A survey on the safety of anesthesia management provided by dental anesthesiologists in Japan: a 5-year survey by the Japanese Dental Society of Anesthesiology.

OBJECTIVES: The Japanese Dental Society of Anesthesiology (JDSA) has conducted a survey on the safety of anesthetic practice provided by dental anesthesiologists. This report includes information on the incidence of life-threating events, which is necessary for evaluating the safety of dental anesthesia. MATERIAL AND METHODS: This study was designed as a retrospective observational questionnaire-based survey. All 32 JDSA accredited training facilities participated in this study. The accredited facilities were requested to provide annual data on basic demographic information concerning anesthetic management during the 5-year period from 2014 to 2018, inclusive. Details regarding life-threatening events were also requested. RESULTS: During the survey period between 2014 and 2018, a total of 219,343 cases of anesthetic management (80,138 cases of general anesthesia, 127,819 cases of sedation, and 11,386 cases of monitoring) were reported by the 32 JDSA accredited training facilities. The overall incidence of life-threatening events occurring during clinical dental anesthesia was 2.14/10,000, while the incidence of anesthesia-related events was 0.96/10,000. No deaths arising from anesthesia-related events occurred. CONCLUSIONS: This is the first survey on clinical outcomes of dental anesthesia to be conducted. The survey results provide evidence supporting the safety of anesthetic management as performed by dental anesthesiologists. CLINICAL RELEVANCE: The results of this study will provide a basis for benchmarking the safety of dental anesthesia not only in Japan, but also around the world.

Fast-track preparation of lung specimens for electron microscope observations of the pulmonary endothelial glycocalyx.

The glycocalyx (GCX) covers the luminal surface of blood vessels and regulates vascular permeability. As GCX degradation predicts various types of vasculopathy, confirming the presence of this structure is useful for diagnosis. Since the GCX layer is very fragile, careful fixation is necessary to preserve its structure. We explored appropriate and feasible methodologies for visualizing the GCX layer using lung tissue specimens excised from anesthetized mice. Each specimen was degassed and immersed in Alcian blue (ALB) fixative solution, and then observed using electron microscopy. Specimens from septic mice were prepared as negative GCX controls. Using these immersion-fixed specimens, the GCX layer was successfully observed using both transmission and scanning electron microscopy; these observations were similar to those obtained using the conventional method of lanthanum perfusion fixation. Spherical aggregates of GCX were observed in the septic mouse specimens, and the GCX density was lower in the septic specimens than in the non-septic specimens. Of note, the presently reported methodology reduced the specimen preparation time from 6 to 2 days. We, therefore, concluded that our novel method could be applied to human lung specimens and could potentially contribute to the further elucidation of vasculopathies.

Cdc42 has important roles in postnatal angiogenesis and vasculature formation.

Cdc42, a Rho family low molecular weight G protein, has important roles in various cell functions, including cytoskeletal rearrangement, cell adhesion and cell proliferation and differentiation. To investigate the involvement of Cdc42 in the activities of vascular endothelial cells, we generated Cdc42 conditional knockout mice in which Cdc42 was time -specifically deficient in vascular endothelial cells (Cdc42 â€‹fl/fl; VE-Cad CreERT: Cdc42 cKO). When the Cdc42 gene was deleted after birth, Cdc42 cKO mice were smaller than the control mice, and died between postnatal day 8 (P8) and P10. Necropsy findings confirmed that these mice had various pathological aberrances in the vessels of most organs, such as blood flow congestion and blood cell invasion. Electron microscopic observations also revealed that capillary endothelial cells were detached from the basement membrane as well as phagocytosis of dead endothelial cells induced by macrophages. Moreover, vascular sprouting from aortic rings induced by VEGF-A was diminished in samples from the Cdc42 cKO mice because of an endothelial cell proliferation defect. These results suggest that Cdc42 in vascular endothelial cells has important roles in blood vessel formation after birth.

Nasopharyngeal Tube Effects on Breathing during Sedation for Dental Procedures: A Randomized Controlled Trial.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Dental procedures under sedation can cause hypoxic events and even death. However, the mechanism of such hypoxic events is not well understood. WHAT THIS ARTICLE TELLS US THAT IS NEW: Apnea and hypopnea occur frequently during dental procedures under sedation. The majority of the events are not detectable with pulse oximetry. Insertion of a nasal tube with small diameter does not reduce the incidence of apnea/hypopnea. BACKGROUND: Intravenous sedation is effective in patients undergoing dental procedures, but fatal hypoxemic events have been documented. It was hypothesized that abnormal breathing events occur frequently and are underdetected by pulse oximetry during sedation for dental procedures (primary hypothesis) and that insertion of a small-diameter nasopharyngeal tube reduces the frequency of the abnormal breathing events (secondary hypothesis). METHODS: In this nonblinded randomized control study, frequency of abnormal breathing episodes per hour (abnormal breathing index) of the patients under sedation for dental procedures was determined and used as a primary outcome to test the hypotheses. Abnormal breathing indexes were measured by a portable sleep monitor. Of the 46 participants, 43 were randomly allocated to the control group (n = 23, no nasopharyngeal tube) and the nasopharyngeal tube group (n = 20). RESULTS: In the control group, nondesaturated abnormal breathing index was higher than the desaturated abnormal breathing index (35.2 [20.6, 48.0] vs. 7.2 [4.1, 18.5] h, difference: 25.1 [95% CI, 13.8 to 36.4], P < 0.001). The obstructive abnormal breathing index was greater than central abnormal breathing index (P < 0.001), and half of abnormal breathing indexes were followed by irregular breathing. Despite the obstructive nature of abnormal breathing, the nasopharyngeal tube did not significantly reduce the abnormal breathing index (48.0 [33.8, 64.4] h vs. 50.5 [36.4, 63.9] h, difference: -2.0 [95% CI, -15.2 to 11.2], P = 0.846), not supporting the secondary hypothesis. CONCLUSIONS: Patients under sedation for dental procedure frequently encounter obstructive apnea/hypopnea events. The majority of the obstructive apnea/hypopnea events were not detectable by pulse oximetry. The effectiveness of a small-diameter nasopharyngeal tube to mitigate the events is limited.

Cooperation of Rho family proteins Rac1 and Cdc42 in cartilage development and calcified tissue formation.

Rac1 and Cdc42, Rho family low molecular weight G proteins, are intracellular signaling factors that transmit various information from outside to inside cells. Primarily, they are known to control various biological activities mediated by actin cytoskeleton reorganization, such as cell proliferation, differentiation, and apoptosis. In order to investigate the functions of Rac1 and Cdc42 in bone formation, we prepared cartilage-specific double conditional knockout mice, Rac1fl/fl; Cdc42fl/fl; Col2-Cre (Rac1: Cdc42 dcKO mice), which died just after birth, similar to Cdc42fl/fl; Col2-Cre mice (Cdc42 cKO mice). Our findings showed that the long tubule bone in Rac1: Cdc42 dcKO mice was shorter than that in Rac1fl/fl; Col2-Cre mice (Rac1 cKO mice) and Cdc42 cKO mice. Abnormal skeleton formation was also observed and disordered columnar formation in the growth plate of the Rac1: Cdc42 dcKO mice was more severe as compared to the Rac1 cKO and Cdc42 cKO mice. Together, these results suggest that Rac1 and Cdc42 have cooperating roles in regulation of bone development.

IL-1ß suppresses nephronectin expression in osteoblasts via ERK1/2 and JNK.

Nephronectin (Npnt), an extracellular matrix protein, is considered to play critical roles in development of various tissues and their functions. In basic science experiments, we found that interleukin-1ß (IL-1ß), well known to have an important role in inflammatory response, inhibited Npnt gene expression in MC3T3-E1 cells, a mouse osteoblastic cell line. The purpose of this study was to investigate mechanisms that govern the regulation of Npnt gene expression by IL-1ß in osteoblasts.

Structural Behavior of the Endothelial Glycocalyx Is Associated With Pathophysiologic Status in Septic Mice: An Integrated Approach to Analyzing the Behavior and Function of the Glycocalyx Using Both Electron and Fluorescence Intravital Microscopy.

BACKGROUND: The endothelial surface layer (ESL) regulates vascular permeability to maintain fluid homeostasis. The glycocalyx (GCX), which has a complex and fragile ultrastructure, is an important component of the ESL. Abnormalities of the GCX have been hypothesized to trigger pathological hyperpermeability. Here, we report an integrated in vivo analysis of the morphological and functional properties of the GCX in a vital organ. METHODS: We examined the behavior of the ESL and GCX, using both electron microscopy (EM) and intravital microscopy (IVM). We also compared morphological changes in the ESL of mouse skin in a glycosidase-treated and control group. Combined approaches were also used to examine both morphology and function in a lipopolysaccharide-induced septic model and the pathophysiological features of leukocyte-endothelial interactions and in vivo vascular permeability. RESULTS: Using IVM, we identified an illuminated part of the ESL as the GCX and confirmed our observation using morphological and biochemical means. In septic mice, we found that the GCX was thinner than in nonseptic controls in both an EM image analysis (0.98 ± 2.08 nm vs 70.68 ± 36.36 nm, P< .001) and an IVM image analysis (0.36 ± 0.15 µm vs 1.07 ± 0.39 µm, P< .001). Under septic conditions, syndecan-1, a representative core protein of the GCX, was released into the blood serum at a higher rate in septic animals (7.33 ± 3.46 ng/mL) when compared with controls (below the limit of detection, P< .001). Significant increases in leukocyte-endothelial interactions, defined as the numbers of rolling or firm-sticking leukocytes, and molecular hyperpermeability to the interstitium were also observed after GCX shedding in vivo. CONCLUSIONS: Using IVM, we visualized an illuminated part of the ESL layer that was subsequently confirmed as the GCX using EM. Severe sepsis induced morphological degradation of the GCX, accompanied by shedding of the syndecan-1 core protein and an increase in leukocyte-endothelial interactions affecting the vascular permeability. Our in vivo model describes a new approach to deciphering the relationship between structural and functional behaviors of the GCX.

Anesthetic Management Using a Laryngeal Mask Airway in a Child With Congenital Bronchial Atresia.

Congenital bronchial atresia is a relatively rare malformation that causes a segmental obstruction of the bronchus during the fetal period. The peripheral lung distal from the obstructed bronchus becomes hyperinflated because of the unidirectional flow through collateral check-valve entry. Positive pressure ventilation during general anesthesia may cause a rupture of the bulla, resulting in pneumothorax. An 8-year-old girl, who had to undergo oral surgery, was diagnosed as having congenital bronchial atresia and one-fifth of her lung was poorly ventilated. We planned to perform general anesthesia under spontaneous respiration using a laryngeal mask, which was well tolerated.

The Amount of Fluid Given During Surgery That Leaks Into the Interstitium Correlates With Infused Fluid Volume and Varies Widely Between Patients.

BACKGROUND: The revised Starling law suggests that intravenously infused fluid may leak into the interstitium and not remain in the intravascular space. This hypothesis is supported by clinical findings that postoperative weight gain is proportional to the amount of infused fluid. The distribution of intravenously administered fluid between the interstitium and intravascular space deserves evaluation, as postoperative weight gain because of intraoperative infusion is an important risk factor for postoperative adverse events. We quantitatively estimated fluid movement in patients undergoing orthognathic surgery by performing a volume kinetic study using hemoglobin concentration as a marker of dilution. METHODS: Forty-one patients scheduled to undergo orthognathic surgery were enrolled in this study. The arterial hemoglobin concentration was measured at each procedural step. Acute normovolemic hemodilution was induced by withdrawing 400 mL of blood followed by the infusion of a known amount of hydroxyethyl starch, enabling the initial blood volume to be estimated. The dilution rate of the arterial hemoglobin concentration enabled the volume of fluid in the intravascular space to be quantified. The fluid volume that leaked into the interstitium was then calculated based on the change in the estimated intravascular plasma volume. RESULTS: The blood volume estimated via this method was close to the value derived from a previously published formula. The mean volume of crystalloid infused as a maintenance fluid was 2062 ± 408 mL, ranging from 1220 to 3050 mL. None of the cases required blood product transfusion. The amount of infused fluid that remained intravascular varied widely from 2.0 to 35.7 mL/kg (mean, 12.0 ± 8.2 mL) after surgery, corresponding to 5.3% to 95.7% of the infused volume. The change in intravascular fluid volume during surgery was not strongly correlated with the infusion amount (Pearson correlation analysis: r = -0.05, P = .75, -0.44 < ρ ≤ 0.35, confidence intervals; Spearman correlation analysis: r = -0.14, P = .38, -0.51 < ρ ≤ 0.27). However, the amount of fluid that leaked into the interstitium during surgery did correlate with the infusion amount (Pearson correlation analysis: r = 0.42, P = .01, 0.03 < ρ ≤ 0.70; Spearman correlation analysis: r =0.45, P = .003, 0.07 < ρ ≤ 0.72). CONCLUSIONS: We found that the increase in intravascular fluid volume caused by intravenous fluid administration was not correlated strongly with the volume of infused fluid. Instead, the amount of fluid leakage into the interstitial space depended on the infused fluid volume. This clinical result supports the revised Starling law, which suggests that intravascular fluid may often leak into the interstitium. More work is needed to better understand the factors governing leakage of infused fluid into the interstitial space.

Novel swine model of transfusion-related acute lung injury.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a life-threatening complication of blood transfusion. Antibodies against human leukocyte antigens in donors' plasma are the major causes of TRALI. Several animal models of TRALI have been developed, and the mechanism underlying TRALI development has been extensively investigated using rodent models. Although sheep models of nonimmune TRALI have been developed, large-animal models of antibody-mediated TRALI are not yet available. STUDY DESIGN AND METHODS: To develop a swine model of TRALI, male Clawn strain miniature pigs were used. A monoclonal antibody (MoAb) against swine leukocyte antigens (SLAs) Class I (4G8, 0.3 or 1.0 mg/kg body weight [BW]) and a control antibody (1.0 mg/kg BW) were injected into the peripheral vein after priming with or without 1 µg/kg BW lipopolysaccharide (LPS; n = 3 each). Lung injury was assessed using PaO2 /FiO2 (P/F) ratio and by chest X-ray imaging. Histopathologic analysis was also conducted. RESULTS: Lung injury could be induced by injecting 4G8 at an amount of 1.0 mg/kg BW, after LPS. The P/F ratio 90 minutes after the administration of 4G8 significantly decreased (p < 0.05). Bilateral infiltration was shown in chest X-ray imaging. Lung injury was confirmed by histopathologic analysis. CONCLUSION: Lung injury in pigs was successfully induced by anti-SLA MoAb. Priming with LPS is a prerequisite for inducing lung injury and the amount of the antibody is a critical condition.

[Perioperative fluid therapy for surgical patients with chronic kidney disease].

Chronic kidney disease (CKD) often accompanies cardiovascular complications, causing postoperative morbidity and even mortality. Since fluid and electrolyte homeostasis is deregulated in CKD patients, fluid therapy itself may cause postoperative morbidity. Recent studies have shown that forced diuresis through fluid overload offers no renoprotective effect and instead has harmful consequences. Fluid overload should be avoided, and the volume load should be used as the rationale for controlling hemodynamics. The emerging concept of a "zero-fluid balance policy" may be beneficial even for CKD patients. Hydroxyethylstarch might not be preferentially used for CKD patients. Hydroxyethylstarch is not contraindicated for CKD patients except in cases with long-term accumulation caused by increased vascular permeability, such as cases with sepsis, as long as an efficient volume expansion is beneficial to the patient. The regulation of renal function through the endocrine system (i.e., renin-angiotensin-aldosterone and vasopressin) is a key target for protecting the kidney in CKD. The recent development of a receptor blocker targeting these endocrine systems may be beneficial for correcting the fluid balance caused by excess intraoperative fluid therapy. The main issue for fluid therapy in surgical CKD patients may not be the quantity of fluid, but rational intervention affecting the endocrine system.

[Anesthetic management of a patient with pulmonary arterial hypertension undergoing caesarean section].

A 38-year-old woman on medical therapy for Basedow disease and hypertension with a history of recent heart failure became pregnant. At the 13th week of gestation, her echocardiography showed pulmonary hypertension with 63 mmHg of estimated systolic pulmonary arterial pressure. At the 26th week of gestation, she was admitted to our hospital with dyspnea and uncontrolled hypertension. After medical treatments, elective caesarean section was scheduled at the 30th week of gestation. While monitoring continuously arterial blood pressure and central venous pressure, continuous infusion of prostaglandin E1 was initiated. After epidural anesthesia had been established, surgical procedure was safely performed. The patient was discharged 9 days after surgery, and her estimated systolic pulmonary arterial pressure dropped to 35 mmHg on echocardiography 2 months after the operation. We speculate that pregnancy induced her severe pulmonary hypertension.

Control of Tongue Position in Patients with Obstructive Sleep Apnea: Concept and Protocol for a Randomized Controlled Crossover Trial.

We hypothesize that the control of tongue position using a newly developed tongue position retainer, where the tongue is held in a protruded position (i.e., intervention A) or in its resting position (i.e., intervention B), is effective for maintaining upper airway patency in obstructive sleep apnea (OSA) compared with no control of tongue position. This is a randomized, controlled, non-blinded, crossover, and two-armed trial (i.e., sequence AB/BA) in 26 male participants (i.e., sample size) who are scheduled to undergo a dental operation under intravenous sedation with OSA (10 ≤ respiratory event index < 30/h). Participants will be randomly allocated into either sequence by a permuted block method, stratified by body mass index. Under intravenous sedation, participants will undergo two interventions, separated by a washout period after receiving intervention A or intervention B using a tongue position retainer after baseline evaluation, before each intervention is provided. The primary outcome is the abnormal breathing index of apnea as determined by the frequency of apnea per hour. We expect that, compared with no control of tongue position, both intervention A and intervention B will improve the abnormal breathing events with superior effects achieved by the former, offering a therapeutic option for OSA.

Exploring the pathophysiological mechanism of interstitial edema focusing on the role of macrophages and their interaction with the glycocalyx.

OBJECTIVES: Glycocalyx lines the vascular intraluminal space that regulates fluid movement between the intra- and extra-vascular compartments. The depletion of glycocalyx (GCX) is associated with leukocyte accumulation, possibly causing the endothelial cells to become hyperpermeable in various organs, including oral tissues. Whether neutrophils or macrophages are responsible for developing interstitial edema remains controversial. We explored the pathophysiological mechanism of interstitial edema by examining the role of reactive neutrophils and macrophages and their interactions with GCX. METHODS: An anti-MHC class I antibody was administered intravenously to male BALB/c mice to induce pulmonary edema. Pulmonary edema was evaluated by measuring the lung wet-to-dry weight ratio. Changes in the GCX were evaluated by electron microscopy and measurements of the serum level of soluble syndecan-1. Heparin sulfate was administered to examine its protective effect on the GCX. The macrophages were depleted using clodronate to examine their role in developing edema. RESULTS: The GCX degradation induced by the anti-MHC class I antibody was accompanied by increased serum syndecan-1 and heparan sulfate levels. Macrophage depletion inhibited the development of pulmonary edema, and the administration of supplemental heparin suppressed the edema. CONCLUSIONS: We demonstrated that the degradation of the GCX induced by the anti-MHC class I antibody was suppressed by macrophage depletion. These results suggest that macrophages may play a key role in interstitial edema. Heparin inhibited both the degradation of the GCX and interstitial edema. This study's results may be extrapolated to develop an interventional strategy for inhibiting interstitial edema in various organs.

[Impact of intraoperative fluid therapy and transfusion on the postoperative outcome].

Recent clinical studies suggest that intraoperative liberal crystalloid infusion causes postoperative edema and various systemic and local complications. Weight gain may be a promising predictor for postoperative complications. "No intravenous infusion should be continued simply because it is a 'routine' component of clinical care." as GIFTASUSP (British consensus of guidelines on intravenous fluid therapy for adult surgical patients) has suggested. Optimal titration of fluid infusion should be considered on the individual basis. Clinical studies may have suggested that approximately 2000-3000 ml shift of extracellular fluid would be the acceptable level not worsening postoperative outcome. Although the safety of transfusion itself has improved, rare complications such as TRALI are still to be aware of. Immediate transfusion for rapid and massive bleeding should salvage life and reduce complication after resuscitation. It is still under research and debate whether transfusion would promote cancer. Unnecessary transfusion should be avoided and any effort to reduce transfusion should be recommended. Too-much or too-low infusion and transfusion causes adverse outcome. Optimizing the volume may be the key for ideal postoperative outcome.

Optimal Timing of Intravenous Acetaminophen Administration for Postoperative Analgesia.

OBJECTIVE: Acetaminophen (APAP) is widely used as an analgesic for postoperative pain relief. However, the pharmacokinetic-pharmacodynamic (PK-PD) properties of intravenous APAP administration remain unclear. We developed a PK-PD model in adult volunteers. METHODS: APAP (1 g) was intravenously administered to 15 healthy volunteers. The pain equivalent current (PEC) was then measured using the pulse current, corresponding to the quantitative value of pain perception. The PK model was developed using a 2-compartment model, and the PD model was developed using a linear model and an effect compartment model. RESULTS: APAP plasma concentration peaked just administration, whereas PEC significantly increased at 90 minutes and lasted through the experimental period (300 minutes). APAP plasma concentrations and PEC were processed for use in the PK-PD model. The developed PK-PD model delineates the analgesic effect profile, which peaked at 188 minutes and lasted until 327 minutes. CONCLUSION: We developed the PK/PD model for APAP administered intravenously. The analgesic effect can be expected ∼90 minutes after administration and to last >5 hours. It is suggested that APAP be administered ∼90 minutes prior to the onset of anticipated postoperative pain.

Anesthesia Management of a Patient With Familial Cold Autoinflammatory Syndrome: A Case Report.

Familial cold autoinflammatory syndrome (FCAS) is a rare phenotype of cryopyrin-associated periodic syndrome (CAPS) and is characterized by repetitive systemic inflammation triggered by cold stimulation. Recently, we treated a 13-year-old female with FCAS/CAPS scheduled to undergo removal of an impacted tooth. To minimize perioperative heat loss, a forced-air warming system was utilized to prewarm the patient for 10 minutes before induction of general anesthesia. The patient's core and peripheral temperatures were monitored with axillary, superficial temporal artery, and rectal thermometers. The difference in temperatures at these 3 locations decreased to 0.4° C within 60 minutes as a result of the forced-air warming system before induction. Perioperative use of the warming system successfully prevented the occurrence any significant redistribution hypothermia and any symptoms of FCAS/CAPS.

Intrinsic properties and synaptic connectivity of Phox2b-expressing neurons in rat rostral parvocellular reticular formation.

The paired-like homeobox 2b gene (Phox2b) is critical for the development of the autonomic nervous system. We have previously demonstrated the distinct characteristics of Phox2b-expressing (Phox2b+) neurons in the reticular formation dorsal to the trigeminal motor nucleus (RdV), which are likely related to jaw movement regulation. In this study, we focused on Phox2b+ neurons in the rostral parvocellular reticular formation (rPCRt), a critical region for controlling orofacial functions, using 2-11-day-old Phox2b-EYFP rats. Most Phox2b+ rPCRt neurons were glutamatergic, but not GABAergic or glycinergic. Approximately 65 % of Phox2b+ rPCRt neurons fired at a low frequency, and approximately 24 % of Phox2b+ rPCRt neurons fired spontaneously, as opposed to Phox2b+ RdV neurons. Stimulation of the RdV evoked inward postsynaptic currents in more than 50 % of Phox2b+ rPCRt neurons, while only one Phox2b+ rPCRt neuron responded to stimulation of the nucleus of the solitary tract. Five of the 10 Phox2b+ neurons sent their axons that ramified within the trigeminal motor nucleus (MoV). Of these, the axons of the two neurons terminated within both the MoV and rPCRt. Our findings suggest that Phox2b+ rPCRt neurons have distinct electrophysiological and synaptic properties that may be involved in the motor control of feeding behavior.

[Albumin and artificial colloids for massive bleeding].

Rapid and massive bleeding has to be counteracted by efficient volume restoration against rapid loss of intravascular volume. There are two phases of volume management for massive bleeding, uncontrolled phase and controlled phase. During initial uncontrolled phase, rapid infusion of crystalloid with RCC (red cell concentrate) is the first choice of volume management to prevent shock and profound decline of hemoglobin level. After shifting to the next controlled phase, artificial colloids and RCC become the next choice for efficient volume restoration. Although albumin has not been proven to improve prognosis in clinical studies, anti-inflammatory effect could be expected. Albumin infusion may be followed in this phase, and also albumin concentrate may be beneficial to reduce subsequent tissue edema due to massive infusion of crystalloid and artificial colloid. A new generation of hydroxyethyl starch is a promising blood substitute, designed with minimum side effect. Although renal damage especially in septic patient and coagulation disorder are theoretically suspected, beneficial effect as volume expansion overwhelms these stochastic side effects. Since the side effect depends on the dose and how much it remains in the body, a purposeful use during volume expansion phase should be recommended.

Exploring the mechanism of hyperpermeability following glycocalyx degradation: Beyond the glycocalyx as a structural barrier.

Pathological hyperpermeability is a morbidity involved in various systemic diseases, including sepsis. The endothelial glycocalyx layer (GCX) plays a key role in controlling vascular permeability and could be a useful therapeutic target. The purpose of the present study was to analyze the functional role of the GCX in vascular permeability and to elucidate its role in pathological conditions. First, male C57BL/6J wild-type mice were used as in vivo models to study the effects of sepsis and the pharmacological digestion of glycosaminoglycans (GAGs) on the GCX. Vascular permeability was evaluated using fluorescein isothiocyanate (FITC)-labeled dextran. Second, the changes in gene expression in vascular endothelial cells after GAGs digestion were compared between a control and a septic model using RNA sequencing. In the in vivo study, the glycocalyx was depleted in both the septic model and the group with pharmacological GAGs digestion. FITC-labeled dextran had leaked into the interstitium in the septic group, but not in the other groups. In the in vitro study, histamine decreased the transendothelial electrical resistance (TEER), indicating an increase in permeability. GAGs digestion alone did not change the TEER, and the effect of histamine on the TEER was not enhanced by GAGs digestion. The gene expression profiles after GAGs digestion differed from the control condition, indicating the initiation of signal transduction. In conclusion, we demonstrated that the structural barrier of the GCX does not solely determine the fluid permeability of the endothelial layer, since enzymatic depletion of the GCX did not increase the permeability. The gene expression findings suggest that the digestion of GAGs alone did not induce hyperpermeability either in vitro or in vivo, although sepsis did induce hyperpermeability. While GAGs degradation by itself does not appear to induce hyperpermeability, it may play an important role in initiating signal transductions.