Stellate Ganglion Block Relieves Long COVID-19 Symptoms in 86% of Patients: A Retrospective Cohort Study

Post-COVID-19 condition, also known as long COVID-19 syndrome and post-acute sequelae of SARS-CoV-2, encompasses an array of symptoms that persist well beyond the initial phase of the viral infection. These symptoms can range in intensity, from mild and manageable to severe and incapacitating. Due to the evolving nature of the SARS-CoV-2 pandemic, treatment protocols for the illness are in a constant state of evolution. The early stage of long COVID-19 syndrome contributes to a dearth of treatment protocols based on empirical evidence, while the absence of a conclusive pathophysiological understanding further complicates the development of such protocols. Current treatment regimens include homeopathic medicine, specialist system-focused treatments, infusion therapies, hyperbaric oxygenation, antivirals, and polypharmacy. The physiological, psychological, and societal impact of long COVID-19 cannot be approached casually and must govern the intensity with which the healthcare community approaches the treatment of long COVID-19 syndrome. In this 41-patient cohort study from a chronic pain management practice, the use of either unilateral or bilateral stellate ganglion block (SGB) was explored to manage symptoms associated with long COVID-19 syndrome. Results indicated that a substantial proportion of patients (86%) experienced a reduction of their symptoms following SGB treatment.


Introduction
Long COVID-19 encompasses a range of lingering symptoms following an acute COVID-19 infection.Defined by the Centers for Disease Control and Prevention (CDC) as symptoms that persist for three or more months post-infection without previous existence [1], data from the U.S. Census Bureau, when analyzed by the CDC's National Center for Health Statistics (NCHS), shows about 7.5% of U.S. adults suffer from these symptoms [1].Studies have found post-COVID symptoms can remain even five weeks after the initial infection, with prevalence rates sometimes as high as 91% [2,3,4].
The CDC lists numerous symptoms of long COVID-19, such as fatigue, exacerbated symptoms after physical or mental exertion, respiratory problems, cognitive issues, sleep disturbances, gastrointestinal problems, and changes in menstrual cycles, among others [1].Zhang et al. used machine learning in a study with 34,605 participants to analyze over 137 symptoms, categorizing them into four distinct sub-phenotypes [5].This differentiation may be useful for future targeted treatment strategies.
The pathophysiology behind long COVID-19 remains a topic of study, but evidence points towards the nervous system's immunomodulatory activities playing a role in symptom manifestation.Several studies have shown links between long COVID-19 and an imbalanced immune response with persistent inflammation.Increased levels of cytokines such as IL-6, TNF-α, IL-1β, IL-8, and IL-10 suggest a sustained inflammatory state [6].The CRP protein, which indicates inflammation, is elevated in long COVID-19 patients [7].Its levels correlate with symptom severity and duration, but there's variability among individuals [6][7][8].
Post-viral symptoms resembling dysautonomia have been reported for various viruses [4].A subset of dysautonomia, Postural Orthostatic Tachycardia Syndrome (POTS), displays several symptoms that overlap with long COVID-19.An incidence of post-COVID dysautonomia is noted at 2.5% [4], which might be an underestimate given the shared symptoms.The sympathetic nervous system's role in long COVID-19 is evident, implying possible therapeutic targeting.
Historically, the nervous and immune systems were thought to function independently.However, research by Elenkov [8] and Tracey [9] has shown their interdependence.Fischer posits that during viral infections like SARS COVID-19, the autonomic nervous system (ANS) plays a crucial role in managing acute hyperinflammation, endothelial dysfunction, and other related issues [10].A malfunctioning ANS, marked by sympathetic hyperactivity, can be observed during these infections [11].
For long COVID-19, the sympathetic system's overactivity coupled with an underactive vagus nerve might allow persistent inflammation.This ongoing inflammation is possibly central to the characteristic symptoms of long COVID-19, as it disrupts the balance between the sympathetic and parasympathetic systems.
Given our understanding of the significant autonomic component in long COVID-19, our intervention targeted the sympathetic nervous system, using a stellate ganglion block to potentially alleviate long COVID-19 symptoms.

Materials And Methods
Study Design: A cohort population that consisted of patients who received a SGB for the treatment of long COVID-19 symptoms in our Colorado clinics between September and December of 2022.Ultrasound guided injection around stellate ganglion.
Sampling: Patients who responded to our post-procedure follow-up via phone call, in person or telehealth meeting.
Data Collection: Data was gathered and stored in an Excel spreadsheet.The data points included 18 items from the CDC list of the most prevalent symptoms associated with long COVID-19 syndrome.For each patient, the data indicated the presence of specific symptoms before the stellate ganglion block (SGB) procedure, and whether these symptoms improved or remained unchanged after the SGB.
Variables and Measurements: Difficulty breathing or shortness of breath, cough, Tiredness/fatigue, chest or stomach pain, joint or muscle pain, tachycardia/palpitations, symptoms that get worse after physical activity, pins and needles feeling, diarrhea, change in smell and taste, fever, dizziness/lightheadedness when standing, difficulty sleeping, rash, mood changes, headache, changes in menstrual cycle, brain fog/confusion, age and gender.Measured as present or not present before SGB and improved or unimproved after SGB.Data analysis: SPSS Version 28.0.1.0paired sample proportions Ethical considerations: All patients included in this study signed an informed consent for the procedure and subsequent collection of de-identified data.
Limitations: Limited sample size and potential bias of only having the patients who completed post procedural follow up.

Results
The treatment outcomes of forty-one patients (18 male and 23 female) with an age range between 18 and 89 who underwent stellate ganglion block (SGB) for long COVID-19 Syndrome were evaluated.The population consisted of patients from the United States who received treatment in our clinics between September and December of 2022 and responded to our post-procedure follow-up calls.The timeframe between the procedure and the data collection was variable depending on patient response times.The evaluation of the patients' long COVID-19 symptoms was based on the CDC list of the most prevalent symptoms of the condition.
There are a substantial proportion of individuals reporting relief, with notable variations in improvement rates between males and females for specific symptoms.The findings demonstrate that a substantial proportion of patients (86%) reported a reduction in at least some of their symptoms.Out of the 35 individuals who experienced symptom relief, a majority of 25 patients (61% of the total patients) reported relief from all the long COVID-19 symptoms they initially presented with [  Ultrasound-guided stellate ganglion blocks (SGBs) were performed with patients lying in a supine position with the head of the bed slightly elevated and turned away from the side of the procedure.This positioning, combined with ultrasound guidance, reduces the risk of unintended outcomes, such as pneumothorax, vascular puncture, or cervical nerve intrusion.Elevating the head of the bed helps decompress the subclavian vessels and turning the head away from the procedure side shortens the distance between the needle entry point and the SG.The blocks were performed following standard aseptic procedures.The cricothyroid notch, the border of the sternocleidomastoid muscle, and Chassaignac's tubercle serve as useful anatomical landmarks during the procedure.A skin marker was used to mark the expected placement of the ultrasound prior to application.The ultrasound probe was positioned transversely at the level of the cricothyroid notch, and the structures of concern were identified, [Figure 1] trachea, esophagus, thyroid gland, blood vessels, muscles, and nerves.A lateral to medial in-plane approach was utilized to avoid the structures of concern and to facilitate ideal needle tip placement.Located anterolaterally to the longus colli muscle, deep to the prevertebral fascia, and superficial to the fascia investing the longus colli muscle.A skin wheal with 1 ml of 1% lidocaine with sodium bicarbonate 8% was made, followed by the introduction of a 2 inch or 4-inch echogenic needle (size determined by body habitus) with continuous ultrasound guidance to the area of the SG.A mixture of 2ml 2% Chlorprocaine, 2ml 1% Lidocaine, and 1 ml 0.2% Ropivacaine was used as the injectate, and real-time ultrasound monitoring was used to ensure proper deposition around the SG [12][13][14][15].This technique did not result in any significant adverse events.Three patients experienced a vagal response, all of which happened immediately after a left-sided block and resolved quickly with reverse Trendelenburg positioning.Transient hoarseness occurred in four patients and resolved upon dissipation of the local anesthetic, which usually occurred within an hour.
Patients who live locally received a right sided SGB unless their symptoms were purely cardiac in nature .
Patients who traveled from out of state, first received a right stellate ganglion block, followed by a left-sided block once the Horner's syndrome (drooping eyelid , pupil constriction, and absence of sweating) from the previous block had resolved.
The resolution of long COVID-19 Symptoms following stellate ganglion block (SGB) was found to occur rapidly, with most patients reporting a noticeable improvement in symptoms within 15 minutes of the block.The resolution of symptoms that could not be clearly evaluated immediately after the SGB (brain fog, fatigue) were observed to occur at different time points, with some patients reporting a steady improvement over one to two weeks, while others reported that their symptoms resolved within a day.However, it should be noted that the current study did not specifically evaluate the time-based resolution of symptoms.
The symptoms most frequently reported by our patients were fatigue, observed in 85% of cases, and brain fog, present in 80% of individuals.These symptoms showed the highest response to treatment, with 77% of patients experiencing fatigue reporting significant relief, and 80% of those suffering from brain fog reporting relief.In our patient group, the loss of taste and smell proved to be the most challenging symptom to treat, with only 56% of patients reporting improvement.Although, we were able to obtain a higher response rate for anosmia with the addition of a trigeminal nerve block [Table 2].
There was a marked statistical significance across all symptoms in response to stellate ganglion block treatment, with p-values below 0.001 for most symptoms, demonstrating the broad effect of the treatment.The exception was "changes in menstruation", for which the significance was still noteworthy with a p-value less than 0.05, in both one-sided and two-sided tests.This suggests a comprehensive impact of the stellate ganglion block treatment across a range of symptoms [

TABLE 3: Paired samples test of significance for each symptom
A gender disparity was observed in both the initial presentation of symptoms and symptom resolution .
Women reported a higher frequency of symptoms related to long COVID-19 however, they also demonstrated a higher rate of symptom resolution [Table 3].

Discussion
The precise mechanism through which SGB ameliorates long COVID-19 symptoms is not fully understood.Fisher et.al. theorize that the immune and inflammatory responses during the acute phase of long COVID-19 and the ensuing post-acute symptoms are due to a malfunction in the Autonomic Nervous System (ANS), particularly sympathetic hyperactivity [10].They argue that SGB, by modulating the ANS, can disrupt overactive processes within nerve-immune-inflammation feedback loops, enabling their self-regulation.Furthermore, SGB's impact goes beyond the ANS, influencing downstream regulatory actions including immune and inflammatory system control, cytokine production, endothelial function, and microcirculatory function regulation [10].SGB has been utilized for a broad spectrum of conditions, including pain syndromes and disorders of the immune and endocrine systems.Lipov et al. suggested that the therapeutic action of SGB might primarily involve sympathetic block-mediated peripheral vasodilation [16].However, given the diversity of SGB applications, they acknowledge that the mechanism might be more multifaceted.Deng et al. demonstrated multiple changes in the neuroendocrine system of rats that received an SGB prior to surgery [17].The changes included reductions in neuronal loss, decreased microglial activation, as well as reductions in inflammatory markers TNF-α, IL-1β, and IL-6.Others have hypothesized that SGB results in changes in voltage-gated sodium channels of peripheral nerves and the central response by spinal feedback loops, thus decreasing symptoms [4].Neuronal growth factor is also suspected to play a role in the effects of a SGB [18].
Numerous research studies and publications have demonstrated the effects of SGB in the modulation of the immune system and hyperinflammation.These effects include the reduction of natural killer cell activity [19,20], as well as the decrease in levels of inflammatory cytokines such as IL-1, IL-4, IL-6, IL-8, and TNF-α, and the concurrent increase of anti-inflammatory cytokine IL-10 and CGRP [21][22][23].Additionally, SGB has been shown to regulate endothelial dysfunction [24], microcirculation, and coagulopathy [20,25,26].Furthermore, it contributes to the reduction of neurogenic pulmonary edema [15,24,27] and pulmonary arterial hypertension [28].Another notable effect is the reduction of pathological positive feedback loops [10,29,30].
The reversal of anosmia (loss of smell) and dysgeusia (altered taste) post-Stellate Ganglion Block (SGB) aligns with the restoration of parasympathetic function due to sympathetic blockade of the Stellate Ganglion (SG), the conduit for all sympathetic innervation of the head and neck.It is plausible to infer that the sympathetic hyperreactivity, also triggers anosmia and dysgeusia by interrupting sympathetic outflow to cranial nerves, specifically CN I (Olfactory), CN VII (Facial), and CN IX (Glossopharyngeal) [14].
The timing for employing SGB in managing long-COVID syndrome may be important, as the degree of neuroadaptation that has occurred may decrease the effectiveness of the SGB.Our clinical observations indicate that delayed SGB, such as in individuals with long standing analogous post-viral ailments (Lyme Disease, Chronic Fatigue Syndrome, Myalgic Encephalopathy) exhibited notably diminished responsiveness to SGB as compared to long COVID-19 patients.Achieving only a 10% -20% reduction in their symptoms with each injection.
In our practice, SGB has proven beneficial in treating long COVID-19 symptoms, and we urge its prompt consideration to avert possible diminished effectiveness due to time-sensitive neuroadaptive changes.
This study's results, based on responses from 41 of 60 treated patients, may not wholly represent all patient experiences.Those with less positive outcomes might have opted out of participating.
The choice of local anesthetic could influence SGB efficacy.We used a mix of Chloroprocaine, Lidocaine, and Ropivacaine.Lidocaine is known for its immunomodulatory properties, while others have not been tested in this context.Further research might help determine the most effective local anesthetic and the underlying therapeutic mechanisms of SGB in long COVID-19 patients.
The use of ultrasound guidance during SGB injections is advocated as it helps to avoid critical structures and reduce the risk of needle placement or injection into unintended structures.In our practice, no serious adverse events were reported from SGB injections performed under ultrasound guidance.
In our clinical practice, right-sided stellate ganglion blocks (SGBs) were the most frequently performed procedure.Bilateral SGBs were reserved for patients who were coming from out-of-state or experiencing predominately dysautonomia related to long COVID-19 syndrome.The physiological effects of SGBs can vary depending on the side of injection.Right-sided SGBs have been shown to result in greater sympathetic blockade than left-sided SGBs, leading to a greater decrease in heart rate and blood pressure, likely due to the right stellate ganglion's dominance and more direct connection to the heart via the cardiac plexus [9,18].In contrast, left-sided SGBs produce a greater degree of parasympathetic effect than right-sided SGBs, leading to a greater increase in heart rate and cardiac output, likely due to the left vagus nerve's stronger influence on the heart and its direct connection to the sinoatrial node [ 9,18].While no data were collected to analyze the relationship between laterality and patient response, we believe it is important to investigate the optimal laterality for administering SGBs based on specific symptoms of long COVID-19.
Six patients failed to experience symptom relief, and further evaluation revealed that three had rare disorders that were contributing to their symptoms.It is noteworthy that these diagnoses were uncommon, leading us to question if there may be undiagnosed underlying medical conditions in some of the remaining patients who were unresponsive to treatment.

Conclusions
The results of our cohort study indicate that SGB is a promising treatment option for patients suffering from long COVID-19 syndrome.The rapid resolution of symptoms and high success rate of treatment make SGB a compelling treatment option for long COVID-19 patients.However, it should be noted that our findings are limited to a specific subset of patients, and further research is needed to confirm these results.The use of ultrasound guidance and the specific anesthetic used may also play a role in the efficacy of SGB, and further studies in these areas are warranted.
A version of this article was previously posted on a pre-print server (medRxiv) on August 15, 2023.
While further double-blind placebo-controlled testing is necessary, the highly favorable patient response to this treatment suggests that it should not be withheld by healthcare providers.Despite the need for additional studies, we believe that this safe and effective procedure should be made broadly available to patients suffering from long COVID-19.protocol versions used throughout the life of the study.Please note, as per USF policy, once the exempt determination is made, the application is closed in BullsIRB.This does not limit your ability to conduct the research.Any proposed or anticipated change to the study design that was previously declared exempt from IRB oversight must be submitted to the IRB as a new study prior to initiation of the change.However, administrative changes, including changes in research personnel, do not warrant a modification or new application.Ongoing IRB review and approval by this organization is not required.This determination applies only to the activities described in the IRB submission and does not apply should any changes be made.If changes are made and there are questions about whether these activities impact the exempt determination, please submit a new request to the IRB for a determination.Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
Consent was obtained or waived by all participants in this study.University of South Florida Institutional Review Board issued approval STUDY005486.The IRB determined that this protocol meets the criteria for exemption from IRB review.In conducting this protocol, you are required to follow the requirements listed in the INVESTIGATOR MANUAL (HRP-103).Your study qualifies for a waiver of the requirement for signed authorization as outlined in the HIPAA Privacy Rule regulations at 45 CFR 164.512(i).A waiver of HIPAA authorization is granted for this retrospective chart review of adult patients who underwent Stellate Ganglion Block for long COVID-19 at Metamorphosis Pain Management within the date range in the protocol.This waiver allows the study team and/or its honest broker to access PHI of the patients in this cohort from the Metamorphosis Pain Management medical record (Kareo EMR).The date range in your protocol may be extended and the number of records reviewed may be increased without submitting a new IRB application, so long as your protocol is revised accordingly and complies with the minimum necessary requirement set forth in the Privacy Rule.Other minor changes, such as addition of a data variable, can also be made without resubmission.As per USF policy, changes to study design (e.g.changes in Institutional Review Board Approval (for research articles) Institutional Review Boards / Research Integrity & Compliance FWA No. 00001669 University of South Florida / 3702 Spectrum Blvd., Suite 165 / Tampa, FL 33612 / 813-974-5638 Page 2 of 2 inclusion/exclusion criteria, change from retrospective to prospective data collection, changes in study sites, etc.) require a new IRB application.Please keep all DisclosuresHuman subjects: