Discussion
According to our knowledge, this is the first study reporting TDM of pregabalin in course of continuous and prolonged intermittent KRT in a critically ill patient. These modalities of KRT, often used as complementary therapies, are considered the preferred dialysis modalities for critically ill patients with AKI, especially in those with hemodynamic instability [13]. As each treatment session is performed over a long-time span, these KRT modalities allow for slower fluid and solute removal, with better hemodynamic tolerance and lower risk of rapid osmolal shift [14]. In addition, due to their extended duration, prolonged KRTs usually provides an efficient daily solute clearance [15]. As detailed in Table 1 , pregabalin has small molecular weight, negligible protein binding and low volume of distribution, thus it is characterized by a significant theorical extracorporeal clearance by KRTs. Data regarding the target therapeutic concentration are still limited. Studies on patients with epilepsy with normal kidney function receiving 150-600 mg daily of the drug, reported a serum level ranging from 2 - 8 microg/mL [10-12, 16]. Optimal therapeutic plasma concentrations for neuropathic pain control have not been established yet. However, studies have demonstrated a dose-response relationship for pregabalin in the treatment of painful conditions, like post-herpetic neuralgia. Given the linear absorption of pregabalin, with plasma concentrations increasing proportionately with increasing dose, pregabalin plasma concentration stability likely plays a crucial role in analgesic effect maintenance [17].
Given the increased adoption of pregabalin also in the ICU, not only as a continuation therapy in patients with chronic neuropathic pain, but also in the setting of multimodal analgesia [6-8, 18], a great degree of attention should be required to avoid the risk of inadequate therapeutic concentrations. Indeed, given the prevalent renal metabolism, a dose adjustment is usually recommended in patients with impaired kidney function (Table 1 ). However, according to the pharmacokinetic profile and in line with the different KRT modalities techniques, our data showed a slow but progressive reduction of pregabalin serum levels in course of the prolonged KRTs (CKRT and SLED,Figure 1 A-B ), while a more rapid and significant reduction during conventional IHD was observed (Figure 1 C ). In this regard, we found that when a modality of continuous KRT is applied for incident AKI (e.g. CVVHDF), the usual recommended pregabalin dose may become insufficient to maintain the therapeutic concentration range (Figure 1A ). Indeed, despite the double daily administration, a slow but progressive decline in serum levels was observed, as reported in a case of gabapentin intoxication treated with CKRT [19]. While in course of the SLED session serum levels remained within the suggested therapeutic range (Figure 1B ), a more severe reduction may be supposed with longer duration (e.g. 12-16 hours) and increased dialysis fluid rate (until 300 ml/min). Finally, as already previously reported in chronic hemodialysis patients [4, 5, 20], TDM data obtained during and after the IHD session confirmed a rapid reduction of serum concentration during the treatment session, along with a subsequent normalization after dialysis, also thanks to the double daily administration (Figure 1C ).
In conclusion, even though more data are needed to confirm our findings, the TDM of pregabalin may represent a useful therapeutic option in critically ill patients, especially in those requiring continuous or prolonged intermittent KRT. This approach could help to achieve the therapeutic effect while minimizing the risk of side effects.