Background Intravenous fluids for perioperative infusion therapy should be isotonic to maintain the body fluid homeostasis in children. Modified fluid gelatin 4% in a balanced electrolyte solution has a theoretical osmolarity of 284 mosmol L-1, and a real osmolality of 264 mosmol kg H2O-1. Because both values are lower than those of 0.9% saline or plasma, gelatin would be expected to be hypotonic in-vitro and in-vivo. Aim We thus hypothesized that the infusion of gelatin would be expected to decrease plasma osmolality. We performed an in-vitro experiment and an in-vivo study to evaluate the impact of gelatin on the osmolality in children. Methods In the in-vitro experiment, full blood samples were diluted with gelatin 4% or albumin (50 g L-1) from 0% (pure blood) to 100% (pure colloid), and the osmolality was measured by freezing-point depression. In the in-vivo study, blood gas analyses from children undergoing major pediatric surgery were collected before and after gelatin infusion, and the osmolality was calculated by a modified version of Zander's formula. Results In the in-vitro experiment, 65 gradually diluted blood samples from five volunteers (age 25-55 years) were analyzed. The dilution with gelatin caused no significant changes in osmolality between 0% and 100%. Compared with gelatin, the osmolality in the albumin group was significantly lower between 50% and 100% dilution (p < .05). In the in-vivo study, 221 children (age 21.4 +/- 30 months) were included. After gelatin infusion, the osmolality increased significantly (mean change 4.3 +/- 4.8 [95% CI 3.7-4.9] mosmol kg H2O-1; p < .01) within a normal range. Conclusions Gelatin in a balanced electrolyte solution has isotonic characteristics in-vitro and in-vivo, despite the low theoretical osmolarity, probably caused by the (unmeasured) negative charges in the gelatin molecules contributing to the plasma osmolality. For a better evaluation of the (real) tonicity of gelatin-containing solutions, we suggest to calculate the osmolality (mosmol kg H2O-1) using Zander's formula. Trial registration ClinicalTrials.gov (ID: NCT02495285).

Muskelrelaxierende Substanzen werden seit Jahrzehnten in der Anästhesie eingesetzt und spielen nach wie vor eine wichtige Rolle in der modernen Anästhesie. Spezielle Patientenpopulationen wie sehr junge oder sehr alte Patienten erfordern eine angepasste Anwendung. Im folgenden Beitrag werden die Besonderheiten der Verabreichung von Muskelrelaxanzien bei geriatrischen Patient*innen erörtert. The administration of neuromuscular blocking agents has been used in anesthesia for decades and continues to play an important role in modern anesthesia. Special patient populations, such as very young or very old patients, require adapted use. The following article discusses the specifics of neuromuscular blocking agents administration in geriatric patients. Article published online: 28 August 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

The recently identified proton-activated chloride (PAC) channel is ubiquitously expressed, and it regulates several proton-sensitive physiological and pathophysiological processes. While the PAC channel is activated by strong acids due to the binding of protons to extracellular binding sites, here, we describe the way in which weak acids inhibit the PAC channel by a mechanism involving a distinct extracellular binding site. Whole-cell patch clamp was performed on wildtype HEK293T cells, PAC-knockout HEK293 cells expressing human (h)PAC mutant constructs, and on hiPSC-derived cardiomyocytes. Proton-induced cytotoxicity was examined in HEK293T cells. Acetic acid inhibited endogenous PAC channels in HEK 293T cells in a reversible, concentration-dependent, and pH-dependent manner. The inhibition of PAC channels was also induced by lactic acid, propionic acid, itaconic acid, and β-hydroxybutyrate. Weak acids also inhibited recombinant wildtype hPAC channels and PAC-like currents in hiPSC-derived cardiomyocytes. Replacement of the extracellular arginine 93 by an alanine (hPAC–Arg93Ala) strongly reduced the inhibition by some weak acids, including arachidonic acid. Although lactic acid inhibited PAC, it did not reduce the proton-induced cytotoxicity examined in wildtype HEK 293 cells. To conclude, weak acids inhibit PAC via an extracellular mechanism involving Arg93. These data warrant further investigations into the regulation of the PAC channel by endogenous weak acids.

Several transient receptor potential vanilloid (TRPV) ion channels are proton-sensitive, and recent structural studies have identified poorly conserved mechanisms for the proton sensitivity of TRPV1, TRPV2 and TRPV5. While such detailed studies are lacking for TRPV3, three distinct intracellular motifs were suggested to be required for a direct channel activation by cytosolic acidification. In this study, we investigated if these mechanisms are also relevant for the activation of TRPV3 by weak acids. Wildtype (WT) and several mutants of human TRPV3 transiently expressed in HEK 293T cells were investigated by whole-cell patch clamp electrophysiology. Cells expressing TRPV3-WT generated membrane currents induced by acetic acid (HOAc), formic acid and carbonic acid at pH 5.0. Activation induced by HOAc was concentration-dependent and increased with decreasing pH values. HOAc also strongly potentiated TRPV3-mediated responses to carvacrol and heat. Among the three suggested motifs for the binding of intracellular protons, only the mutant TRPV3-Asp512Ala exhibited an almost complete loss of HOAc sensitivity. The mutation of two C-terminal charged residues (Gln689/Asp727) even resulted in a clear gain of function for both HOAc and heat, and the mutation of the 2-APB-binding site His426 did not significantly abrogate HOAc sensitivity. Finally, insertion of the recently identified binding site in TRPV2 for the weak acid probenecid into TRPV3 (Glu216His) resulted in an increased HOAc sensitivity. To conclude, our data confirm that TRPV3 is sensitized and activated by several weak acids. While Asp512 appears to be a critical intracellular proton-modulating site, a more profound understanding of the mechanisms dictating the proton sensitivity of TRPV3 may require structural studies.