1.1 Background 1.1.1.Post-Acute Sequelae of SARS-CoV-2 (PASC) Since the onset of the COVID-19 pandemic, demands for rapid mobilization of research initiatives and treatment protocols continue to grow. While some people recover quickly from COVID-19, an increasing number of individuals previously infected with the SARS-CoV-2 virus report experiencing new, returning, or ongoing health problems long after recovery from the acute disease.The CDC and NIH define these long-term effects of COVID-19 by the broad research term Post-Acute Sequelae of SARS-CoV-2 infection (PASC), which is characterized by the presence of persistent or recurrent symptoms in patients who have recovered from an acute SARS-CoV-2 infection. PASC, also known as post-COVID conditions (PCC) or long COVID, presents in different ways and can affect the function of many different organs and systems including respiratory, neurological, and digestive systems. Most commonly, PASC symptoms include fatigue, post-exertional malaise, shortness of breath, "brain fog," sleep problems, fever, anxiety, and depression. Other symptoms include persistent cough, chest pain or chest discomfort, headache, heart palpitations, joint or muscle pain, diarrhea, nausea, abdominal pain, fever, dizziness, anosmia, or ageusia. Symptoms can vary between patients as some will experience only one of these symptoms while others may have two or more. The severity of symptoms range from mild to severe and can be debilitating. There is no test to diagnose post-COVID conditions. The symptoms of PASC can be difficult to explain and clinical evaluations or testing from routine blood tests, chest x- rays, and electrocardiograms may be normal, making it difficult for healthcare providers to recognize. Though more prevalent in people who had severe COVID-19 illness, anyone who has been infected with the virus that causes COVID-19 can experience post-COVID conditions, even people who had mild illness or no symptoms from a SARS- CoV-2 infection. Healthcare providers consider a diagnosis of post-COVID conditions based on a patient's health history, including if they had a diagnosis of COVID-19 either by a positive test or by symptoms or exposure. PASC can have significant effects beyond managing the physical symptoms. Many people report that long COVID symptoms prevent them from returning to work or school or cause them difficulties in performing everyday tasks or even walking short distances. Pain centers seeing patients with PASC report most patients would meet the definition of chronic primary pain with major distress based on the ICD-11 chapter for chronic pain (Wadehra). Furthermore, recent guidance states PASC, or Long COVID, can qualify as a disability under the American Disability Act if it limits at least one major life activity. The current research and understanding of PASC indicates it acts similarly to syndromes of chronic pain and sympathetic nervous system dysfunction that may be targeted by existing interventions. The symptoms can be functionally debilitating and can severely diminish quality of life, so identifying effective treatments and management strategies that address this disease may prove to have significant implications in the wake of the COVID-19 Pandemic.

1.1.2. Treatment for Post-Acute Sequelae of SARS-CoV-2 (PASC) As PASC has only recently been defined as a distinct disease state, it is not well understood yet and targeted and effective treatment options are extremely limited. PASC can affect many different organ systems, so current treatments are often multi- disciplinary, focusing on symptomatic management and treatment of underlying health problems. Clinicians have suggested that effective treatment should manage related pain and dysfunction. Many PASC symptoms that fail to respond to traditional treatment protocols are associated with dysautonomia. Dysautonomia is abnormal activity of involuntary body functions that are regulated by the sympathetic nervous system, such as heart rate, breathing and digestion. Sympathetic innervation plays a vital role in the communication between the immune system and the nervous system, but pathologies, such as elevated cytokine levels, can disrupt this relationship and promote sympathetic responses and subsequent inflammatory problems. In this way, the well-documented cytokine storm response to a SARS-CoV-2 infection results from sympathetic activation as the autonomic nervous system responds to pro-inflammatory cytokines. During elevated sympathetic signaling, the brainstem responds by integrating this information into "sickness behaviors," a set of behavioral responses which closely resembles PASC symptoms. As PASC may persist over weeks or months, persistent dysfunctional or inappropriate sympathetic signaling may potentially contribute to or exacerbate symptoms. Furthermore, prolonged dysautonomia is associated with impaired cerebral blood flow (CBF) in conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), and other poorly understood sympathetically-mediated chronic illnesses like complex regional pain syndrome (CRPS). In general, impaired CBF causes a range of clinical symptoms such as cognitive dysfunction, impaired memory and attention, and reduced visual, gustatory or olfactory function. The clinical presentations in these conditions parallel many common symptoms of PASC. Ongoing research and case studies are working to better understand the pathophysiology and effective treatments for PASC. The purpose of this study is to identify patients with continued hyperactivation of the sympathetic nervous system that can be targeted with existing treatments. A cases series conducted in 2021 showed promising results supporting Stellate ganglion blocks to reduce symptoms of Long COVID, or PASC. The case series reported sustained positive clinical outcomes for two Long COVID patients after treatment with SGB, identifying the pathophysiology for their symptoms as a regional sympathetically mediated dysautonomia. The results suggest SGB could be an effective intervention for at least a subset of Long COVID patients. Researchers conclude that although the application of SGB in PASC is novel, it is a promising and attractive therapeutic for a condition that currently lacks effective treatment options.

1.1.3. Dual Sympathetic Blocks (Stellate Ganglion Blocks) Sympathetic nerve blocks are established procedures used by many pain management providers as an effective method to diagnose or treat pain involving the nerves of the sympathetic nervous system. A block of the sympathetic nerves at the Stellate Ganglion in the upper neck has been used for decades to treat complex, sympathetically-mediated pain syndromes affecting the head, face, neck and arms. The stellate ganglion nerve bundle carries sympathetic signaling to many body regions and organs, including the head, neck, upper limbs, thymus, heart, lungs, lacrimal gland, salivary gland, thyroid gland and pineal gland. Injection of local anesthetic near the stellate ganglion can block activity of the entire cervical sympathetic chain, as evidenced by the physiological signs of a successful stellate ganglion block (SGB) collectively known as "Horner's Syndrome" which includes ipsilateral ptosis, meiosis, anhidrosis, and facial flushing. Researchers suggest the SGB can alleviate symptoms of dysautonomia by providing local recalibration of regional sympathetic influence, central integration of the effects of increased CBF, or rebalancing of the interaction between the nervous and immune systems. During the procedure, a physician uses x-ray or ultrasound imaging to guide a needle into a bundle of nerves located near the base of the neck. The physician then injects a local anesthetic into the nerve tissue like a dentist delivers numbing medicine before a dental procedure. The anesthetic lasts only a few hours, but the effects of the procedure can last for several weeks or longer in some cases. The use of Marcaine (bupivacaine) is indicated for local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures (including sympathetic nerve blocks), and for obstetrical procedures. The drug is lawfully marketed as a prescription drug product, and this investigation is not intended to support a significant change in the advertising for the product. There is increasing evidence that PASC has a similar profile to many pain syndromes, and dysautonomia appears to play an important role among the clinical manifestations in both the acute and chronic phase of SARS-CoV-2 infection. Thus, the use of sympathetic blocks in this study is meant to be included under the current indications for the treatment: an effective method to diagnose or treat pain involving the nerves of the sympathetic nervous system.

1.1.4. Theoretical Models There are a few published case series that seek to make further connections between PASC symptoms and autonomic dysfunction. Researchers express that the safety profile for Dual Sympathetic Blocks (Stellate ganglion blocks) is well established and has been used for nearly a century to treat a variety of sympathetically-mediated medical conditions. The lack of effective treatments for Long COVID/PASC makes the DSB an attractive therapeutic modality that deserves further investigation.

1.2 Rationale for Current Study This investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug. Clinicians have suggested that effective treatment for PASC should manage related pain and dysfunction. A sympathetic nerve block is used to both diagnose dysfunction and treat pain caused by the sympathetic nervous system. Sympathetic nerve blocks including the stellate ganglion blocks have been widely used by pain management physicians and their safety is well proven for the treatment of sympathetically-mediated pain syndromes.

Though PASC has only recently been defined, emerging and continued research supports the understanding that the SARS-CoV-2 infection affects the autonomic nervous system. Therefore, this study hopes to analyze the effectiveness of sympathetic nerve blocks to identify and treat symptoms of sympathetically-mediated pain or dysfunction in patients with PASC. The propensity of the PASC to lead to long-term illness and impairments calls for clinical trials aimed at prevention and treatment. The PROMIS-29 and COMPASS-31 surveys will be administered as part of the screening process to identify autonomic dysfunction. Patients who report symptoms of pain that interferes with daily function and at least one autonomic symptom that recurs or persists for 4 weeks or more after a SARS-CoV-2 infection meet the current criteria for PASC and may be eligible to participate. Findings from the current study may provide much needed insight into the state of the PASC disease and guidance for future clinical studies.