Improvement in ICU Mortality From Sepsis Associated With Recuperation From Septic Multiple-Organ Failure: A Retrospective, Single-Center, Cohort Study.

BACKGROUND: Although mortality due to sepsis has decreased in recent decades, there are few studies on the timing of death during ICU stay. Characteristics of patients related to changes over the years of ICU death and changes in the timing of ICU death will provide new insights for future sepsis management. METHODS: This was a single-center, retrospective study. Patients admitted to the ICU for sepsis between 2005 and 2019 were included in the study. The study period was divided into three five-year intervals, and the timing of death in the ICU was divided into early-stage (1-3 ICU days), mid-stage (4-14 ICU days), and late-stage (15 or more ICU days). Patient characteristics related to ICU death at three five-year intervals and the timing of death were evaluated. RESULTS: ICU mortality for sepsis has decreased over time (2005-2009, 30.2%; 2010-2014, 21.0%; 2015-2019, 12.1%; p<0.01). In the timing of death, only mid-stage mortality decreased. Multiple-organ failure (OR, 4.53; 95% CI, 2.79-7.48) and hematological malignancies (OR, 2.48; 95% CI, 1.19-5.07) were associated with ICU mortality over entire study periods. Only multiple-organ failure was associated with ICU mortality at the five-year intervals (OR, 5.94; 95% CI, 2.73-13.7 for 2005-2009; OR, 4.01; 95% CI, 1.82-9.31 for 2010-2014; OR, 2.58; 95% CI, 1.05-6.59 for 2015-2019). Mid-stage mortality of multiple-organ failure decreased (2005-2009, 12.8%; 2010-2014, 7.6%; 2015-2019, 1.6%; p=0.02). However, early- and late-stage mortality of multiple-organ failure did not change. CONCLUSIONS: Improvement in mid-stage mortality in septic patients with multiple-organ failure can contribute to the improvement of overall ICU mortality in patients with sepsis.

Albumin protects the ultrastructure of the endothelial glycocalyx of coronary arteries in myocardial ischemia-reperfusion injury in vivo.

Myocardial ischemia-reperfusion (I/R) injury induces endothelial glycocalyx (GCX) degradation. Several candidate GCX-protective factors including albumin have been identified, few have been demonstrated in in vivo studies and most albumins used to date have been heterologous. Albumin is a carrier protein for sphingosine 1-phosphate (S1P), which has protective effects on the cardiovascular system. However, changes inhibited by albumin in the endothelial GCX structure in I/R in vivo via the S1P receptor has not been reported. In this study, we aimed to determine whether albumin prevents the shedding of endothelial GCX in response to I/R in vivo. Rats were divided into four groups: control (CON), I/R, I/R with albumin preload (I/R + ALB), and I/R + ALB with S1P receptor agonist fingolimod (I/R + ALB + FIN). FIN acts as an initial agonist of S1P receptor 1 and downregulates the receptor in an inhibitory manner. The CON and I/R groups received saline and I/R + ALB and I/R + ALB + FIN groups received albumin solution before left anterior descending coronary artery ligation. Our study used rat albumin. Shedding of endothelial GCX was evaluated in the myocardium by electron microscopy, and the concentration of serum syndecan-1 was measured. Thus, albumin administration maintained the structure of endothelial GCX and prevented shedding of endothelial GCX via the S1P receptor in myocardial I/R, and FIN annihilated the protective effect of albumin against I/R injury.

Cardiac Failure Requiring Veno-Arterial Extracorporeal Membrane Oxygenation (VA-ECMO) Management in a Refeeding Syndrome Patient with Diabetic Ketoacidosis: A Case Report.

BACKGROUND Refeeding syndrome is a complex metabolic disorder that develops following rapid nutritional administration after a long period of undernutrition. The onset mechanism involves intracellular transport of phosphorus, potassium, and water, in association with rapid glucose administration. The resulting hypophosphatemia is extremely dangerous and can cause severe heart failure and fatal arrhythmia. We successfully used extracorporeal cardiopulmonary support to manage a case of refeeding syndrome that occurred during the course of treatment of diabetic ketoacidosis. There are only a few reports of the use of cardiopulmonary support for the treatment of refeeding syndrome. CASE REPORT A 72-year-old man was admitted to the hospital for treatment of diabetic ketoacidosis. Despite receiving insulin and nutrition therapy, QT prolongation and ventricular fibrillation appeared on the electrocardiogram. Although coronary angiography was performed in consideration of the possibility of ischemic heart disease, no significant stenosis of the coronary arteries was identified. Due to persistent hypotension and recurrence of ventricular fibrillation, extracorporeal cardiopulmonary support was commenced in the ICU. His serum phosphorus level showed a marked decrease on his first day in the ICU, for which daily replacement therapy was administered during his ICU stay. No fatal arrhythmia developed thereafter. He was weaned off extracorporeal cardiopulmonary support on the fourth day of his ICU stay and was subsequently discharged from the hospital. CONCLUSIONS We suggest vigilant monitoring of electrolytes, including phosphate levels, in diabetic ketoacidosis patients, and active circulatory support, as required, in patients with refeeding syndrome.

Efficacy of Automatic Retention Pressure of a Double-Lumen Tube Cuff: An Artificial Intubation Model.

BACKGROUND: The movement of a double-lumen endotracheal tube (DLT) out of its appropriate position during thoracic surgery can result in the loss of one-lung ventilation (OLV), especially during pulmonary resection and node dissection. Our study aimed to validate the efficacy of automatic retention pressure control of the DLT bronchial cuff in maintaining OLV in an artificial intubation model. MATERIALS AND METHODS: A 35-Fr left-sided DLT was intubated to the left main bronchus in an intubation simulator and connected to an anesthesia machine. The inspiratory volume, respiratory rate, and inspiratory-expiratory ratio were set at 500 mL, 12 times/min, and 1:2, respectively. A 1-kg right main bronchial traction in the lateral right was provided after OLV was established. SmartCuff (Smiths Medical, Minneapolis, Minnesota, USA) was used to maintain cuff pressure. The efficacy of retention pressure with SmartCuff (Group S) and without SmartCuff (Group WS) was compared. The primary outcome was the rate of tidal volume (TV) reduction following bronchial traction in the two groups. RESULTS: The TVs were 289.8 ± 28.9 mL and 242.8 ± 31.9 mL in Group S and Group WS, respectively (P = 0.003). The rate of TV reduction after bronchial traction was significantly lower in Group S (29 ± 5%) than in Group WS (43 ± 6%) (P < 0.001). CONCLUSIONS: Automatic retention pressure control of the DLT bronchial cuff improves the rate of TV reduction during right main bronchial traction in an artificial intubation model. Continuous retention cuff pressure may be useful in maintaining OLV during thoracic surgery.

Assessing the validity of a linear inflation method in noninvasive blood pressure monitoring during the induction period of general anaesthesia.

Inflationary noninvasive blood pressure (iNIBP) monitoring can determine BP in a shorter time compared to conventional deflationary NIBP (dNIBP) monitoring. We assessed the efficacy of iNIBP monitoring during induction of general anaesthesia and tracheal intubation, which can cause rapid changes in haemodynamics. Our study included 14 surgery patients receiving tracheal intubation under general anaesthesia. Blood pressure was continuously measured using iNIBP monitoring. We recorded the percentage of successful iNIBP monitoring (measurements made without switching to dNIBP mode) during anaesthesia induction. We obtained 326 BP-measurements from 14 patients. The iNIPB mode was able to perform 90.9% of the measurements during the induction of general anaesthesia. iNIBP could determine BP even during periods of high blood pressure variability (31.6% [interquartile range; 22-40]). Our results validate the utility of iNIBP monitoring during the induction period of general anaesthesia, despite the rapid haemodynamic changes.

Effects of glucocorticoid on postnatal development of rat sublingual glands.

Hormones have been reported to be involved in salivary gland's growth and development, but few studies have investigated the effects of glucocorticoids on the morphology of the sublingual glands around the weaning period. The objective of this study was to ascertain the effects of glucocorticoid administration on rat sublingual glands around the weaning period. Male Wistar rats were administered triamcinolone, a glucocorticoid, once every other day from 8 days after birth (experimental group). A control group was given vehicle only. The sublingual glands were then extracted at 15, 20, 25, and 30 days after birth. Samples thus obtained were subjected to Alcian blue and periodic acid-Schiff staining, lectin staining, and immunohistochemical staining to assess cellular proliferative potential. And acinar cell circumferences were measured. We found that glucocorticoid had no effect on the production of acid or neutral mucopolysaccharides by acinar cells around the weaning period. Glucocorticoid administration resulted in hypertrophy of acinar cells between 15 and 30 days after birth. Early appearance of changes in α-mannose, α-glucosamine, and N-acetylglucosamine in secretory granules suggested that glucocorticoid may have acted to promote cell differentiation. The glucocorticoid had no effect on the proliferative potential of sublingual gland acinar cells around the weaning period.

Immunohistochemical study of the lymphatic vessels in major salivary glands of the rat.

This study was designed to examine whether lymphatic vessels are present in the lobules of major salivary glands in the rat. Immunostaining with an antibody against podoplanin, a lymphatic endothelial cell marker, was performed on sections of the submandibular, sublingual and parotid glands. Light microscopy demonstrated podoplanin-positive lymphatic vessels around the interlobular ducts and the interlobular arteries and veins in the interlobular connective tissue in all of the major salivary glands. No podoplanin-positive lymphatic vessels were found in the lobules. Electron microscopy also demonstrated lymphatic endothelial cells showing podoplanin expression only in the interlobular connective tissue. These findings suggest that the lymphatic system of the rat major salivary glands originates in the interlobular connective tissue, and not in the lobules.

The structure of tight junctions in mouse submandibular gland.

Salivary gland cells are joined by junctional complexes consisting of a tight junction (TJ), zonula adherens and one or more desmosomes. TJs regulate paracellular permeability, maintain separate apical and basolateral membrane domains, and serve as signaling centers. We examined TJs of mouse submandibular glands (SMG) in thin sections and freeze-fracture replicas. TJs between acinar cells and between intercalated duct cells had 2-6 parallel strands on the protoplasmic fracture face, with occasional branches, interconnections and free ends, and corresponding grooves on the extracellular face. Granular duct cell TJs had 2-30 strands, a depth of

Histological analysis of the sublingual gland in rats with streptozotocin-induced diabetes.

This study was designed to examine whether the sublingual gland parenchyma is influenced by the development of insulin-dependent diabetes mellitus. The sublingual glands of rats with streptozotocin-induced diabetes were examined by light and electron microscopy. In order to define the limiting membrane of mucous granules in more detail, samples processed by rapid freezing following by freeze-substitution in addition to chemical fixation were also prepared for electron microscopy. Light and electron microscopy showed vacuole-like structures considered to be lipid droplets in the cytoplasm of serous demilune cells, the largest reaching 4 microm in diameter. Electron microscopy of the chemically fixed samples revealed granule-like structures in addition to the mucous granules proper in the mucous cell cytoplasm. However, electron microscopy of the freeze-substitution fixed samples demonstrated no limiting membrane on the surface of the granule-like structures, although this was clearly observed on the surface of the mucous granules. Accordingly, the granule-like structures present in the mucous cell cytoplasm appeared to be lipid droplets. These findings suggest that the sublingual gland mucous cells become dysfunctional during the development of insulin-dependent diabetes mellitus, although to a slighter degree than the serous demilune cells.

Interaction between transcellular and paracellular water transport pathways through Aquaporin 5 and the tight junction complex.

To investigate potential physiological interactions between the transcellular and paracellular pathways of water transport, we asked whether targeted deletion of Aquaporin 5 (AQP5), the major transcellular water transporter in salivary acinar cells, affected paracellular transport of 4-kDa FITC-labeled dextran (FITC-D), which is transported through the paracellular but not the transcellular route. After i.v. injection of FITC-D into either AQP5 wild-type or AQP5-/- mice and saliva collection for fixed time intervals, we show that the relative amount of FITC-D transported in the saliva of AQP5-/- mice is half that in matched AQP5+/+ mice, indicating a 2-fold decrease in permeability of the paracellular barrier in mice lacking AQP5. We also found a significant difference in the proportion of transcellular vs. paracellular transport between male and female mice. Freeze-fracture electron microscopy revealed an increase in the number of tight junction strands of both AQP5+/+ and AQP5-/- male mice after pilocarpine stimulation but no change in strand number in female mice. Average acinar cell volume was increased by approximately 1.4-fold in glands from AQP5-/- mice, suggesting an alteration in the volume-sensing machinery of the cell. Western blots revealed that expression of Claudin-7, Claudin-3, and Occludin, critical proteins that regulate the permeability of the tight junction barrier, were significantly decreased in AQP5-/- compared with AQP5+/+ salivary glands. These findings reveal the existence of a gender-influenced molecular mechanism involving AQP5 that allows transcellular and paracellular routes of water transport to act in conjunction.

Morphological changes in the rat sublingual gland parenchyma with aging.

BACKGROUND: The characteristics of mucous cells in the aging rat sublingual gland were investigated in this study. Particular attention was paid to accumulated amyloid protein and changes of the properties of the secretory granules at the histochemical and ultrastructural level. OBJECTIVE: This study was designed to examine age-related morphological changes in the sublingual gland of male Wistar rats from 12 to 27 months. METHODS: For light microscopy, the sublingual glands were fixed with 10% neutral-buffered formalin, embedded in paraffin, and processed for Alcian blue, Congo red, and TUNEL staining. For transmission electron microscopy, some of the samples were fixed with Karnovsky solution, postfixed with 2% osmium tetroxide, and embedded in epoxy resin for pronase treatment. RESULTS: The sublingual gland showed slight shrinkage after 21 months. After 24 months, Congo red staining showed positive reaction to the intralobular connective tissue surrounding the terminal portions and to the interlobular connective tissue around the blood vessels and the excretory ducts. At 27 months, some of the granules in the serous demilunes had difficulty in digesting with pronase treatment. The appearance rate of TUNEL-positive cells was low in both mucous and serous portions during the observation period, though the positive cell number was higher in the serous than in the mucous portion. CONCLUSIONS: These findings indicate that the rat sublingual gland accumulates amyloid protein in the parenchyma and changes the properties of secretory granules of the acinar cells in the serous demilune with aging, though apoptosis of the parenchymal cells and the decrease of the gland weight are slight.

Granule types and their morphological changes in terminal cluster and acinar cells in the late pre- and early postnatal rat sublingual gland.

The developmental characteristics of serous cells appearing in the rat sublingual gland from the late prenatal to the early postnatal period were investigated in this study. Particular attention was paid to the morphological changes observed in the secretory granules at the histochemical and ultrastructural level. On prenatal day 18, granules with homogeneous high electron density (Type I granules), and mottled granules (Type II granules) with heterogeneous electron density appeared in the narrow luminar cytoplasm of cells constituting the terminal clusters. On prenatal day 19, these granules decreased in number and were replaced by bipartite granules (Type III granules) composed of a highly electron-dense core and a more electron-lucent rim. Pronase treatment almost completely digested the Type I and II granules and the electron-dense core of the Type III granules, although some of the Type I and II granules in serous demilunes at a later stage were insufficiently digested. On prenatal day 19.5, homogeneous granules of low electron density (Type IV granules) appeared in the terminal clusters and acini, and increased in number daily, making up 92.8% of the total granules on postnatal day 28. The granule morphology on electron microscopy, Alcian blue, and periodic acid-Schiff staining strongly suggested that Type I and II granules were serous granules, Type IV granules were mucous granules, and Type III granules were transforming-type granules. None of the secretory cells showed chromatin condensation, which is a characteristic of apoptosis. These findings suggest that the developing rat sublingual gland from the late prenatal to early postnatal period has numerous serous granules in the terminal clusters and acini, and that the majority of granules are replaced by mucous granules through transforming-type granules. In addition, because apoptotic figures of secretory cells could not be detected, it appears that most of the serous cells in the developing rat sublingual gland might have changed to mucous cells.

Morphological changes in mouse sublingual gland parenchyma subjected to chorda tympani resection.

Morphological changes in the mouse sublingual gland parenchyma subjected to parasympathetic nerve block were investigated. Mice were subjected to unilateral resection of the chorda tympani, near its point of joining with the lingual nerve. After 1, 2, 3, 5, 10 or 20 weeks, the mice were killed and their sublingual glands were removed and processed for light and electron microscopy. Two weeks after resection, the space between the adjoining lobules of the glands on the treated side began to be expanded, and by 10 weeks were 10 times the size of the spaces in the glands of the untreated mice. Three weeks after resection, the lobule area decreased to about 72% of the area of glands in the untreated mice and the acinus area to about 52%. However, no significant difference was seen between the numbers of acini in each group. Electron microscopy showed that the glands on the treated side contained fewer secretory granules than the glands in the untreated mice, though there was no difference in size. Neither the lobules of the glands on the treated side nor those of the glands of the untreated mice contained many TUNEL-positive cells. These findings suggest that following parasympathetic nerve resection, mouse sublingual gland acinar cells undergo atrophy with a reduction size rather than cell death.