Now exists a scientific proof of increased lymphatic pumping using octreotide: what is its actual role in the chylothorax healing process?

The lymphatic system is essential for life by carrying protein and fatty compounds to the blood circulation. It plays a key role in the homeostasis of all body's tissues. Despite already being identified in the 17th century, this complex network composed of contractile and valvular vessels [1] has remained relatively unknown to clinicians. Yet, it is implicated in the spread of infections and cancers, exceptional situations such as chylothorax or chyloperitoneum and in rare primary or secondary lymphatic diseases (lymphedema, etc.). Chylothorax, regardless of its cause, often presents a significant therapeutic challenge. In certain situations, this event can be life-threatening for patients. The 2 mechanisms leading to chylothorax are either a direct trauma of lymphatic vessel or its rupture from increased pressure due to obstruction. If postoperative chylothorax occurs in a patient without underlying lymphatic disease, it is often easy to treat. Indeed, the lymphatic vessels composed of contractile and valvular lymphatic pacemaker also named ‘lymphangion’ enable rapid healing of small-caliber vessels [2]. Conversely, managing ‘spontaneous’ chylothorax associated with primary or secondary lymphatic disease is a real challenge. The inexhaustible loss of chyle combined with a fat-free diet can lead to the patient's death due to cachexia. Sometimes, both mechanisms are intertwined. For instance, a patient undergoing mediastinal or lung surgery may have an unrecognized lymphatic condition, leading to postoperative chyle leakage. It is the result of valvular incontinence of lymphatic vessels, allowing chyle to reflux into the pleural cavity. The non-closure of lymphatic vessels during lymph node dissection explains this chylous leakage. It can be challenging to stop it because the reflux originates directly from collaterals connected to the thoracic duct. A large retrospective series of cancer excisions identified predictive factors for chylothorax: lobectomy, surgery on the right side, tumour involvement of mediastinal nodes and robot-assisted surgical procedures [3].

The 3 key actions to be started once chylothorax is diagnosed are: reducing chyle production, promoting pleural emptying to encourage closure of the leak and maintaining good nutritional status. To achieve this, it is crucial to remove from the diet long-chain fatty acids that use lymphatic vessels to reach the venous circulation and replace it by small-sized soluble fats (medium-chain triglycerides). These smaller fats bypass the lymphatic network, entering directly into the venous system after being transported by the portal system. Emptying the pleural cavity through unique evacuation or rather permanent drainage facilitates the closure of the leak by the mechanical effect of neighbouring organs (lung, diaphragm and mediastinum). However, this closure is only possible if lymphatic flow is minimized. Nutritional support is crucial to prevent chylothorax from transforming into abundant fluid leakage and resulting in uncontrollable anasarca due to major protein loss. A hypercaloric and hyperproteic diet is best administered orally, often complemented by parenteral nutrition. Contrary to commonly held beliefs, oral nutrition should not be suppressed as it is a far superior route to normalize protein and albumin levels.

In chylothorax management, somatostatin and other somatostatin analogues have long been used as an adjuvant to these aforementioned therapeutic measures. In 1979, a canine model reported a significant reduction in plasma triglyceride levels using somatostatin [4]. This validated the hypothesis of somatostatin's role in homeostasis but did not precisely identify the mechanisms involved. In 1981, another canine model demonstrated that physiological doses of somatostatin reduced chyle flow in the thoracic duct [5]. Again, the mechanisms involved were never formally identified. Hypotheses included a direct effect of somatostatin analogues on chyle production and the possible increase in lymphatic contraction. Despite the lack of evidence regarding the modes of action, the use of somatostatin has become almost systematic in treating chylous leakages.

The originality of Holm-Weber's work [6] was to conduct randomized preclinical study combined with a short pilot clinical study to assess the direct impact of octreotide on lymphatic contractility. The preclinical study identified a significant increase in the frequency and intensity of contractions in thoracic duct’s segments incubated with octreotide and 2 other somatostatin analogues. No effect was observed in the same analysis using mesenteric lymphatic vessels. It is challenging to explain the cause of this difference because both types of vessels transport chyle, and the contractile structure ‘lymphangion’ exists in both [1]. It is possible that the number of ‘lymphangions’ is not the same in the 2 cases and could impact the reported results. It is known that the thoracic duct comprises 5–20 ‘lymphangions’ depending on its length, but imprecisely quantified for mesenteric lymphatics [7].

The results of the clinical part of the study were negative. No change in the activity of peripheral lymphatic vessels was detected in healthy subjects treated by octreotide [6]. Once again, it is possible that the receptors involved in the reactivity to octreotide differ between peripheral limb lymphatic vessels, which only transport lymph, and more central ones that transport chyle.

To our knowledge, this study is the first scientifically validated study about the action mechanisms of octreotide (and other somatostatin analogues) on the thoracic duct. We congratulate the authors for undertaking such work.

Due to their complexity, surpassing that of blood vessels, lymphatic vessels justify further anatomical and physiological studies already initiated by enthusiasts in lymphology [8]. The functional aspect of these lymphatic vessels remains a broad field of investigation to explore, and the tools used by Holm-Weber et al. [6] offer possibilities for further research. The involvement of the lymphatic system in many pathologies and recent therapies such as immunotherapy should encourage researchers to develop this aspect of lymphatic diseases within a multidisciplinary strategy.

From reading and reflecting on the positive results of this preclinical study focusing on thoracic duct, I have learnt that now a scientific proof exists of Octreotid’s effectiveness for increasing lymphatic pumping. The use of Octreotic alone in chylothorax’s treatment is not enough but associated with the key measures detailed in the first part of this editorial; it may be a real help for healing.

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