Silence of the lymphs: some anaesthetic regimens inhibit lymphatic pumping

The effect of anaesthesia on lymphatic function has not been well studied, but it has implications for experimental results intended to create a better understanding of how the lymphatic system works and is controlled. Further, anaesthesia may be altering lymphatic function in patients under long-term sedation, contributing to fluid volume management challenges encountered daily in intensive care units around the world. In this issue of The Journal of Physiology, Bachmann et al. (2019) present the first comprehensive study of the effects of different anaesthetic regimens on lymphatic contractility.

As the lymphatic systems lacks a central pump to move fluid, lymphatic vessel contractility is necessary to return lymph back to the central circulation. Using elegant isolated collecting lymphatic vessel models ex vivo and intravital imaging of lymphatic vessels in vivo, the molecular control of lymphatic pumping has begun to be uncovered (Muthuchamy & Zawieja, 2008), including the role for calcium and nitric oxide signalling in regulating the strength and frequency of lymphatic contraction (Padera et al. 2016). However, there are discrepancies in the values of lymphatic contraction frequency reported in published work, making it difficult to compare results from different experiments (Bachmann et al. 2019). Further, there is concern that experimental factors may mask true molecular effects on lymphatic function, making it even more challenging to develop our understanding of the molecular control of the lymphatic system. Bachmann et al. (2019) have identified the type of anaesthesia used on a mouse as one critical experimental parameter that has led to the wide variation in reported lymphatic contraction frequencies. The report studied six common anaesthetic regimens used for intravital imaging and elegantly showed that isoflurane- and pentobarbital-based regimens depress lymphatic function, whereas ketamine-based regimens have limited effect on lymphatic function. The authors recommend that lymphatic researchers use ketamine-based regimens in future work in order to improve the ability to compare results and better interpret mechanistic studies of lymphatic contractility. These results also prompt two important research questions. First, by what mechanism do these anaesthetic regimens impair lymphatic contractility? Second, can these effects of anaesthesia on lymphatic function lead to poor outcomes for patients, particularly those under long-term sedation?

Anaesthesia for surgical procedures in the clinical setting is generally administered to patients on a short time scale on the order of minutes to hours. In such cases, general anaesthesia is often achieved using inhaled volatile anaesthetics (halogenated ethers such as isoflurane, sevoflurane and desflurane) and/or combinations of intravenous agents including propofol, opioid infusions (such as remifentanil, fentanyl and sufentanil), dexmedetomidine (the S-enantiomer of medetomidine) and ketamine. With this broad repertoire, clinicians can tailor an anaesthetic and analgesic regimen that is suitable for the particular patient and procedure. This strategy is possible in part because different anaesthetic and analgesic agents have overlapping, but distinct mechanisms of action, pharmacokinetic and pharmacodynamics profiles, and side effects. While much is known about the receptors affected by various anaesthetic agents, open questions remain about how these agents produce their central anaesthesia and analgesia, as well as their more peripheral side effects. The findings presented by Bachmann et al. suggest that the effects of anaesthetics on lymphatic function are a piece of this clinical puzzle worthy of further study. Bachmann et al. focus on anaesthetic combinations commonly utilized in rodent studies. However, exploring the impact of individual agents on lymphatic pumping would be illuminating and help identify new molecular signalling pathways involved in lymphatic pumping. Similarly, considering other common, clinically relevant anaesthetic and sedative regimens, as well as delving further into the mechanism by which specific anaesthetics affect lymphatic pumping would be extremely valuable to our understanding of the molecular control of lymphatic contractility and how these agents impact surgical patients. Further, exploring whether anaesthetics have differential effects on lymphatic vessels from different tissues will be important (Zawieja et al. 2018).

Interestingly, after a short exposure to anaesthetics in the operating room, otherwise healthy patients do not routinely show signs of profound oedema, although there may be many subclinical effects on lymphatic return to the vasculature which have not yet been measured. In contrast, oedema is frequently observed in patients who are chronically exposed to anaesthetics (days to months), for example in the intensive care unit (ICU) setting. Systemic oedema has many adverse pathophysiological and clinical effects, including but not limited to impeding gastrointestinal function, increasing the difficultly of gaining peripheral vascular access, and prolonging intubation in the case of pulmonary oedema. The aetiology of oedema in ICU patients is typically attributed to a plethora of overlapping clinical factors such as heart failure, intensive administration of intravenous fluids, and the inflammatory state present in many illnesses. Oedema is common in critically ill patients suffering from sepsis and septic shock. While the mechanism underlying oedema in sepsis has previously been attributed to the breakdown of vascular endothelial barriers in the circulatory system, recent evidence demonstrates that methicillin-resistant Staphylococcus aureus causes sustained collecting lymphatic vessel dysfunction, including loss and disorganization of lymphatic muscle cells (Jones et al. 2018). The work of Bachmann et al. suggests that perhaps another precipitating event in the development of oedema in ICU patients is the effect of anaesthetic agents on lymphatic vessels. While inhaled volatile anaesthetic agents are only rarely used in the ICU, intravenous agents such as propofol, dexmedetomidine, opioids and ketamine are used routinely. Increasing our understanding of the effects of these agents on lymphatic vessel function and the mechanisms that mediate these effects may have a direct, positive impact on the clinical outcomes of critically ill patients. The seminal work by Bachmann et al. has opened the door to these future studies.