Changes in Plasma Glycine Concentration in General Anesthesia With Remifentanil: A Prospective Observational Pilot...

Remifentanil-based anesthesia has been associated with postanesthetic shivering (PAS) and postoperative pain consistent with opioid-induced hyperalgesia (OIH). PAS and OIH have been suggested to involve N-methyl-D-aspartate (NMDA) receptor signaling. Glycine participating in the NMDA receptor functions as a co-agonist. Commercial remifentanil formulations contain glycine as an excipient, raising the question of whether perioperative exposure to this medication increases circulating glycine levels, potentially including those in the central nervous system.

The objective of this study is to confirm the elevation of plasma glycine and its perioperative course during general anesthesia with glycine-containing remifentanil.

An open-label, single-center, preliminary prospective observational study was performed in adults undergoing elective pancreaticoduodenectomy. Patients with renal dysfunction or liver dysfunction were excluded. Balanced anesthesia included desflurane, propofol, remifentanil (Ultiva; 7.5 mg glycine per 1 mg remifentanil) infused at 0-0.2 μg/kg/min, fentanyl, and rocuronium. No glycine-containing IV fluids were administered. Plasma glycine was quantified by enzyme-linked immunosorbent assay at six time points: pre-induction (T0), 120 min after induction (T1), end of remifentanil (T2), and one hour (T3), two hours (T4), and three hours (T5) after completion. PAS, Face Pain Scale-revised (FPS-R), ICU Confusion Assessment Method (CAM-ICU), and ionized magnesium on ICU admission were recorded exploratorily. Changes over time were assessed using a repeated-measures ANOVA with the Greenhouse-Geisser correction and Dunnett comparisons versus T0 (α = 0.05).

Twelve patients were enrolled, and 10 participants completed the protocol. Plasma glycine ranged from 200 to 500 μmol/L. There was no significant increase at any remifentanil infusion rate. Compared with pre-induction, plasma glycine levels were significantly lower at two hours (T4) and three hours (T5) post-remifentanil (p < 0.05). One patient exceeded the reference range for glycine despite preservation of hepatic and renal function. The study was not powered to test associations with PAS or OIH.

In surgical patients with preserved organ function, anesthesia with glycine-containing remifentanil did not elevate plasma glycine levels in 9 of 10 cases, limiting evaluation of an NMDA receptor-mediated mechanism. Further investigation should consider evaluating plasma concentrations when high-concentration remifentanil or glycine-containing formulations are used concomitantly.