Cervicothoracic Sympathetic Block Evaluation for Post COVID Condition

A Randomized Controlled Trial for Cervicothoracic Sympathetic Chain Block Against Sham Injection Evaluation for Post COVID Condition: the CeASE RCT

Post-COVID Condition (PCC) affects roughly 2.1 million Canadians, carrying an annual economic burden of CAD $7.8-50.6 billion. It presents across multiple organ systems with symptoms including fatigue, brain fog, palpitations, and orthostatic intolerance, at an annual cost of CAD $1,675-$7,340 per case.

A key mechanism underlying many treatment-resistant PCC symptoms appears to be dysautonomia abnormal autonomic nervous system function driven by immune-mediated sympathetic overactivity. Persistent inflammation (cytokine storms, T/B-cell dysfunction, microclots) sustains sympathetic hyperactivity, which in turn perpetuates systemic inflammation and "sickness behaviors" resembling PCC symptoms.

Current treatments including beta blockers, ivabradine, fludrocortisone, and rehabilitation are limited by variable responses, side effects, and the complication of post-exertional symptom exacerbation. Emerging therapies (SSRIs, low-dose naltrexone, antihistamines, HBOT) show promise but lack robust trial evidence.

Cervicothoracic sympathetic chain block (CSB) a local anesthetic block of the cervical and upper thoracic sympathetic ganglia is a promising intervention that reduces sympathetic outflow, improves cerebral blood supply, and lowers pro-inflammatory cytokines. Small observational studies (16 studies, 224 patients) show benefit for PCC symptoms, but all lack placebo controls and have significant methodological heterogeneity.

The proposed study aims to fill this gap with a double-blind, placebo-controlled RCT to rigorously evaluate CSB's efficacy, magnitude of benefit, and durability in PCC patients.

Post COVID Condition (PCC): In the wake of the COVID-19 pandemic, while many individuals recover fully from an acute COVID-19 infection, a substantial proportion experience ongoing or evolving symptoms well beyond the initial illness. These prolonged effects are broadly referred to as long COVID, also commonly referred to as the post-COVID conditions (PCC). The WHO defines long COVID as a condition following confirmed or probable SARS-CoV-2 infection, with symptoms lasting at least 2 months, typically beginning 3 months postinfection, and not explained by an alternative diagnosis. In Canada, at least 15 million people were infected with COVID-19 and 1 in 5 adults who had COVID-19 developed long-lasting symptoms after their initial infection. Of those, more than half (58.2% or about 2.1 million people) still have ongoing symptoms, defined as PCC. The annual economic burden of PCC in Canada is significant, with estimates from a Public Health Agency of Canada report suggesting a total healthcare cost between CAD 7.8 and CAD 50.6 billion. Costs per case can range from CAD 1,675 to CAD 7,340 in the first year after infection, with unvaccinated individuals experiencing higher costs and quality-adjusted life-year decrements.

Manifestations of and autonomic dysfunction in PCC: PCC presents in diverse ways and can affect multiple organ systems, including the cardiovascular, respiratory, neurological, and gastrointestinal systems. There is a range of symptoms that are encompassed within the syndrome of PCC, including fatigue, shortness of breath, chest pain, palpitations, headache, cognitive impairment ('brain fog'), rashes, anxiety, depression, gastrointestinal upset, persistent anosmia, and more with chronic fatigue and dyspnea as the most common. When cardiovascular or autonomic symptoms are present, clinicians are advised to evaluate for conditions associated with long-term sequelae of COVID-19 infection including myalgic encephalomyelitis or chronic fatigue syndrome; post-exertional malaise and post-exertional symptom exacerbation, dysautonomia with cardiac manifestations (e.g. inappropriate sinus tachycardia and postural orthostatic tachycardia syndrome (POTS: sustained and symptomatic increase in heart rate of ≥30 bpm within 10 minutes of standing without a drop in systolic BP ≥20 mmHg or diastolic BP ≥10 mmHg)), and mast cell activation syndrome (MCAS).

While some symptoms result from tissue damage of COVID-19, persistent symptoms despite tissue repair suggest additional mechanisms in PCC. A key hypothesis implicates pathological inflammation, potentially driven by persistent viral presence, T-cell dysfunction, and B-cell hyperactivity,sustaining a hyperinflammatory state. This process contributes to cytokine storms, immune dysregulation, multiorgan inflammation, reactivation of latent pathogens, autoimmunity, and microclot formation. The sympathetic nervous system plays a critical role in immune regulation. Sympathetic fibers innervate primary and secondary lymphoid organs, and immune cells express adrenergic receptors and neuropeptides, enabling modulation by neurotransmitters released from sympathetic nerve terminals. Through these mechanisms, the SNS regulates both immune homeostasis and pathological activation. This neuroimmune cross-talk provides context for understanding the role of SNS in chronic inflammation, including PCC. Symptoms resembling autonomic dysfunction have also been observed following various viral infections such as HIV and herpes viruses, and a similar pattern is evident in PCC. Symptoms such as brain fog, fatigue, chest pain, palpitations, and severe orthostatic intolerance syndromes suggest an interaction between inflammation and autonomic hyperactivity. These findings implicate the sympathetic nervous system as a potential therapeutic target for PCC.

Many PCC symptoms that are resistant to conventional treatments have been associated with dysautonomia an abnormal functioning of the autonomic nervous system, which regulates involuntary bodily functions such as heart rate and blood pressure, respiration, and digestion. While the underlying pathophysiology of PCC remains incompletely understood, emerging evidence suggests that the autonomic dysfunction in these patients reflect immune-mediated dysregulation of the autonomic nervous system. The sympathetic branch of the autonomic nervous system plays a key role in neuroimmune communication; however, this delicate balance can be disturbed by elevated levels of pro-inflammatory cytokines, which drive sympathetic overactivity and contribute to systemic inflammation. In SARS-CoV-2 infection, this process has been well described in the literature and attributed to the cytokine storm, in which sympathetic activation is a central component of the immune response. Heightened sympathetic signaling further engages the brainstem to initiate "sickness behaviors" a cluster of physiological and behavioral responses that closely resemble the symptomatology of PCC. When this state of sympathetic hyperactivity persists over time, it may contribute to, or exacerbate, the chronic and debilitating symptoms experienced by individuals with PCC.

Treatment approaches for PCC: Medications such as ivabradine, beta blockers, midodrine, and fludrocortisone are recommended by the Canadian POTS guidelines and may improve orthostatic tolerance and cerebral perfusion in POTS patients, including those with PCC. However, responses are highly variable, access remains a barrier, and side effects can be limiting. Rehabilitation is further complicated by post-exertional symptom exacerbation (PESE), which makes structured exercise risky for many PCC patients. Preliminary studies outside of PCC suggest possible benefit from transcutaneous vagus nerve stimulation and jugular vein compression collars, but do not achieve symptom remission and benefits may wane once the user stops wearing the device.

Current treatment approaches include very few interventions backed by clinical trials, emerging therapies from patient-led research, and off-label or self-directed treatments. There is growing evidence for symptom-based pharmacologic treatments for specific PCC phenotypes including hyperbaric oxygen therapy (HBOT). Antihistamines have shown benefit in patients with MCAS features, improving symptoms in small studies. Other off-label therapies with emerging support include SSRIs, which may reduce neuroinflammation and brain fog by modulating serotonin and cytokine pathways; Maraviroc, a CCR5 antagonist that may disrupt the monocytic-endothelial-platelet axis in inflammatory states; and low-dose naltrexone, which may restore function in natural killer cells to reduce post-COVID fatigue and pain.

Role of cervicothoracic sympathetic chain block for PCC: The cervicothoracic sympathetic chain includes the superior, middle, intermediate, inferior cervical and the upper thoracic sympathetic ganglia. The inferior cervical sympathetic and the first thoracic sympathetic ganglia combine to form the stellate ganglion on each side and these ganglia are located at the level of the first rib, posterolateral to the longus colli muscle. The right stellate ganglion innervates the sinoatrial node and the right ventricle and its stimulation results in chronotropy, increased contractility, and arrhythmias. Its post ganglionic fibers also innervate the right side of the face, the right upper limb and the right lung and bronchi. The left stellate ganglion innervates the atrioventricular node and the left ventricle and its stimulation results in chronotropy, increased contractility, and arrhythmias. Its post ganglionic fibers also innervate the left side of the face, the left upper limb and the left lung and bronchi.

The cervicothoracic sympathetic chain block (CSB) is a local anesthetic block of the middle and lower cervical and upper thoracic sympathetic trunk. We have demonstrated that an ultrasound-guided injection of 5 cc of LA in the sympathetic chain at the level of the sixth cervical transverse process spreads from the fourth cervical to the first thoracic levels and blocks middle and lower cervical and upper thoracic sympathetic ganglia. We have also evaluated variations in relevant sonoanatomy for anterior and lateral approaches for CSB in a large cohort. More recently, we and others have synthesized the evidence for the role of CSBs in non-pain indications with autonomic hyperfunction including arrhythmias, peripheral vascular disease, anxiety, and other medical conditions associated with autonomic dysfunction. The effectiveness of CSB for these conditions stems from the intervention's ability to block sympathetically mediated disease manifestations. These blocks manifest their therapeutic effects through three main mechanisms: 1) blocking neural connections in the region of innervation (cervical sympathetic trunk); 2) improving blood supply to organs including the brain; and 3) reducing the plasma concentration of stress hormones and pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α,) and downregulation of NF- κB signaling. There is also evidence for persistence of therapeutic benefit from multiple consecutive CSB from a few weeks to one year despite the local anesthetics having a half-life of a few hours.

The left stellate ganglion has a greater influence on heart rate and contractility as compared to the right. Left-sided CSB have shown benefit in alleviating symptoms of PCC in cohort studies by obtunding the activity of the sympathetic nervous system outflow. A recent scoping review reported results of CSB in 16 small observational studies on 224 patients with PCC with preliminary evidence for alleviating symptoms of autonomic dysfunction in patients with PCC. However, all these studies lacked placebo or sham intervention-controlled comparators, and the reported outcomes were subjective. Further, there was considerable heterogeneity in the approach to achieving CSB in terms of laterality, injectate composition and volume, and frequency of procedures. Given the subjective nature of PCC, it is crucial to distinguish between the therapeutic benefit and the placebo effects of this intervention while also establishing the magnitude and longevity of this benefit.

To address this gap, our research group is uniquely positioned to evaluate the efficacy of CSB in a double-blind, randomized controlled trial, establishing more rigorous evidence for its potential role in the treatment of PCC.

Inclusion criteria

1. Age 18 years or older
2. PCC following COVID-19 infection with symptoms lasting for at least three months
3. Ability to read, write, and understand English
4. Quantified autonomic symptoms from at least one domain as reported by the patient on the screener Composite Autonomic Symptom Score (COMPASS-31), i.e. a COMPASS-31 score greater than 0. COMPASS-31 assesses 6 domains of autonomic symptoms: Orthostatic Intolerance, Vasomotor, Secretomotor, Gastrointestinal, Bladder, and Pupillomotor.
5. Patients should be stable on any PCC-related medications for at least four weeks.

Exclusion criteria

1. History of co-existing conditions that are a contraindication for SGBCSBCSB:

   1. Unilateral vocal cord paralysis; Severe chronic obstructive pulmonary disease (FEV1 between 30-50% of predicted value)
   2. Recent myocardial infarction (within the last one year), Cardiac conduction block of any degree
   3. Glaucoma
   4. Infection or mass at injection site, bleeding disorders

2. Comorbid conditions that could confound study results, such as:

   1. Active autoimmune disorders
   2. Pre-existing autonomic dysfunction (e.g. POTS, IST, and CRPS) prior to COVID-19
   3. Untreated psychiatric conditions (e.g. severe anxiety or PTSD requiring medication adjustments during the study period)

3. Recent history of major surgery or cerebrovascular events within the last three months

4. Allergy to local anesthetic; Inability to extend the neck for any reason (e.g. severe arthritis)

5. History of prior stellate ganglion block