The Utility of Surgical Cardiac Sympathetic Denervation in the Management of Ventricular Arrhythmias for all Etiologies: A Systematic Review

  

    
First Author
    
Overall Risk of Bias
    
Class Evidence
  
  

    
Sgrò [15]
    
Low
    
2++
  
  

    
Shah [14]
    
Moderate
    
2+
  
  

    
Téllez [29]
    
Serious
    
3
  
  

    
Haranal [24]
    
Serious
    
3
  
  

    
Vaseghi 2017 [18]
    
Low
    
2++
  
  

    
Jang [26]
    
Serious
    
3
  
  

    
Antiel [19]
    
Low
    
2-
  
  

    
Waddell-Smith [20]
    
Low
    
2+
  
  

    
Roston [28]
    
Moderate
    
2-
  
  

    
DeFerrari [23]
    
Low
    
2++
  
  

    
Vaseghi 2014 [17]
    
Moderate
    
2-
  
  

    
Nordkamp [27]
    
Moderate
    
3
  
  

    
Hofferberth [25]
    
Moderate
    
3
  
  

    
Bos [16]
    
Moderate
    
3
  
  

    
Coleman [22]
    
Moderate
    
3
  
  

    
Bourke [21]
    
Moderate
    
2-
  
  

    
Collura [8]
    
Serious
    
3
  

Table 4: Overall risk of bias and level of evidence for included studies.

Discussion

Quality of Evidence

At last review, the only placebo-controlled trial that examined CSD was performed in 1992 [31], whereby beta-blockade or CSD was administered to high-risk patients post myocardial infarction (MI), and compared to beta-blockade or placebo in low-risk patients. While there are 2 randomised studies of CSD underway currently, both compare CSD alone to CSD and optimal medical treatment and neither have had results published at last review. Thus, patient data examined for this review were based on observational studies only.

Patients across all studies were referred for denervation due to failure, intolerance or non-adherence to first-line therapies. This demonstrates the limited feasibility of randomised control trials in this setting: in the first instance, superiority or non-inferiority trials would not apply to a last-line therapy. Secondly, there would be compelling ethical issues surrounding the randomisation of patients to an arm with no treatment in the absence of other options.

Stellate ganglion blockade, as mentioned above, has also been used to manage patients with intractable VA, but the desired outcome of SGB is to manage patients in the acute phase of ventricular arrhythmia, and the patient is no longer protected once the anaesthetic agent had been metabolised. Thoracic epidural anaesthesia utilises injection or infusion of the T1- T5 nerve roots with local anaesthetic agents, thereby blocking stimulation from the sympathetic chain [32] but has not been evaluated in the literature to the extent of CSD. Apart from the study by Bourke et al. mentioned in this paper [21], its appearance in the literature is limited to one case report [33], animal studies [34,35] and review articles such as Dusi, Zhu and Ajijola, 2019 [32]. This treatment modality is also considered a temporary measure in contrast to the definitive strategy of CSD. Accordingly, suitable controls are scarce in medical practice, and this explains the use of case-control studies to assess the efficacy of the procedure. Equally, trials for diseases considered rare (less than 1/2000 patients, such as LQTS and CPVT) are less likely to be randomised or double-blinded, with fewer active comparators, and predictably, fewer patients enrolled [30]. Thus, with diminishing feasibility of RCTs, investigation of CSD for ventricular arrhythmias may always be limited to observational studies.

The only studies with prospectively collected data on review of the literature were those that examined QoL and satisfaction with surgery, and were not focused on the actual success of the procedure in terms of arrhythmia control. Ten of the studies examined utilised some form of comparator group, but this mostly referred to pre- and post-operative status. The study by Bourke et al. [21] was the only study in the review for which the comparator group was a different treatment modality. Regression models were used in three studies only, to account for confounding variables. Interestingly, the study by Vaseghi et al. [17] that compared LCSD to Bilateral Cardiac Sympathetic Denervation (BCSD) did not use propensity matching or regression models, which may have been due to the low numbers in each arm of the study group. Selection bias was noted in this study, and this may have led to overestimation of difference in outcomes between BCSD and LCSD. It is possible to evaluate CSD effectively utilising well-designed observational studies, and some of the publications in this review fulfil this criteria. Consistent reporting of positive outcomes gives some generalizability to the less rigorous studies, but case series cannot be used in isolation to assess CSD.

Indication for CSD

Etiology/LCSD vs. BCSD: Studies of reasonably high evidence level (2+) demonstrated a clinical benefit of CSD in both structural heart disease and inherited arrhythmias, but overall, there was a bigger evidence base, due to the presence of larger and more rigorous studies, in the congenital population. One case-control study by Vaseghi et al [18]. reported worse outcomes for patients with symptomatic VA who underwent left-sided denervation over bilateral. However, this result is somewhat confounded by the fact that VT cycle length was significantly longer in the left-sided group, which was found to be an independent predictor of recurrence itself. Despite the limitations of the evidence, the data reviewed demonstrated survival benefit, as well as reduction or resolution of symptomatic VA in patients with LQTS and CPVT across all relevant studies. This could be a justification for the re-classification of CSD in this context from class II to class I evidence in the next iteration of the European Guidelines, which would be in keeping with the guidelines issued by the American Heart Association (AHA) [35].

For patients with symptomatic VA and structural heart disease, an improvement in survival and VA recurrence was also observed, though not to the same extent as the congenital population due to a much poorer baseline. There may be an additional benefit of bilateral denervation in patients with symptomatic VA and structural heart disease only, although more data is needed on this matter.

Primary Prevention

There were six studies examined for this systematic review that analysed outcomes of symptomatic patients only. Asymptomatic patients who underwent CSD as a primary prevention strategy were included in all other studies in small numbers, apart from the review by Bos et al. [16], in which 61% of the patients studied were asymptomatic, and none experienced symptoms during the 3.6 year follow-up period. One critique of the inclusion of asymptomatic patients is that the follow-up period required to detect symptoms becomes unclear. Nonetheless, in all studies where CSD was used for primary prevention, apart from Hofferberth et al. [25] (one asymptomatic patient experienced postoperative cardiac events), and the studies examining QoL (outcomes for primary prevention not discussed separately in either paper), all patients remained asymptomatic for the duration of follow-up. Though follow-up duration was varied, the studies by Jang et al. [26], De Ferrari et al. [23], Roston et al. [28], and Bos et al. [16] all followed patients for over 2 years. In summary, consistency in positive outcomes was seen across the studies reviewed regarding the use CSD in asymptomatic patients with inherited arrhythmias, therefore it would be reasonable to consider CSD as a primary prevention strategy in this patient population.

Assessment of Complications

Acute complications were discussed in most of the literature reviewed, with the exception of two studies, possibly due to the variation in surgical technique and length of study duration seen in these studies. The rest of the publications reported similar low rates of pneumothorax, haemothorax and transient ptosis or Horner’s syndrome. One study [22] described one case of conversion to open thoracotomy. This may have been an outlier in a small study group, but a 4% conversion to open thoracotomy is higher than described in other sympathectomy studies [4] and adds undesired morbidity to the procedure.

There was greater inconsistency in the reporting of chronic sequelae, and many of the studies reported no lasting complications. However, Vaseghi et al. [17] reported persistent abnormal sweating in 9.7% and skin sensitivity in 12.3% of patients who underwent BCSD. Jang et al. [16] reported abnormal sweating in all patients at follow-up, and the two studies that focused on chronic complications, Antiel et al. [19] and Waddell-Smith et al. [20] reported that almost all patients had persistent changes, such as abnormal sweating, dry skin, shoulder tip pain, or unilateral temperature changes, and permanent ptosis. Both of these studies found that, despite a high rate of minor postoperative complications, patients tended to be satisfied with the outcome across both adult and pediatric populations. Overall, the data demonstrated inconsistent reporting of chronic complications, with a rate of persistent postoperative symptoms that may be significantly higher than some studies have reported. More evidence is needed in this regard, and would be useful for patient counseling in the preoperative period.

Surgical Technique

All but two studies [14,28] described the surgical technique used for sympathectomy, with VATS featuring as the main approach to the thorax. None of the studies included patients who had undergone the procedure using Robotic Assisted Thoracic Surgery (RATS) as the approach to the chest. Two studies [23,27] included patients who underwent a supraclavicular approach to the thorax. Four studies [14,17,18,29] included patients who underwent bilateral sympathectomy. Where described, the studies assessed for this article used a VATS 3 port technique to remove the lower half of the stellate ganglion, along with roots of T2 to T4. Of the patients who underwent a VATS procedure, the majority underwent single lung ventilation. One study [8] used bronchial blockade for their ventilation strategy. The majority of the studies described histological confirmation of the specimen intraoperatively. One study only [18] utilised chest drains in the perioperative period.

Conclusion

Cardiac sympathetic denervation was found to provide benefit for patients with ventricular arrhythmias and either structural heart disease or inherited arrhythmia syndromes, in cases of refractory disease or in patients who require a primary prevention strategy where first-line therapies are not tolerated. The evidence for this is entirely observational, however the risk of bias observed was largely moderate or low.

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