Long COVID management: a mini review of current recommendations and underutilized modalities.

Long COVID is a condition that develops in a subset of patients after COVID-19 infection comprising of symptoms of varying severity encompassing multiple organ systems. Currently, long COVID is without consensus on a formal definition, identifiable biomarkers, and validated treatment. Long COVID is expected to be a long-term chronic condition for a subset of patients and is associated with suffering and incapacity. There is an urgent need for clear management guidelines for the primary care provider, who is essential in bridging the gap with more specialized care to improve quality of life and functionality in their patients living with long COVID. The purpose of this mini review is to provide primary care providers with the latest highlights from existing literature regarding the most common long COVID symptoms and current management recommendations. This review also highlights the underutilized interventions of stellate ganglion blocks and low-dose naltrexone, both with well-established safety profiles demonstrated to improve quality of life and functionality for patients suffering with some symptoms of long COVID, and encourages prompt referral to interventional pain management.

Stellate Ganglion Block Attenuates LPS-Induced Acute Lung Injury by Activating Sirt3 Regulation of Oxidative Stress and Inflammation.

Stellate ganglion blocks (SGBs) has been applied in clinics to alleviate pain-related syndromes for almost a century. In recent years, it has been reported that SGB can attenuate acute lung injury (ALI) in animals. However, the details of these molecular mechanisms remain complex and unclear. In this study, rats were randomly divided into four groups: group C (receiving no treatment), group NS (receiving the intratracheal instillation of normal saline), group L (receiving the intratracheal instillation of LPS) and group LS (receiving SGB after the intratracheal instillation of LPS). The pathological damage of lung tissue, arterial blood gases, the differentiation of alveolar macrophages (AMs) and inflammatory cytokines (IL-1ß, IL-6, IL-10) were detected. Furthermore, the oxidative stress indexes (ROS, CYP-D, T-SOD, Mn-SOD and CAT) in serum and the levels of Sirt3 signaling-associated proteins (JAK2/STAT3, NF-κb p65, CIRP and NLRP3) in the lungs were measured. The results revealed that SGB could attenuate lung tissue damage, improve pulmonary oxygenation, promote the differentiation of AMs to the M2 phenotype, decrease the secretion of IL-1ß and IL-6, and increase the secretion of IL-10. Meanwhile, SGB was found to inhibit the production of ROS and CYP-D, and enhance the activities of T-SOD, Mn-SOD and CAT. Furthermore, SGB upregulated Sirt3 and downregulated JAK2/STAT3 and NF-κb p65 phosphorylation, CIRP and NLRP3. Our work revealed that SGB could attenuate LPS-induced ALI by activating the Sirt3-mediated regulation of oxidative stress and pulmonary inflammation; this may shed new light upon the protection of SGB and provide a novel prophylactic strategy for LPS-induced ALI.

Objective Evaluation of Stellate Ganglion Block Effects Using Ultrasound Wave Intensity Technology: A Study on Hemodynamics.

Purpose: Emerging evidence suggests that although Horner's syndrome manifests observable facial changes, it may not comprehensively evaluate the hemodynamic alterations associated with stellate ganglion block (SGB). This study endeavors to systematically evaluate the influence of SGB on the elasticity and flow velocity of the common carotid artery (CCA) and brachial artery utilizing ultrasound wave intensity analysis (usWIA). Particularly, it focuses on patients necessitating monitoring for its effects on specific organs or regions. Methods: Totally, we selected 33 patients, where only 31 patients (comprising 15 males and 16 females) were included between September 2020 to January 2022 after screening patients who require SGB treatment for painful disorders. The side on which the SGB was administered depended on the patient's painful side, 13 cases underwent left stellate ganglion block (LSGB), and 18 cases underwent right stellate ganglion block (RSGB). Wave intensity (WI) data were collected by usWIA on the CCA and brachial artery before the administration of SGB and after the manifestation of Horner's syndrome. We then compared the changes in these data pre- and post-SGB using SPSS 26.0. Results: The results showed an increase in arterial compliance (AC) of the CCA and brachial artery on the blocked side after SGB (P < 0.05). In contrast, pressure-strain elastic modulus (EP) and arterial stiffness pulse wave velocity (PWVß) decreased (for all P < 0.05). Furthermore, the minimum velocity (Vmin) of the CCA exhibited a significant increase (P < 0.01), while wave intensity pulse wave velocity (PWVwi) was significantly reduced (P < 0.01). In contrast, on the contralateral side of the CCA, EP and PWVß increased after SGB (for all P < 0.05), while AC decreased (P < 0.05). Conclusion: SGB has been observed to enhance the elasticity and blood flow velocity of arteries within its innervated areas. In clinical practice, usWIA can serve as an objective measurement tool for assessing the impact of SGB on arterial elasticity and flow velocity in specific organs or regions. Furthermore, unilateral SGB has been noted to diminish the arterial elasticity of the CCA on the contralateral side.

QUESTION: How to accurately and objectively evaluate the hemodynamic changes of SGB on targeted organs or regions? FINDINGS: SGB increased the elasticity and blood flow velocity of the arteries on the blocked side by usWIA. Meaning: The usWIA could serve as an objective measurement tool for assessing the effects of SGB on arterial elasticity and blood flow velocity, especially for patients needing evaluation of its impact on the upper limbs.

Reduction of long COVID symptoms after stellate ganglion block: A retrospective chart review study.

The SARS-CoV-2 pandemic has left millions of individuals with a host of post-viral symptoms that can be debilitating and persist indefinitely. To date there are no definitive tests or treatments for the collection of symptoms known as "Long COVID" or Post-acute sequelae of COVID-19 (PASC). Following our initial case report detailing improvement of Long COVID symptoms after sequential bilateral stellate ganglion blockade (SGB), we performed a retrospective chart analysis study on individuals treated with the same protocol over the course of six months (2021-2022) in our clinic. Patients self-reported symptoms on a 10-point scale as part of optional patient follow-up using an online survey. After one month or more following treatment, patients reported striking reductions in Fatigue, Worsening of Symptoms following Mental and Physical Activity, Memory Problems, Problems Concentrating, Sleep Problems, Anxiety, and Depression. Loss of Taste and Loss of Smell in some individuals did not respond to treatment, likely indicating structural damage following infection. This study suggests that neuromodulation may provide relief of Long COVID symptoms for at least a subset of individuals, and provides support for prospective studies of this potential treatment.

Sympathetic Duet: Simultaneous Stellate Ganglion Block and Thoracic Epidural Analgesia in the Successful Termination of Ventricular Storm.

This article discusses the management of ventricular storm (VS), a condition characterized by recurrent episodes of sustained ventricular tachycardia or fibrillation, which poses a significant risk of mortality. Prompt intervention is crucial, yet surgical options are often limited due to the patient's unstable condition. This case report presents a 47-year-old female who experienced VS during a planned surgical procedure. Despite initial stabilization, she continued to experience life-threatening arrhythmias, prompting the implementation of simultaneous stellate ganglion block (SGB) and thoracic epidural analgesia (TEA) catheters. This combined approach successfully controlled the arrhythmias, allowing for subsequent surgical interventions. The article emphasizes the potential of SGB and TEA as a bridge to definitive therapies for refractory VS, highlighting the need for further research to solidify their role in clinical practice.

Advances in the Treatment of Neuropathic Pain by Sympathetic Regulation.

PURPOSE OF REVIEW: To explore the mechanism and therapeutic effect of sympathetic nerve regulation on neuropathic pain. RECENT FINDINGS: A comprehensive search was conducted in the PubMed and CNKI libraries, using the following keywords: stele ganglion block, neuropathic pain, sympathetic nerve block, sympathetic chemical destruction, and sympathetic radiofrequency thermocoagulation. We selected and critically reviewed research articles published in English that were related to sympathetic modulation in the treatment of neuropathic pain. The collected literature will be classified according to content and reviewed in combination with experimental results and clinical cases. Neuropathic pain was effectively treated with sympathetic regulation technology. Its mechanism includes the inhibition of sympathetic nerve activity, regulation of the inflammatory response, and inhibition of pain transmission, which greatly alleviates neuropathic pain in patients. Stellate ganglion blocks, thoracic and lumbar sympathectomies, chemical destruction, and radiofrequency thermocoagulation have been widely used to treat neuropathic pain. Sympathetic regulation can effectively relieve pain symptoms and improve the patient's quality of life by inhibiting sympathetic nerve activity, reducing the production and release of pain-related mediators, and inhibiting pain transmission. CT-guided radiofrequency thermocoagulation of the thoracic and lumbar sympathetic nerves is effective and durable, with few complications, and is recommended as a treatment for intractable neuropathic pain.

Clinical efficacy of high-voltage pulsed radiofrequency combined with stellate ganglion block in the acute phase of thoracic and dorsal herpes zoster neuralgia under dual guidance of ultrasound and C-arm.

OBJECTIVES: A single therapeutic approach is not always successful in the treatment of herpes zoster neuralgia, and the appropriate combination of different treatments deserves further exploration. In this study, we investigated the clinical efficacy of high-voltage long-duration pulsed radiofrequency (PRF) combined with stellate ganglion block (SGB) in the acute phase of thoracic and dorsal herpes zoster neuralgia under dual guidance of ultrasound and C-arm. METHODS: 79 cases of acute zoster neuralgia were grouped premised upon differing therapeutic approaches: standard voltage PRF (group S, the temperature, duration, pulse width, frequency and voltage were set to 42 °C, 300 s, 20 ms, 2 Hz, and 45 V), high-voltage long-duration PRF (group H, parameters of PRF were set to 42 °C, 900 s, 20 ms, 2 Hz, and 90 V, respectively), and high-voltage long-duration PRF combined with SGB (group C, parameter settings for PRF are the same as those for group H). The therapeutic outcomes were assessed utilizing the numeric rating scale (NRS), Pittsburgh sleep quality index (PSQI), and Hamilton anxiety rating scale (HAMA). The incidence of clinically significant postherpetic neuralgia post-treatment had been documented. RESULTS: Compared to baseline, scores of NRS, PSQI, and HAMA at each time point post-treatment decreased across all groups, and the decrease was more significant in the C group than in the S group. At the later stage of treatment, the consumption of pregabalin and tramadol and the plasma levels of interleukin-6 and galectin-3 in the C group were significantly lower than those in the S group. The incidence of PHN in the C group was significantly lower than in the S group. CONCLUSIONS: The combination of high-voltage long-duration PRF combined with SGB under dual guidance of ultrasound and C-arm represents a safe, effective, environmentally friendly, and cost-efficient method for treating AZN, significantly improving sleep quality, alleviating anxiety, and reducing the risk of PHN occurrence.

Analgesic efficacy of stellate ganglion block in head and neck cancer pain: A case series.

Patients with head and neck cancer (HNC) have ongoing pain but Stellate ganglion block which is a sympatholytic block may be a viable therapy for treating it. The data were retrospectively collected from five histopathologically confirmed HNC patients who had completed chemotherapy and radiation doses. Stellate ganglion block was given to these patients and was subsequently monitored for 3 months to assess pain alleviation and overall satisfaction. Over a 3-month period, there was a decrease in the pain levels with a better quality of life so the stellate ganglion block can be a promising modality for reducing the pain of HNC.

Efficacy of ultrasound-guided stellate ganglion block in relieving acute postoperative pain: a systematic review and meta-analysis.

OBJECTIVE: The efficacy of ultrasound-guided stellate ganglion block (SGB) in alleviating postoperative pain remains unclear. This meta-analysis was performed to determine the efficacy of ultrasound-guided SGB in relieving acute postoperative pain in patients undergoing surgery with general anesthesia. METHODS: This systematic review and meta-analysis focused on randomized controlled trials comparing SGB with control or placebo. The primary outcome was the pain score at 24 hours after surgery. A random-effects model was used to calculate the mean difference (MD) or risk ratio with a confidence interval (CI) of 95%. RESULTS: Eight studies involving 470 patients were included in the meta-analysis. The results revealed that ultrasound-guided SGB was significantly associated with a lower pain score at 24 hours after surgery (MD = -0.74; 95% CI = -1.39, -0.08; I2 = 86%; low evidence) and at 8 hours after surgery (MD = -0.65; 95% CI = -1.03, -0.28; I2 = 29%; moderate evidence). CONCLUSION: Ultrasound-guided SGB is effective in alleviating acute postoperative pain. However, considering the limited number of trials performed to date, more large-scale and high-quality randomized controlled trials are required to confirm these findings.

Stellate Ganglion Block Therapy for Complex Regional Pain Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Sympathetic ganglion block (SGB) technique is becoming increasingly prevalent in the treatment of complex regional pain syndromes (CRPS). Given the varied reported effectiveness of these techniques and the heterogeneity of treatment regimens, there is an urgent need for consistent and high-quality evidence on the efficacy and safety of such procedures. OBJECTIVES: This study aimed to compare the efficacy of SGB therapy for CRPS-related pain. STUDY DESIGN: A meta-analysis of randomized controlled trials (RCTs). METHODS: PubMed, EMBASE, Web of Science, CINAHL, US National Institutes of Health Clinical Trials Registry, Google Scholar, and Cochrane Library Databases were systematically searched between January 1967 and April 2023. A meta-analysis of the included RCTs on SGB was conducted to evaluate the effectiveness and risk of bias (ROBs) of SGB. RESULTS: After screening 8523 records, 12 RCTs were included in this meta-analysis. Compared with controls, the visual analog pain score decreased by a weighted mean difference (WMD) of -6.24 mm (95% CI, -11.45, -1.03; P = 0.019) in the random-effects model, and the numerical scale score was reduced by a WMD of -1.17 mm (95% CI, -2.42, 0.08; P = 0.067) in the fixed-effects model, indicating a pain relief. The methodological quality of the included RCTs was high, with an average PEDro score of 7.0 (range: 5-9). LIMITATIONS: The number of included trials was limited. CONCLUSIONS: SGB therapy can reduce pain intensity in patients with CRPS with few adverse events. However, owing to the relatively high heterogeneity of the included RCTs, a larger sample of high-quality RCTs is needed to further confirm this conclusion.

Cease the storm - Successful stellate ganglion block in terminating refractory electrical storm.

An electrical storm also known as a ventricular tachycardia storm (VT storm) tends to recur and form a vicious cycle, eventually leading to a refractory electrical storm, refractory to electrical and pharmacological cardioversion. The treatment of refractory VT storm is challenging. Here we discuss the case of a middle-aged gentleman who presented to our emergency department 6 months apart with a refractory VT storm. When all the anti-arrhythmic agents and multiple cardioversion attempts failed in terminating the storm, we attempted ultrasound-guided stellate ganglion block. On both occasions, it successfully terminated the storm. Hence emergency physicians need to be aware of the right technique and timing of stellate ganglion block and ultrasound-guided needle tracking, as it can be a final rescue technique in treating refractory electrical storm in the emergency department.

Effect of ultrasound-guided stellate ganglion block on lung protection for patients undergoing one-lung ventilation.

OBJECTIVE: To explore the potential effect of ultrasound-guided stellate ganglion block (SGB) on lung protection for patients undergoing one-lung ventilation (OLV). METHODS: A total of 123 patients undergoing elective one-lung ventilation surgery were selected as research subjects in this prospective study. These patients were randomly divided into the SGB group, control group and blank group on average. Stellate ganglion block was carried out in the SGB and control groups. Patients in the SGB group were injected with 6 ml mixture of 0.25% ropivacaine hydrochloride and 1% lidocaine hydrochloride, while those in the control group were injected with 6 mL of 0.9% saline. Punctures weren't performed for patients in the blank group. The same induction and maintenance of general anesthesia was adopted for all three groups. Hemodynamics, respiratory parameters and arterial blood gas analysis were recorded after entering the operation room (T0), pre-OLV (T1), 30 min after OLV (T2), 60 min after OLV (T3), at the end of surgery (T4), and 30 min after extubation (T5). Oxygenation index (OI), pulmonary shunt fraction (Qs/Qt) and pH value were compared at different time points. Intravenous serum was collected at T0, T3 and T5 for the detection of surfactant proteins A (SP-A), superoxide dismutase (SOD), malondialdehyde (MDA), interleukin-6 (IL-6) and interleukin-10 (IL-10) levels, respectively. The complications related to SGB after surgery and the postoperative pulmonary complications within 72 h were recorded. RESULTS: At T1, T2, and T3, MAP level in SGB group was lower than that in blank and control groups (P<0.05). At T2, and T3, SGB group had lower hear rate (HR), peak airway pressure (Ppeak) and tidal volume (TV) than blank and control groups (all P<0.05). From T2 to T5, SGB group had higher OI but lower Qs/Qt than blank and control groups (both P<0.05). At T3 and T5, SGB group had lower SP-A, IL-6, and MDA levels but higher IL-10 and SOD levels than blank and control groups (all P<0.05). There was one case of hypoxemia in the blank group within 72 h after surgery. CONCLUSION: Ultrasound-guided SGB has lung-protective effects on patients undergoing OLV, which significantly improves patients' OI, reduces intrapulmonary shunts, declines ventilator-induced lung damage, and inhibits inflammatory response as well as oxidative stress (China Clinical Trial Registry, registration number ChiCTR2000033385, https://www.chictr.org.cn).

Establishment of stellate ganglion block in mice.

BACKGROUND: There have been no reports on the successful implementation of stellate ganglion block (SGB) in mice. OBJECTIVES: This study aims to investigate a new method for implementing SGB in mice by placing them in a supine position with abducted upper limbs and touching the trachea and sternoclavicular joint with the hand. METHODS: Fifty BABL/C mice, 8-10 weeks, were selected and randomly divided into four groups: control group (n = 5); SGB-R group (n = 15); SGB-L group (n = 15); and SGB-L + R (group n = 15). SGB was administered with 0.15% ropivacaine solution in a volume of 0.1 mL. The control group received equal volumes of saline. Horner's syndrome, heart rate, and complications such as brachial plexus block, vascular injury, pneumothorax, local anesthetic toxicity, and death were observed. RESULTS: Horner's syndrome developed in 100% of SGB surviving mice; no difference was seen in the time to onset (100.4 ± 13.4 vs 96.7 ± 12.4, mean ± SD, seconds) and duration (264.1 ± 40.5 vs 296.3 ± 48.0, mean ± SD, min) of Horner's syndrome in the left and right SGB (P > 0.05). Compared with the control group (722 [708-726], median [IQR], bpm), the heart rate was significantly slowed down in the right SGB (475 [451.5-491], median [IQR], bpm) (P < 0.05). While the heart rate was slowed down after performing the left SGB, the difference was not statistically significant (P > 0.05). The overall complication rate was 18.4%, with a brachial plexus block rate of 12.3%, a vascular injury rate of 4.6%, and a mortality rate of 1.5%, as well as no local anesthetic toxicity (includes bilateral implementation of SGB) or pneumothorax manifestations were found. CONCLUSIONS: This method allows for the successful implementation of SGB in a mouse model.

Ultrasound-guided stellate ganglion block benefits the postoperative recovery of patients undergoing laparoscopic colorectal surgery: a single-center, double-blinded, randomized controlled clinical trial.

BACKGROUND: With the increasing prevalence of colorectal cancer (CRC), optimizing perioperative management is of paramount importance. This study investigates the potential of stellate ganglion block (SGB), known for its stress response-mediating effects, in improving postoperative recovery. We postulate that preoperative SGB may enhance the postoperative recovery of patients undergoing laparoscopic CRC surgery. METHODS: We conducted a randomized controlled trial of 57 patients undergoing laparoscopic colorectal cancer surgery at a single center. Patients, aged 18-70 years, were randomly assigned to receive either preoperative SGB or standard care. SGB group patients received 10 mL of 0.2% ropivacaine under ultrasound guidance prior to surgery. Primary outcome was time to flatus, with secondary outcomes encompassing time to defecation, lying in bed time, visual analog scale (VAS) pain score, hospital stays, patient costs, intraoperative and postoperative complications, and 3-year mortality. A per-protocol analysis was used. RESULTS: Twenty-nine patients in the SGB group and 28 patients in the control group were analyzed. The SGB group exhibited a significantly shorter time to flatus (mean [SD] hour, 20.52 [9.18] vs. 27.93 [11.69]; p = 0.012), accompanied by decreased plasma cortisol levels (mean [SD], postoperatively, 4.01 [3.42] vs 7.75 [3.13], p = 0.02). Notably, postoperative pain was effectively managed, evident by lower VAS scores at 6 h post-surgery in SGB-treated patients (mean [SD], 4.70 [0.91] vs 5.35 [1.32]; p = 0.040). Furthermore, patients in the SGB group experienced reduced hospital stay length (mean [SD], day, 6.61 [1.57] vs 8.72 [5.13], p = 0.042). CONCLUSIONS: Preoperative SGB emerges as a promising approach to enhance the postoperative recovery of patients undergoing laparoscopic CRC surgery. CLINICAL TRIAL REGISTRATION: ChiCTR1900028404, Principal investigator: Xia Feng, Date of registration: 12/20/2019.

The usefulness of stellate ganglion block with ultrasound-guided lateral paracarotid approach in ventricular arrhythmias: A case series.

Ventricular arrhythmias are life-threatening cardiac events. Sympathetic nervous system blockade represents a crucial therapeutic method for refractory ventricular arrhythmias. Ultrasound (US) imaging for stellate ganglion block (SGB) suggests potential for its application to safer and more accurate methods. We had thirteen patients diagnosed with refractory ventricular arrhythmia and referred to the pain clinic for SGB. We visited the intensive care unit (ICU) and performed SGB with the lateral paracarotid approach technique in the ICU. Using a new approach, we easily performed SGB and felt the convenience of the procedure in the ICU. In eleven cases, we also confirmed that the effect of the block with the new technique was satisfactory. SGB, with the new technique, revealed efficiency in the recovery process of the patients. We recommended the lateral paracarotid approach technique for SGB when a patient in an ICU showed ventricular arrhythmias and should be treated with SGB.

A modified approach to percutaneous ultrasound-guided left stellate ganglion block for drug-refractory electrical storm: a case report.

Background: The use of percutaneous stellate ganglion block (SGB) in the management of drug-refractory electrical storm (ES) has been increasingly reported in the last years. Few data are available on the safety, duration, and dosage of local anaesthetic used. Case summary: A 66-year-old male patient with a history of ischaemic cardiomyopathy and an implantable cardioverter-defibrillator (ICD) presented to the emergency room complaining several ventricular arrhythmias and ICD shocks received in the last 24 h. He was treated with many lines of anti-arrhythmic drugs but his condition deteriorated with cardiovascular instability and respiratory distress, so he was intubated. The ES still worsened (82 episodes of ventricular arrhythmias), so we performed an ultrasound-guided left SGB, using a modified technique, with success in suppressing the ventricular arrhythmias. The patient was then treated with electrophysiological study and catheter ablation. Discussion: The ultrasound approach to SGB is feasible in emergency setting, and it is safe and effective also using a modified and easier technique in patient with difficult sonographic visualization of the neck structures. Moreover, it is possible and safe to use a combination of short-acting rapid-onset local anaesthetic with a long-lasting one with a good outcome.

Continuous stellate ganglion block for ventricular arrhythmias: case series, systematic review, and differences from thoracic epidural anaesthesia.

AIMS: Percutaneous stellate ganglion block (PSGB) through single-bolus injection and thoracic epidural anaesthesia (TEA) have been proposed for the acute management of refractory ventricular arrhythmias (VAs). However, data on continuous PSGB (C-PSGB) are scant. The aim of this study is to report our dual-centre experience with C-PSGB and to perform a systematic review on C-PSGB and TEA. METHODS AND RESULTS: Consecutive patients receiving C-PSGB at two centres were enrolled. The systematic literature review follows the latest Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Our case series (26 patients, 88% male, 60 ± 16 years, all with advanced structural heart disease, left ventricular ejection fraction 23 ± 11%, 32 C-PSGBs performed, with a median duration of 3 days) shows that C-PSGB is feasible and safe and leads to complete VAs suppression in 59% and to overall clinical benefit in 94% of cases. Overall, 61 patients received 68 C-PSGBs and 22 TEA, with complete VA suppression in 63% of C-PSGBs (61% of patients). Most TEA procedures (55%) were performed on intubated patients, as opposed to 28% of C-PSGBs (P = 0.02); 63% of cases were on full anticoagulation at C-PSGB, none at TEA (P < 0.001). Ropivacaine and lidocaine were the most used drugs for C-PSGB, and the available data support a starting dose of 12 and 100 mg/h, respectively. No major complications occurred, yet TEA discontinuation rate due to side effects was higher than C-PSGB (18 vs. 1%, P = 0.01). CONCLUSION: Continuous PSGB seems feasible, safe, and effective for the acute management of refractory VAs. The antiarrhythmic effect may be accomplished with less concerns for concomitant anticoagulation compared with TEA and with a lower side-effect related discontinuation rate.