 27 
 
None of the Time 
 
GENERAL HEALTH: 
How true or false is each of the following statements for you? 
 
I seem to get sick a little easier than other people 
Definitely true 
Mostly true 
Don't know 
Mostly false 
Definitely false 
I am as healthy as anybody I know 
Definitely true 
Mostly true 
Don't know 
Mostly false 
Definitely false 
I expect my health to get worse 
Definitely true 
Mostly true 
Don't know 
Mostly false 
Definitely false 
My health is excellent 
Definitely true 
Mostly true 
Don't know 
Mostly false 
Definitely false