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EUS-guided celiac ganglia neurolysis versus celiac plexus neurolysis: dying to know which is better
EDITORIAL
EUS-guided celiac ganglia neurolysis versus celiac plexus neurolysis: dying to know which is better In this issue of Gastrointestinal Endoscopy, Kappelle et al1 took on the daunting task of finding out what actually happens during attempted EUS-guided celiac plexus neurolysis (CPN) and EUS-guided ganglia neurolysis (CGN) in a cadaver model. In the former, the neurolytic agent is injected around the ganglia, whereas in the latter, it is injected in the ganglia. There are multiple reasons to suspect that targeted ganglia injection is unnecessary or inappropriate: (1) if there are multiple ganglia, many ganglia would need injection (not just 1 or 2), (2) if the ganglia are very small, there is not much space to inject anything anyway, (3) several controlled trials have shown that not targeting ganglia (CPN) is quite effective (so it would be hard to show significant clinical superiority for CGN),2 (4) the data supporting the superiority of CGN over CPN are flawed,3 and (5) CPN is painful, but sticking the needle directly into the ganglia is even worse! (Unpublished observation.) Several findings of this study appear to confirm the futility of CGN, but owing to the limitations of the cadaver model, it leaves some cogent issues unresolved. Regarding the number of ganglia, it appears clear that the number of ganglia visible by EUS is small (generally 1 or 2), and they are seen mostly (66%) on the left side or anterior to the celiac axis (30%). Therefore, right-sided ganglia are visible in only 4% of cases. However, in the cadavers, the actual number of ganglia identified was generally twice as high (3-5), and approximately 50% (1-2 per cadaver) were found on the right side (despite generally being invisible by EUS). This is potentially useful information. Presumably, if EUS views only a fraction of the existing ganglia, and if pain relief correlates with the number of ganglia exposed to sclerosant (which makes sense but is unproven), then a technique that safely spreads the drug beyond visible ganglia would be preferable. The study also confirms that the celiac ganglia are quite small, that targeted injection of even small amounts of sclerosant is difficult (high resistance was experienced during direct injection), and that sclerosant diffuses well beyond the capsule of the targeted ganglia.
Low-volume left-sided CGN did not show any diffusion of dye to the right side, whereas high-volume injection (by CPN or CGN, and whether central or bilateral) showed comparable, bilateral, wide spread of dye, and higher calculated (not measured) tissue concentrations of alcohol than with lowvolume CGN. Therefore, low-volume CGN appears to be inadequate to treat unseen, particularly right-sided, ganglia. Some might also argue that the wide spread of all tested methods of high-volume injections supports the concept that there is no advantage to bilateral over central CPN; however, the bilateral approach did appear to produce a slightly higher tissue concentration of alcohol.
Because, as this study shows, most ganglia are lateral to the celiac axis, the most appropriate intervention for the control group in a randomized trial is bilateral CPN. Until a study comparing CGN with bilateral CPN is published, the superiority of either method remains uncertain.
Copyright ª 2017 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2017.03.014
As the authors point out, “The fact that a cadaver model was used may well have influenced the spread of ethanol to some extent; a cadaver model does not take tissue oxygenation, inflammatory response, blood circulation, and in-vivo elasticity of structures into account. Despite the attempt to minimize the effect of these factors by using unembalmed cadavers within 36 hours postmortem, the possible effects of these factors on ethanol distribution could complicate extrapolation of the data to the clinical situation.” Furthermore, the cadavers were frozen immediately after the injection procedures, but it is unclear how long it took for them to become completely frozen. It is therefore unclear how much time the fluid had to diffuse, and it is impossible to know in this model (or in vivo) whether the diffusion was fast or slow. Most importantly, it is impossible to discern whether the calculated tissue alcohol concentration would correlate with histologic damage or pain relief in vivo, although there are data that support this concept.4,5 Similarly, the study provides no information as to whether CGN produces more neuronal damage
664 GASTROINTESTINAL ENDOSCOPY Volume 86, No. 4 : 2017
www.giejournal.org
Sahai
than CPN (ie, whether injecting in the ganglia destroys more tissue than injecting around the ganglia). It is unclear why the authors seem to assume that CGN is more effective than CPN and offer hypotheses as to why this is so. The only randomized trial of CGN versus CPN actually compared CGN with central CPN (which is not an appropriate control) and therefore potentially biased the results in favor of CGN.6 Because, as this study shows, most ganglia are lateral to the celiac axis, the most appropriate intervention for the control group in a randomized trial is bilateral CPN. Until a study comparing CGN with bilateral CPN is published, the superiority of either method remains uncertain. Kappelle et al1 have provided some unique and interesting information. But on the basis of this study and the available literature, high-volume bilateral CPN (not CGN) appears the be the technique most likely to distribute sclerosant to the most ganglia, at the highest concentration, and without the potential for added paindwhich may be associated with targeted ganglia injection.
Editorial
Anand V. Sahai, MD, MSc (Epid), FRCPC Service de Gastroentérologie CHUM, Hôpital Saint Luc Montréal, Québec, Canada Abbreviations: CGN, celiac ganglia neurolysis; CPN, celiac plexus neurolysis.
REFERENCES
The author disclosed no financial relationships relevant to this publication.
1. Kappelle WFW, Bleys RLAW, van Wijck AJM, et al. EUS-guided celiac ganglia neurolysis: a clinical and human cadaver study (with video). Gastrointest Endosc 2017;86:655-63. 2. Nagels W, Pease N, Bekkering G, et al. Celiac plexus neurolysis for abdominal cancer pain: a systematic review. Pain Med 2013;14:1140-63. 3. Sahai AV. The benefit of celiac ganglion injection remains unclear. Endoscopy 2013;45:854. 4. Iwata K, Yasuda I, Enya M, et al. Predictive factors for pain relief after endoscopic ultrasound-guided celiac plexus neurolysis. Dig Endosc 2011;23:140-5. 5. Sakamoto H, Kitano M, Kamata K, et al. EUS-guided broad plexus neurolysis over the superior mesenteric artery using a 25-gauge needle. Am J Gastroenterol 2010;105:2599-606. 6. Doi S, Yasuda I, Kawakami H, et al. Endoscopic ultrasound-guided celiac ganglia neurolysis vs. celiac plexus neurolysis: a randomized multicenter trial. Endoscopy 2013;45:362-9.
www.giejournal.org
Volume 86, No. 4 : 2017 GASTROINTESTINAL ENDOSCOPY 665
DISCLOSURE
EUS-guided celiac ganglia neurolysis versus celiac plexus neurolysis: dying to know which is better In this issue of Gastrointestinal Endoscopy, Kappelle et al1 took on the daunting task of finding out what actually happens during attempted EUS-guided celiac plexus neurolysis (CPN) and EUS-guided ganglia neurolysis (CGN) in a cadaver model. In the former, the neurolytic agent is injected around the ganglia, whereas in the latter, it is injected in the ganglia. There are multiple reasons to suspect that targeted ganglia injection is unnecessary or inappropriate: (1) if there are multiple ganglia, many ganglia would need injection (not just 1 or 2), (2) if the ganglia are very small, there is not much space to inject anything anyway, (3) several controlled trials have shown that not targeting ganglia (CPN) is quite effective (so it would be hard to show significant clinical superiority for CGN),2 (4) the data supporting the superiority of CGN over CPN are flawed,3 and (5) CPN is painful, but sticking the needle directly into the ganglia is even worse! (Unpublished observation.) Several findings of this study appear to confirm the futility of CGN, but owing to the limitations of the cadaver model, it leaves some cogent issues unresolved. Regarding the number of ganglia, it appears clear that the number of ganglia visible by EUS is small (generally 1 or 2), and they are seen mostly (66%) on the left side or anterior to the celiac axis (30%). Therefore, right-sided ganglia are visible in only 4% of cases. However, in the cadavers, the actual number of ganglia identified was generally twice as high (3-5), and approximately 50% (1-2 per cadaver) were found on the right side (despite generally being invisible by EUS). This is potentially useful information. Presumably, if EUS views only a fraction of the existing ganglia, and if pain relief correlates with the number of ganglia exposed to sclerosant (which makes sense but is unproven), then a technique that safely spreads the drug beyond visible ganglia would be preferable. The study also confirms that the celiac ganglia are quite small, that targeted injection of even small amounts of sclerosant is difficult (high resistance was experienced during direct injection), and that sclerosant diffuses well beyond the capsule of the targeted ganglia.
Low-volume left-sided CGN did not show any diffusion of dye to the right side, whereas high-volume injection (by CPN or CGN, and whether central or bilateral) showed comparable, bilateral, wide spread of dye, and higher calculated (not measured) tissue concentrations of alcohol than with lowvolume CGN. Therefore, low-volume CGN appears to be inadequate to treat unseen, particularly right-sided, ganglia. Some might also argue that the wide spread of all tested methods of high-volume injections supports the concept that there is no advantage to bilateral over central CPN; however, the bilateral approach did appear to produce a slightly higher tissue concentration of alcohol.
Because, as this study shows, most ganglia are lateral to the celiac axis, the most appropriate intervention for the control group in a randomized trial is bilateral CPN. Until a study comparing CGN with bilateral CPN is published, the superiority of either method remains uncertain.
Copyright ª 2017 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2017.03.014
As the authors point out, “The fact that a cadaver model was used may well have influenced the spread of ethanol to some extent; a cadaver model does not take tissue oxygenation, inflammatory response, blood circulation, and in-vivo elasticity of structures into account. Despite the attempt to minimize the effect of these factors by using unembalmed cadavers within 36 hours postmortem, the possible effects of these factors on ethanol distribution could complicate extrapolation of the data to the clinical situation.” Furthermore, the cadavers were frozen immediately after the injection procedures, but it is unclear how long it took for them to become completely frozen. It is therefore unclear how much time the fluid had to diffuse, and it is impossible to know in this model (or in vivo) whether the diffusion was fast or slow. Most importantly, it is impossible to discern whether the calculated tissue alcohol concentration would correlate with histologic damage or pain relief in vivo, although there are data that support this concept.4,5 Similarly, the study provides no information as to whether CGN produces more neuronal damage
664 GASTROINTESTINAL ENDOSCOPY Volume 86, No. 4 : 2017
www.giejournal.org
Sahai
than CPN (ie, whether injecting in the ganglia destroys more tissue than injecting around the ganglia). It is unclear why the authors seem to assume that CGN is more effective than CPN and offer hypotheses as to why this is so. The only randomized trial of CGN versus CPN actually compared CGN with central CPN (which is not an appropriate control) and therefore potentially biased the results in favor of CGN.6 Because, as this study shows, most ganglia are lateral to the celiac axis, the most appropriate intervention for the control group in a randomized trial is bilateral CPN. Until a study comparing CGN with bilateral CPN is published, the superiority of either method remains uncertain. Kappelle et al1 have provided some unique and interesting information. But on the basis of this study and the available literature, high-volume bilateral CPN (not CGN) appears the be the technique most likely to distribute sclerosant to the most ganglia, at the highest concentration, and without the potential for added paindwhich may be associated with targeted ganglia injection.
Editorial
Anand V. Sahai, MD, MSc (Epid), FRCPC Service de Gastroentérologie CHUM, Hôpital Saint Luc Montréal, Québec, Canada Abbreviations: CGN, celiac ganglia neurolysis; CPN, celiac plexus neurolysis.
REFERENCES
The author disclosed no financial relationships relevant to this publication.
1. Kappelle WFW, Bleys RLAW, van Wijck AJM, et al. EUS-guided celiac ganglia neurolysis: a clinical and human cadaver study (with video). Gastrointest Endosc 2017;86:655-63. 2. Nagels W, Pease N, Bekkering G, et al. Celiac plexus neurolysis for abdominal cancer pain: a systematic review. Pain Med 2013;14:1140-63. 3. Sahai AV. The benefit of celiac ganglion injection remains unclear. Endoscopy 2013;45:854. 4. Iwata K, Yasuda I, Enya M, et al. Predictive factors for pain relief after endoscopic ultrasound-guided celiac plexus neurolysis. Dig Endosc 2011;23:140-5. 5. Sakamoto H, Kitano M, Kamata K, et al. EUS-guided broad plexus neurolysis over the superior mesenteric artery using a 25-gauge needle. Am J Gastroenterol 2010;105:2599-606. 6. Doi S, Yasuda I, Kawakami H, et al. Endoscopic ultrasound-guided celiac ganglia neurolysis vs. celiac plexus neurolysis: a randomized multicenter trial. Endoscopy 2013;45:362-9.
www.giejournal.org
Volume 86, No. 4 : 2017 GASTROINTESTINAL ENDOSCOPY 665
DISCLOSURE