Epinephrine, absorption, and local anaesthetic systemic toxicity: insights from continuous fascial block pharmacokinetic models

Summary

Fascial plane blocks have become increasingly popular owing to their technical ease and inclusion in postoperative analgesia guidelines, although uncertainties about their mechanisms and safety remain. A recent study of the impact of epinephrine on levobupivacaine pharmacokinetics in continuous fascial plane blocks proposes a potential safe dosing threshold and highlights the role of epinephrine in reducing systemic absorption. The study presents promising findings that advance our understanding of local anaesthetic pharmacokinetics in fascial blocks while raising important questions about drug absorption, patient-specific risk factors for local anaesthetic systemic toxicity, and the incompletely understood microanatomy of fascial tissues.

Fascial plane blocks have grown increasingly popular over the past quarter of a century as safer and more technically accessible alternatives to neuraxial techniques.^1,2 Among these, the transversus abdominis plane (TAP) block, one of the earliest described plane blocks, and the erector spinae plane (ESP) block, described in 2016 and applied for a variety of indications, have become particularly popular. These blocks, and fascial plane blocks more generally, are considered to be volume dependent, as higher volumes of local anaesthetic drugs are deemed necessary to achieve greater anaesthetic spread and clinical efficacy. However, the use of large volumes carries an increased risk of local anaesthetic systemic toxicity (LAST), particularly in the absence of well-defined minimum effective local anaesthetic concentrations and volumes for the various block types, especially when continuous infusion catheter techniques are used.

In this issue of the British Journal of Anaesthesia, Araneda and colleagues³ describe the effects of epinephrine on the pharmacokinetics of local anaesthetics during both continuous TAP and continuous ESP blocks. In particular, the authors developed levobupivacaine pharmacokinetic models for continuous TAP and ESP blocks, with and without epinephrine, to explore the safety profile of higher-dose administration strategies analysing different intermittent bolus and continuous infusion regimens. The models were based on data from three sources: previously published pharmacokinetic data from patients receiving continuous TAP blocks; published data on the pharmacokinetics of i.v. bupivacaine; and data from patients undergoing video-assisted thoracoscopic surgery who received continuous ESP blocks. The authors concluded that these continuous techniques appear to be safe when performed using either intermittent boluses or continuous infusion of levobupivacaine at a dose of 300 mg per day, which is proposed as a potentially ‘safe’ daily threshold for these approaches.

A recent pragmatic pharmacokinetic analysis⁴ of bupivacaine and ropivacaine redosing in truncal catheters similarly found that commonly used dosing strategies in the literature align with the slowest pharmacokinetic elimination rates, suggesting these approaches are likely safe. However, the study by Araneda and colleagues³ addressed the gap in knowledge regarding levobupivacaine, which was not previously described.

Pharmacokinetic studies are frequently used to inform safe dosing regimens for routine regional anaesthesia practice. This approach is based on the understanding that one of the most feared complications of regional anaesthesia, LAST, is dose dependent. Accordingly, it is reasonable for clinicians to seek knowledge of both the toxicity threshold and the doses likely to exceed it.

Literature reviews on dosing regimens in patients undergoing TAP and paravertebral infusions identified higher doses of local anaesthetics as a risk factor for LAST,⁵ and some authors have suggested weight-based dosing to reduce LAST.⁶ However, LAST still occurs with commonly used dosing strategies,⁷ and with plasma concentrations typically considered ‘safe’.^8,9 Furthermore, the same studies show that although exceeding the upper dosing limits is relatively common, the actual occurrence of LAST remains a rare phenomenon.^5,6 This suggests the existence of distinct patient subgroups, some with a higher tolerance to local anaesthetics, and possibly others with an unusually low sensitivity threshold. Although the existence of such individuals is supported by multiple case reports and clinical observations, identifying the precise causes of variability in toxicity thresholds is inherently challenging, particularly given the low incidence of LAST (<1%),⁵ which limits the ability to systematically evaluate all potential covariates, even though factors such as concomitant medications, hypercarbia, electrolyte imbalances, carnitine deficiency, CYP-inhibiting medications, breakthrough bolus doses, and the use of bilateral catheters in continuous infusions have been suggested as contributors.^5,9

Although we commend Araneda and colleagues³ for their valuable contribution, it is important for practitioners to recognise that LAST is a complex phenomenon, and it is unlikely that any single model will predict toxicity in all patients. Therefore, although dose remains a primary risk factor, close monitoring is essential regardless of the dose administered, particularly during continuous infusions, and especially when these are administered on general wards.

Another important consideration is that the model was developed using data from patients undergoing video-assisted thoracic surgery (ESP group) and healthy volunteers (TAP group), with blood samples collected up to 90 min after the nerve block. From these data, the authors constructed a predictive model for continuous infusion. However, protein-binding dynamics play a crucial role in the pathophysiology of LAST, as the unbound fraction of local anaesthetic determines the onset of toxicity.¹⁰

This model is clearly unsuitable for patients with conditions such as malnutrition or hepatic dysfunction, as these alter circulating protein levels and, consequently, drug-binding dynamics. Moreover, certain plasma proteins, such as α₁-acid glycoprotein, increase after surgery because of surgical stress, thereby enhancing protein-binding capacity for local anaesthetics.⁸ Because Araneda and colleagues³ only measured levobupivacaine levels up to 90 min after the block, some uncertainty remains regarding the predictive accuracy of the model, particularly in estimating unbound levobupivacaine concentrations after surgery and in specific patient populations. This raises the possibility of both overestimation and underestimation.

The addition of epinephrine to local anaesthetics is used to enhance the safety of regional anaesthesia by inducing local vasoconstriction. This effect reduces systemic absorption, lowers peak plasma concentrations, and thereby decreases the risk of LAST.¹¹ In the present study, use of epinephrine in both block types significantly reduced the bioavailability of levobupivacaine and prolonged its absorption half-life. These findings are consistent with previous reports.¹² In the context of continuous infusion techniques, where cumulative dosing raises important safety concerns, use of epinephrine as an adjuvant might represent a practical strategy for mitigating systemic toxicity, particularly when using high-volume fascial plane blocks.

One of the most intriguing aspects of the study by Araneda and colleagues³ is the lack of significant differences in levobupivacaine absorption profiles between the TAP and ESP blocks. This finding suggests similar tissue absorption conditions between the fascial planes of the erector spinae and transversus abdominis muscles. This is particularly notable given that ESP and TAP are macroscopically distinct, with differing tributary vessels, muscle layers, and fascial architecture.

Although the macroscopic differences might make this result appear paradoxical, we propose that the explanation lies in the microscopic structure of the fasciae. It is crucial to consider that fasciae are not inert layers; they are well-vascularised, richly innervated structures containing internal lymphatic plexuses.¹³ Superficial fasciae¹⁴ contain a dense and evenly distributed vascular network, with vessel diameters from 13 to 65 μm. These vessels are innervated by sympathetic fibres, indicating a potential role for sympathetic activity in regulating fascial vascularisation, drug adsorption, and possibly influencing ischaemic processes.¹⁵ A similar vascular network, accompanied by an extensive lymphatic plexus,^16,17 has been identified in deep fascia, providing a plausible explanation for the rapid absorption of local anaesthetics observed during fascial plane blocks.¹⁸

To further understand drug absorption, it is necessary to examine the fascial interstitium. This hyaluronic acid-rich compartment forms the more viscous layers of fascia and maintains continuous structural integrity throughout the body via smaller interstitial spaces. These channels facilitate exchange of nutrients and waste products¹⁹ and might significantly influence both cell trafficking and anaesthetic drug distribution.

Remarkably, similar interstitial spaces exist in the adventitia of blood vessels, directing interstitial fluid flow towards the heart at a higher velocity than in other tissues.²⁰ It remains unclear how these fascial microstructures influence anaesthetic absorption and distribution. Moreover, no comparative studies have systematically examined the properties of different fasciae across anatomical regions, sexes, age groups, or in relation to previous trauma, leaving a significant knowledge gap regarding the variability of fascial function in regional anaesthesia. However, the findings by Araneda and colleagues³ suggest that there are more similarities than differences between these two fascial planes.

A central assumption to this line of inquiry remains unanswered: are continuous TAP and ESP blocks truly effective, and should they be adopted into routine clinical practice? Meta-analyses of continuous fascial techniques appear promising,^21,22 but conclusive evidence remains limited, as continuous TAP and ESP blocks are considerably less studied than their single-shot counterparts.

Moreover, both TAP and ESP blocks demonstrate variable patterns of local anaesthetic spread, influenced by numerous confounding factors related to the operator, the patient, and the technique itself.²³ This variability is particularly pronounced for the ESP block, with studies reporting inconsistent anaesthesia patterns among patients.²⁴ Notably, spread into the paravertebral space, often cited as the key mechanism for ESP block efficacy, occurs in only about one-third of cases.^25,26

Given this variability, one might ask: what is the actual mechanism of action of these continuous blocks if their anatomical spread is so inconsistent? A compelling hypothesis is that systemic absorption plays a substantial role in their analgesic effect.²⁷ Indeed, the terminal half-life of local anaesthetics administered via single-shot blocks is significantly prolonged compared with i.v. administration,^4,18 suggesting that the drugs might be retained in a tissue ‘depot’, from which they are gradually released into the systemic circulation. This effect could be amplified by continuous infusion, potentially contributing to prolonged analgesia via systemic mechanisms.

In light of these factors, we believe the study by Araneda and colleagues³ raises as many questions as it answers. Yet, is this not the essence of scientific progress: a continuous cycle of inquiry, data collection, and evolving hypotheses? We hope this study will serve as a catalyst for further investigation and form the basis for future well-designed trials to determine the true value and role of continuous fascial plane blocks in clinical practice.

Declaration of interest

The authors declare that they have no conflicts of interest.