Dexmedetomidine versus haloperidol for sedation of non-intubated patients with hyperactive delirium during the night in a high dependency unit: study protocol for an open-label, parallel-group, randomized controlled trial (DEX-HD trial).

BACKGROUND: Delirium is common in critically ill patients. Haloperidol has long been used for the treatment of delirium. Dexmedetomidine has recently been used to treat delirium among intubated critically ill patients. However, the efficacy of dexmedetomidine for delirium in non-intubated critically ill patients remains unknown. We hypothesize that dexmedetomidine is superior to haloperidol for sedation of patients with hyperactive delirium, and would reduce the prevalence of delirium among non-intubated patients after administration. We will conduct a randomized controlled trial to compare dexmedetomidine and haloperidol for the treatment of nocturnal hyperactive delirium in non-intubated patients in high dependency units (HDUs). METHODS: This is an open-label, parallel-group, randomized controlled trial to compare the efficacy and safety of dexmedetomidine and haloperidol for nocturnal hyperactive delirium in non-intubated patients at two HDUs of a tertiary hospital. We will recruit consecutive non-intubated patients who are admitted to the HDU from the emergency room, and allocate them in a 1:1 ratio to the dexmedetomidine or haloperidol group in advance. The allocated investigational drug will be administered only when participants develop hyperactive delirium (Richmond Agitation-Sedation Scale [RASS] score ≥1 and a positive score on the Confusion Assessment Method for the ICU between 19:00 and 6:00 the next day) during the night at an HDU. Dexmedetomidine is administered continuously, while haloperidol is administered intermittently. The primary outcome is the proportion of participants who achieve the targeted sedation level (RASS score of between -3 and 0) 2h after the administration of the investigational drug. Secondary outcomes include the sedation level and prevalence of delirium on the day following the administration of the investigational drugs, and safety. We plan to enroll 100 participants who develop nocturnal hyperactive delirium and receive one of the two investigational drugs. DISCUSSION: This is the first randomized controlled trial to compare the efficacy and safety of dexmedetomidine and haloperidol for sedation of non-intubated critically ill patients with hyperactive delirium in HDUs. The results of this study may confirm whether dexmedetomidine could be another option to sedate patients with hyperactive delirium. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCT1051220015, registered on 21 April 2022.

Numerical investigation of side emission from large-area vertical-cavity surface-emitting lasers.

For large-area ion-implanted vertical-cavity surface-emitting lasers (VCSELs), side emission from the edges of a chip disturbs the laser emission of a VCSEL mode, and suppression of it is fundamental. In this paper, we present results of a numerical investigation of the side emission from large-area VCSELs. We have modeled a VCSEL structure by an infinitely broad layer structure with mirror loss at the edge surfaces. Estimated threshold gains indicate that laser emission occurs either in a VCSEL mode or in an edge-emitting Fabry-Perot (EEFP) mode. Calculated emitter length dependence of the threshold gain of these modes shows good agreement with experimental results, and the side emission is verified to be the laser emission of the EEFP mode. We have also discussed the way to suppress the side emission and confirmed that our recent achievement of over 200 W quasi-continuous-wave output from an ion-implanted VCSEL array is due to antireflection coatings of the edges and introduction of optical losses in ex-emitter regions.

High power density vertical-cavity surface-emitting lasers with ion implanted isolated current aperture.

We report on GaAs-based high power density vertical-cavity surface-emitting laser diodes (VCSELs) with ion implanted isolated current apertures. A continuous-wave output power of over 380 mW and the power density of 4.9 kW/cm2 have been achieved at 15 °C from the 100-µm-diameter aperture, which is the highest output characteristic ever reported for an ion implanted VCSEL. A high background suppression ratio of over 40 dB has also been obtained at the emission wavelength of 970 nm. The ion implantation technique provides an excellent current isolation in the apertures and would be a key to realize high power output from a VCSEL array.

Identification and functional characterization of the first nucleobase transporter in mammals: implication in the species difference in the intestinal absorption mechanism of nucleobases and their analogs between higher primates and other mammals.

Nucleobases are important compounds that constitute nucleosides and nucleic acids. Although it has long been suggested that specific transporters are involved in their intestinal absorption and uptake in other tissues, none of their molecular entities have been identified in mammals to date. Here we describe identification of rat Slc23a4 as the first sodium-dependent nucleobase transporter (rSNBT1). The mRNA of rSNBT1 was expressed highly and only in the small intestine. When transiently expressed in HEK293 cells, rSNBT1 could transport uracil most efficiently. The transport of uracil mediated by rSNBT1 was sodium-dependent and saturable with a Michaelis constant of 21.2 microM. Thymine, guanine, hypoxanthine, and xanthine were also transported, but adenine was not. It was also suggested by studies of the inhibitory effect on rSNBT1-mediated uracil transport that several nucleobase analogs such as 5-fluorouracil are recognized by rSNBT1, but cytosine and nucleosides are not or only poorly recognized. Furthermore, rSNBT1 fused with green fluorescent protein was mainly localized at the apical membrane, when stably expressed in polarized Madin-Darby canine kidney II cells. These characteristics of rSNBT1 were almost fully in agreement with those of the carrier-mediated transport system involved in intestinal uracil uptake. Therefore, it is likely that rSNBT1 is its molecular entity or at least in part responsible for that. It was also found that the gene orthologous to the rSNBT1 gene is genetically defective in humans. This may have a biological and evolutional meaning in the transport and metabolism of nucleobases. The present study provides novel insights into the specific transport and metabolism of nucleobases and their analogs for therapeutic use.

Functional identification of SLC43A3 as an equilibrative nucleobase transporter involved in purine salvage in mammals.

The purine salvage pathway plays a major role in the nucleotide production, relying on the supply of nucleobases and nucleosides from extracellular sources. Although specific transporters have been suggested to be involved in facilitating their transport across the plasma membrane in mammals, those which are specifically responsible for utilization of extracellular nucleobases remain unknown. Here we present the molecular and functional characterization of SLC43A3, an orphan transporter belonging to an amino acid transporter family, as a purine-selective nucleobase transporter. SLC43A3 was highly expressed in the liver, where it was localized to the sinusoidal membrane of hepatocytes, and the lung. In addition, SLC43A3 expressed in MDCKII cells mediated the uptake of purine nucleobases such as adenine, guanine, and hypoxanthine without requiring typical driving ions such as Na(+) and H(+), but it did not mediate the uptake of nucleosides. When SLC43A3 was expressed in APRT/HPRT1-deficient A9 cells, adenine uptake was found to be low. However, it was markedly enhanced by the introduction of SLC43A3 with APRT. In HeLa cells, knock-down of SLC43A3 markedly decreased adenine uptake. These data suggest that SLC43A3 is a facilitative and purine-selective nucleobase transporter that mediates the cellular uptake of extracellular purine nucleobases in cooperation with salvage enzymes.

Identification and functional characterization of rat riboflavin transporter 2.

We have newly identified rat riboflavin transporter 2 (rRFT2) and its human orthologue (hRFT2), and carried out detailed functional characterization of rRFT2. The mRNA of rRFT2 was highly expressed in jejunum and ileum. When transiently expressed in human embryonic kidney (HEK) 293 cells, rRFT2 could transport riboflavin efficiently. Riboflavin transport mediated by rRFT2 was Na(+)-independent but moderately pH-sensitive, being more efficient in acidic conditions than in neutral and basic conditions. Kinetic analysis indicated that rRFT2-mediated riboflavin transport was saturable with a Michaelis constant (K(m)) of 0.21 microM. Furthermore, it was specifically and strongly inhibited by lumiflavin, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), and to a lesser extent by amiloride. Such ability to transport riboflavin in a specific manner, together with its high expression in the small intestine, indicates that RFT2 may play a role in the intestinal absorption of riboflavin.