Background: Lidocaine exerts antinociceptive effects when applied systemically. The mechanisms are not fully understood but glycinergic mechanisms might be involved. The synaptic glycine concentration is controlled by glycine transporters. Whereas neurons express two types of glycine transporters, astrocytes specifically express glycine transporter 1 (GlyT1). This study focuses on effects of lidocaine and its major metabolites on GlyT1 function. Methods: The effects of lidocaine and its metabolites monoethylglycinexylidide (MEGX), glycinexylidide, and N-ethylglycine on GlyT1 function were investigated in uptake experiments with [¹⁴C]-labeled glycine in primary rat astrocytes. Furthermore, the effect of lidocaine and its metabolites on glycine-induced currents were investigated in GlyT1-expressing Xenopus laevis oocytes. Results: Lidocaine reduced glycine uptake only at toxic concentrations. The metabolites MEGX, glycinexylidide, and N-ethylglycine, however, significantly reduced glycine uptake (P < 0.05). Inhibition of glycine uptake by a combination of lidocaine with its metabolites at a clinically relevant concentration was diminished with increasing extracellular glycine concentrations. Detailed analysis revealed that MEGX inhibits GlyT1 function (P < 0.05), whereas N-ethylglycine was identified as an alternative GlyT1 substrate (EC₅₀ = 55 μM). Conclusions: Although lidocaine does not function directly on GlyT1, its metabolites MEGX and N-ethylglycine [corrected] were shown to inhibit GlyT1-mediated glycine uptake by at least two different mechanisms. Whereas N-ethylglycine [corrected] was demonstrated to be an alternative GlyT1 substrate, MEGX was shown to inhibit GlyT1 activity in both primary astrocytes and in GlyT1-expressing Xenopuslaevis oocytes at clinically relevant concentrations. These findings provide new insights into the possible mechanisms for the antinociceptive effect of systemic lidocaine.

Glycine transporter 1 (GlyT1) plays a crucial role in regulating extracellular glycine concentrations and might thereby constitute a new drug target for the modulation of glycinergic inhibition in pain signaling. Consistent with this view, inhibition of GlyT1 has been found to induce antinociceptive effects in various animal pain models. We have shown previously that the lidocaine metabolite N-ethylglycine (EG) reduces GlyT1-dependent glycine uptake by functioning as an artificial substrate for this transporter. Here, we show that EG is specific for GlyT1 and that in rodent models of inflammatory and neuropathic pain, systemic treatment with EG results in an efficient amelioration of hyperalgesia and allodynia without affecting acute pain. There was no effect on motor coordination or the development of inflammatory edema. No adverse neurological effects were observed after repeated high-dose application of EG. EG concentrations both in blood and spinal fluid correlated with an increase of glycine concentration in spinal fluid. The time courses of the EG and glycine concentrations corresponded well with the antinociceptive effect. Additionally, we found that EG reduced the increase in neuronal firing of wide-dynamic-range neurons caused by inflammatory pain induction. These findings suggest that systemically applied lidocaine exerts antihyperalgesic effects through its metabolite EG in vivo, by enhancing spinal inhibition of pain processing through GlyT1 modulation and subsequent increase of glycine concentrations at glycinergic inhibitory synapses. EG and other substrates of GlyT1, therefore, may be a useful therapeutic agent in chronic pain states involving spinal disinhibition.

Body temperature homeostasis is accurately regulated by complex feedback‐driven neuronal mechanisms, which involve a multitude of thermoregulatory pathways. Thus, core temperature is constantly maintained within a narrow range. As one of the most effective regulatory systems skin temperature is dependent on skin blood flow. Skin blood flow in turn is highly dependent on sympathetic activity. Regional anaesthesia leads to blockade not only of somatosensory and motor nerve fibres but also of sympathetic fibres. As a consequence, vasoconstrictor tonic activity is abrogated and a vasodilation leads to an increase in skin blood flow and temperature. The aim of this review was to summarize the general physiology of thermoregulation and skin temperature as well as the alterations during regional anaesthesia. The main focus was the usefulness of measuring skin temperature as an indicator of regional anaesthesia success. According to the available literature, assessment of skin temperature can indeed serve to predict success of regional anaesthesia. Hence, it is important to realize that relevant and reliable temperature increase is only seen in the most distal body parts, ie fingers and toes. More proximally, temperature changes are frequently small and inconsistent, which means that assessment of block levels is not possible by temperature measurement. Furthermore, relevant skin temperature increases will only be observed in patients, which are initially vasoconstricted. In conclusion, measurement of skin temperature represents a reliable and feasible diagnostic tool to assess and predict the success or failure of regional anaesthesia procedures, especially in patients in which sensory testing is impossible.

In neuraxial anesthesia, increase of skin temperature is an early sign of successful block. Yet, during peripheral nerve block of the lower extremity, increase in skin temperature is a highly sensitive, but late sign of a successful block. We hypothesized that after interscalene brachial plexus block, a rise in skin temperature follows impairment of sensation during successful nerve block and occurs only distally, as observed in the lower extremity. In the present study, we prospectively evaluated the changes in skin temperature after interscalene brachial plexus blockade in 45 patients scheduled for elective shoulder surgery. We assessed pinprick and cold sensation as well as skin temperature at sites of the skin innervated by the median, ulnar, radial, axillary and musculocutaneous nerve. At the skin areas innervated by the axillary and musculocutaneous nerve, skin temperature did not increase after successful block. At the distal sites, innervated by the median, ulnar, and radial nerve, skin temperature increased significantly (1.9-2.1°C within 30 min) after successful block while it did not after failed nerve block or on the contralateral side. In these areas attenuation of skin sensation preceded a measurable rise in skin temperature (≥1°C) in 56.3% of nerve blocks, occurred at the same time in 35.2%, and in 8.5% the temperature rise occurred first. Assessment of skin temperature cannot predict the success of an interscalene brachial plexus block of the axillary and musculocutaneous nerve. Distally, the increase of skin temperature has a high sensitivity and specificity but occurs later than the loss of sensory and motor functions. Therefore, the measurement of skin temperature during interscalene blockade is of limited clinical value.

Flow diversion (FD) is a novel endovascular technique based on the profound alteration of cerebrovascular hemodynamics, which emerged as a promising minimally invasive therapy for intracranial aneurysms. However, delayed post-procedural stroke remains an unexplained concern. A consistent follow-up-regimen has not yet been defined, but is required urgently to clarify the underlying cause of delayed ischemia. In the last two years, 223 patients were treated with six different FD devices in our center. We identified subacute, FD-induced segmental vasospasm (SV) in 36 patients as a yet unknown, delayed-type reaction potentially compromising brain perfusion to a critical level. Furthermore, 86% of all patients revealed significant SV approximately four weeks after treatment. In addition, 56% had SV with 25% stenosis, and 80% had additional neointimal hyperplasia. Only 13% exhibited SV-related high-grade stenosis. One of those suffered stroke due to prolonged SV, requiring neurocritical care and repeated intra-arterial (i.a.) biochemical angioplasty for seven days to prevent territorial infarction. Five patients suffered newly manifested, transient hemicrania accompanying a compensatorily increased ipsilateral leptomeningeal perfusion. One treated vessel obliterated permanently. Hence, FD-induced SV is a frequent vascular reaction after FD treatment, potentially causing symptomatic ischemia or even stroke, approximately one month post procedure. A specifically early follow-up-strategy must be applied to identify patients at risk for ischemia, requiring intensified monitoring and potentially anti-vasospastic treatment.