Conventional risk prediction models fail to accurately predict mortality risk among patients with coronavirus disease 2019 in intensive care units: a difficult time to assess clinical severity and quality of care.

Since the start of the coronavirus disease 2019 (COVID-19) pandemic, it has remained unknown whether conventional risk prediction tools used in intensive care units are applicable to patients with COVID-19. Therefore, we assessed the performance of established risk prediction models using the Japanese Intensive Care database. Discrimination and calibration of the models were poor. Revised risk prediction models are needed to assess the clinical severity of COVID-19 patients and monitor healthcare quality in ICUs overwhelmed by patients with COVID-19.

Lung-thorax compliance measured during a spontaneous breathing trial is a good index of extubation failure in the surgical intensive care unit: a retrospective cohort study.

BACKGROUND: Extubation failure is associated with mortality and morbidity in the intensive care unit. Ventilator weaning protocols have been introduced, and extubation is conducted based on the results of a spontaneous breathing trial. Room for improvement still exists in extubation management, and additional objective indices may improve the safety of the weaning and extubation process. Static lung-thorax compliance reflects lung expansion difficulty that is caused by several conditions, such as atelectasis, fibrosis, and pleural effusion. Nevertheless, it is not used commonly in the weaning and extubation process. In this study, we investigated whether lung-thorax compliance is a good index of extubation failure in adults even when patients pass a spontaneous breathing trial. METHODS: In a single-center, retrospective cohort study, patients over 18 years of age were mechanically ventilated, weaned with proportional assist ventilation, and underwent a spontaneous breathing trial process in surgical intensive care units of Kagawa University Hospital from July 2014 to June 2016. Extubation failure was the outcome measure of the study. We defined extubation failures as when patients were reintubated or underwent non-invasive positive-pressure ventilation within 24 h after extubation. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the clinical involvement of several parameters. The area under the curve (AUC) was calculated to assess the discriminative power of the parameters. RESULTS: We analyzed 173 patients and compared the success and failure groups. Most patients (162, 93.6%) were extubated successfully, and extubation failed in 11 patients (6.4%). The averages of lung-thorax compliance values in the success and failure groups were 71.9 ± 23.0 and 43.3 ± 14.6 mL/cmH2O, respectively, and were significantly different (p < 0.0001). In the ROC curve analysis, the AUC was highest for lung-thorax compliance (0.862), followed by the respiratory rate (0.821), rapid shallow breathing index (0.781), Acute Physiology and Chronic Health Evaluation II score (0.72), heart rate (0.715), and tidal volume (0.695). CONCLUSIONS: Lung-thorax compliance measured during a spontaneous breathing trial is a potential indicator of extubation failure in postoperative patients.

Guanylyl Cyclase A in Both Renal Proximal Tubular and Vascular Endothelial Cells Protects the Kidney against Acute Injury in Rodent Experimental Endotoxemia Models.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Natriuretic peptides are used, based on empirical observations, in intensive care units as antioliguric treatments. We hypothesized that natriuretic peptides prevent lipopolysaccharide-induced oliguria by activating guanylyl cyclase A, a receptor for natriuretic peptides, in proximal tubules and endothelial cells. METHODS: Normal Sprague-Dawley rats and mice lacking guanylyl cyclase A in either endothelial cells or proximal tubular cells were challenged with lipopolysaccharide and assessed for oliguria and intratubular flow rate by intravital imaging with multiphoton microscopy. RESULTS: Recombinant atrial natriuretic peptide efficiently improved urine volume without changing blood pressure after lipopolysaccharide challenge in rats (urine volume at 4 h, lipopolysaccharide: 0.6 ± 0.3 ml · kg · h; lipopolysaccharide + fluid resuscitation: 4.6 ± 2.0 ml · kg · h; lipopolysaccharide + fluid resuscitation + atrial natriuretic peptide: 9.0 ± 4.8 ml · kg · h; mean ± SD; n = 5 per group). Lipopolysaccharide decreased glomerular filtration rate and slowed intraproximal tubular flow rate, as measured by in vivo imaging. Fluid resuscitation restored glomerular filtration rate but not tubular flow rate. Adding atrial natriuretic peptide to fluid resuscitation improved both glomerular filtration rate and tubular flow rate. Mice lacking guanylyl cyclase A in either proximal tubules or endothelium demonstrated less improvement of tubular flow rate when treated with atrial natriuretic peptide, compared with control mice. Deletion of endothelial, but not proximal tubular, guanylyl cyclase A augmented the reduction of glomerular filtration rate by lipopolysaccharide. CONCLUSIONS: Both endogenous and exogenous natriuretic peptides prevent lipopolysaccharide-induced oliguria by activating guanylyl cyclase A in proximal tubules and endothelial cells.

Oxygen management in mechanically ventilated patients: A multicenter prospective observational study.

PURPOSE: To observe arterial oxygen in relation to fraction of inspired oxygen (FIO2) during mechanical ventilation (MV). MATERIALS AND METHODS: In this multicenter prospective observational study, we included adult patients required MV for >48h during the period from March to May 2015. We obtained FIO2, PaO2 and SaO2 from commencement of MV until the 7th day of MV in the ICU. RESULTS: We included 454 patients from 28 ICUs in this study. The median APACHE II score was 22. Median values of FIO2, PaO2 and SaO2 were 0.40, 96mmHg and 98%. After day two, patients spent most of their time with a FIO2 between 0.3 and 0.49 with median PaO2 of approximately 90mmHg and SaO2 of 97%. PaO2 was ≥100mmHg during 47.2% of the study period and was ≥130mmHg during 18.4% of the study period. FIO2 was more likely decreased when PaO2 was ≥130mmHg or SaO2 was ≥99% with a FIO2 of 0.5 or greater. When FIO2 was <0.5, however, FIO2 was less likely decreased regardless of the value of PaO2 and SaO2. CONCLUSIONS: In our multicenter prospective study, we found that hyperoxemia was common and that hyperoxemia was not corrected.

D-allose ameliorates cisplatin-induced nephrotoxicity in mice.

Cisplatin (cis-diamminedichloroplatinum II) is a potent antineoplastic agent widely used to treat various forms of cancer. However, its therapeutic use is limited because of dose-dependent nephrotoxicity. Inflammatory mechanisms may play an important role in the pathogenesis of cisplatin nephrotoxicity. D-allose is an aldo-hexose present in nature that recently has been demonstrated to inhibit production of inflammatory mediators in septic kidneys. The purpose of this study was to determine the protective effects of D-allose on cisplatin-induced nephrotoxicity. Cisplatin (20 mg/kg) was administered by intraperitoneal injection to mice in the cisplatin group and the cisplatin plus D-allose group, as was normal saline to control group mice. D-allose was intraperitoneally administered immediately after cisplatin injection. Serum and renal tumor necrosis factor (TNF)-alpha concentrations, renal monocyte chemoattractant protein-1 (MCP-1; a chemotactic factor for monocytes), renal function, histological changes and renal cortex neutrophil infiltration were determined 72 h after cisplatin injection. The serum TNF-alpha concentration in the cisplatin plus D-allose (400 mg/kg body weight) group significantly decreased in comparison with that in the cisplatin group. The renal TNF-alpha and MCP-1 concentrations in the cisplatin plus D-allose group significantly decreased in comparison with those in the cisplatin group. Neutrophil infiltration in the cisplatin plus D-allose group was significantly lower than that in the cisplatin group. Cisplatin-induced renal dysfunction and renal tubular injury scores were attenuated by D-allose treatment. These results reveal that D-allose attenuates cisplatin-induced nephrotoxicity by suppressing renal inflammation. Hence, D-allose may become a new therapeutic candidate for treatment of cisplatin-induced nephrotoxicity.

[Remifentanil is useful for cardiovascular stability during cesarean delivery in a parturient with Marfan's syndrome].

A 25-year-old parturient with Marfan's syndrome was scheduled for cesarean delivery. She suffered with severe scoliosis and asymptomatic aortic root dilatation. To establish a cardiovascular stability and prevent aortic dissection perioperatively, we selected the use of remifentanil, an ultra-short acting opioid analgesic with general anesthesia. General anesthesia was induced with remifentanil (0.2 microg x kg(-1) x min(-1)), propofol (100 mg), and vecuronium bromide (10 mg). Anesthesia was maintained with 100% O2, sevoflurane (1-1.5%), and remifentanil (0.2-0.25 microg x kg(-1) x min(-1)). She remained hemodynamically stable during surgery. A lively infant was delivered and Apgar scores were 8 and 9 at 1 and 5 min, respectively. Their post-delivery courses were uneventful. Remifentanil was useful for anesthetic management in a pregnant patient with Marfan's syndrome undergoing cesarean delivery, although attention to infant's respiratory condition should be paid because remifentanil can cross the placenta.

Atrial natriuretic peptide enhances recovery from ischemia/reperfusion-induced renal injury in rats.

Recovery from ischemic acute kidney injury requires the replacement of damaged tubular cells. This repair process involves epidermal growth factor (EGF) synthesized in medullary the thick ascending limbs (mTAL) of Henle. Atrial natriuretic peptide (ANP), a hormone synthesized by the cardiac atria, increases glomerular filtration rate and renal medullary blood flow. However, the effects of ANP on renal recovery after I/R-induced renal injury remain unclear. We therefore examined whether human ANP enhances recovery from I/R-induced renal injury by reducing damage to EGF-producing kidney cells in a rat model. Male Wistar rats weighing 200-240 g were observed for 48 h after reperfusion following 45-min renal ischemia. Rats were intravenously administered alpha-human ANP (alpha-hANP) at 0.2 microg/kg/min beginning immediately after ischemia and continuing for 2 h after reperfusion. Outer medullary blood flow (OMBF), EGF mRNA, serum blood urea nitrogen (BUN) and creatinine levels as indicators of glomerular function were measured, while urinary N-acetyl beta-D-glucosaminidase (NAG) was used as a specific indicator of proximal tubular function. OMBF was increased by alpha-hANP after reperfusion and maintained significantly higher mRNA level of EGF in the kidney 24 h after reperfusion. I/R-induced increases in serum concentrations of BUN and creatinine and urinary concentrations of NAG were also reduced by alpha-hANP, with improved histopathological changes, including acute tubular necrosis at 24-48 h after reperfusion. This report is the first to demonstrate that alpha-hANP accelerates recovery following renal ischemic insult by reducing the damage to EGF-producing kidney cells.

Protective action of D-ribose against renal injury caused by ischemia and reperfusion in rats with transient hyperglycemia.

Hyperglycemia amplifies the inflammatory state after ischemia/reperfusion (I/R), and activated neutrophils have been implicated in the development of I/R-induced renal injuries. D-ribose is a naturally occurring monosaccharide found in all living cells. In this study, we examined whether D-ribose attenuates I/R-induced renal injury by reducing neutrophil activation in rats with transient hyperglycemia. Male Wistar rats were divided into sham (n = 24), control (n = 64), and D-ribose (n = 32) groups. Rats received intraperitoneal injection of glucose (3 g/kg) 30 min before induction of ischemia to induce transient hyperglycemia. Anesthetized rats underwent right nephrectomy and subsequent occlusion of the left renal artery and vein for 45 min. D-ribose (400 mg/kg) was intravenously administered 30 min before induction of ischemia. D-ribose significantly reduced the degree of the I/R-induced increases in renal concentrations of cytokine-induced neutrophil chemoattractant-1 (a chemotactic factor for the activation of neutrophils and chemotaxis to the site of injury) and myeloperoxidase (an indicator of neutrophils infiltration). D-ribose also reduced the I/R-induced increases in serum levels of blood urea nitrogen and creatinine, and improved histological changes, including acute tubular necrosis in the corticomedullary junction fields. These results indicate that D-ribose reduces the I/R-induced acute renal injury in rats with transient hyperglycemia, probably by reducing neutrophil activation. D-ribose might thus be useful for surgical procedures, such as renal transplant surgery, under hyperglycemia.

Hypoxia-inducible factor-1 alpha has a key role in hypoxic preconditioning.

Sublethal hypoxia induces tolerance to subsequent hypoxic insults in a process known as hypoxic preconditioning (HP). Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a key transcription protein involved in the mechanism of HP. In this study, we investigated the effects of HP on tissue oxygenation and expression of HIF-1 alpha gene targets in the brain using neural cell-specific HIF-1 alpha-deficient mice. The animals were exposed to 8% oxygen for 3 hours. Twenty-four hours later, the oxygen partial pressure (pO(2)) of brain tissue and gene expression were measured during hypoxia. HP improved the pO(2) of brain tissue during subsequent hypoxia with upregulated inducible nitric oxide synthase in wild-type mice, whereas HP had no detectable effect in the mutant mice. Our results indicate that the protective effects of HP may be partially mediated by improving tissue oxygenation via HIF-1 alpha and inducible nitric oxide synthase.

D-ribose attenuates ischemia/reperfusion-induced renal injury by reducing neutrophil activation in rats.

The ischemia/reperfusion (I/R) represents a common pathological mechanism that causes renal injuries. A monosaccharide D-allose has been shown to inhibit neutrophil activation, which is involved in the I/R-induced organ injuries. We therefore examined the role of D-ribose in the I/R-induced renal injury using a rat model. D-ribose, a monosaccharide found in all living cells, serves as a key component of adenosine-5'-triphosphate and nicotinamide adenine dinucleotide. Male Wistar rats were divided into the sham, control and D-ribose groups. In the control and D-ribose groups, rats were subjected to 45 min of left renal ischemia, followed by 24 h of reperfusion, while the I/R procedure was not performed in the sham group. Rats were intravenously administered D-ribose (sham group and D-ribose group, 400 mg/kg) or saline (control group) 30 min before ischemia. Blood urea nitrogen (BUN), serum creatinine and urinary N-acetyl beta-D-glucosaminidase (NAG) were measured as indicators of glomerular function and proximal tubular function. We also measured cytokine-induced neutrophil chemoattractant-1 (CINC-1) and myeloperoxidase concentrations to assess neutrophil activation and infiltration, respectively. The tissue sections were scored to evaluate the tubular injury. In the control group, BUN, creatinine, NAG, CINC-1, myeloperoxidase, histological severity score, and number of infiltrating neutrophils were increased following I/R insult, as compared with the sham group. Such increases in biochemical markers, severity score, and infiltrating neutrophils were significantly inhibited in the D-ribose group. Thus, D-ribose ameliorates the I/R-induced renal injury probably by inhibiting neutrophil activation, and may be useful in attenuating the renal injury associated with renal ischemia.

JTE-607, an inflammatory cytokine synthesis inhibitor, attenuates ischemia/reperfusion-induced renal injury by reducing neutrophil activation in rats.

Renal ischemia/reperfusion (I/R) injury is one of the main causes of postoperative renal failure. Activated neutrophils are implicated in the development of I/R-induced renal failure. JTE-607 has been reported to be a potent inhibitor of the multiple inflammatory cytokines in the endotoxic shock mouse model and heart Langendorff perfusion model. In this study, we examined whether JTE-607 attenuates I/R-induced renal injury by reducing neutrophil activation. Male wistar rats were intravenously administered JTE-607 (JTE group, 30 mg/kg) or 5% mannitol (control group) 30 min before ischemia. JTE-607 reduced the I/R-induced increases in the serum concentrations of blood urea nitrogen and creatinine, and improved the histopathologic changes, including acute tubular necrosis. I/R-induced an increase in neutrophil activation, reflected by increases in renal cytokine-induced neutrophil chemoattractant (CINC)-1 and myeloperoxidase (MPO) concentrations which were significantly reduced by JTE-607. These findings indicate that JTE-607 attenuates I/R-induced acute renal injury, probably by inhibiting neutrophil activation. JTE-607 might be a novel therapeutic strategy for the protection of postoperative renal failure in surgery associated with renal ischemia as well as renal transplantation.

Atrial natriuretic peptide attenuates ischemia/reperfusion-induced renal injury by reducing neutrophil activation in rats.

Activated neutrophils have been implicated in the development of ischemia/reperfusion (I/R)-induced renal failure. Cytokine-induced neutrophil chemoattractant-1 (CINC-1), a major factor in acute inflammation, is responsible for the activation of neutrophils and for neutrophil chemotaxis to sites of injury. Atrial natriuretic peptide (ANP), a hormone synthesized by the cardiac atria, was shown to possess anti-inflammatory potential due to its potency to inhibit the production of inflammatory mediators. We examined whether the human form of ANP attenuates I/R-induced renal injury by reducing neutrophil activation in a rat model. Male Wistar rats weighing 200-240 g were observed for 24 h after reperfusion following 45-min renal ischemia. Rats were intravenously administered alpha-human ANP (alpha-hANP, 0.2 microg/kg/min) beginning immediately after ischemia and continuing for 2 h after reperfusion. CINC-1 and myeloperoxidase (MPO) concentrations were measured to assess activation of the infiltrating neutrophil. Blood urea nitrogen and serum creatinine and urinary N-acetyl beta-d-glucosaminidase (NAG) were measured as indicators of glomerular function and as a specific indicator of proximal tubular function, respectively. alpha-hANP significantly inhibited I/R-induced increases in renal CINC-1 and MPO concentrations. alpha-hANP also reduced I/R-induced increases in the concentrations of blood urea nitrogen and serum creatinine, and improved histopathologic changes, including acute tubular necrosis. These findings indicate that alpha-hANP attenuates I/R-induced acute renal injury, at least in part by reducing neutrophil activation, and may be useful in surgeries, associated with renal ischemia, as well as in renal transplantation.

D-allose protects against endotoxemic acute renal injury.

D-allose is a monosaccharide. We previously reported that D-allose attenuated renal injury by inhibiting the activation of neutrophils after renal ischemia/reperfusion. Lipopolysaccharide (LPS) triggers sepsis syndrome by activating monocytes to produce proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, which potently stimulates the activation of neutrophils. This study was undertaken to examine the effects of D-allose on renal injury in the systemic inflammatory response induced by LPS administration, with emphasis on systemic TNF-alpha and the activation of neutrophils in the rat kidney. Serum and renal TNF-alpha, renal cytokine-induced neutrophil chemoattractant (CINC)-1, and myeloperoxidase (MPO) concentrations, and renal function after LPS administration were evaluated. D-allose (400 mg/kg body weight) inhibited LPS-induced increases in serum and renal TNF-alpha concentrations and renal CINC-1 and MPO concentrations after LPS administration, as well as the subsequent neutrophil-mediated renal injury. These findings may have important implications in understanding the biologic functions of D-allose. D-allose may prove useful in protecting against acute renal injury in systemic inflammatory responses to LPS.

Urinary trypsin inhibitor ameliorates renal tissue oxygenation after ischemic reperfusion in rats.

PURPOSE: In order to determine the mechanism of the protective effect of a urinary trypsin inhibitor (UTI) on renal ischemic reperfusion injury, we measured the tissue oxygen partial pressure pO2 in both the renal cortex and medulla in rats, using electron paramagnetic resonance (EPR) oximetry. METHODS: We allocated the rats to three groups: normal saline (NS) group, a UTI 50,000 U x kg(-1) (LD) group, and a UTI 150,000 U x kg(-1) (HD) group, with the normal saline and UTI being administered 30 min before ischemia. Renal ischemia was achieved by inflating the balloon of a vascular occluder that had been placed around the abdominal aorta just above the bifurcation of the renal artery. Cortical and medullary pO2 were measured every 10 min during ischemia (30 min) and reperfusion (60 min) by EPR oximetry; also, systemic cardiopulmonary parameters were measured. RESULTS: The pO2 in the cortex and medulla decreased to less than 2 mmHg during ischemia in all groups. At 60 min after reperfusion, the pO2 values in the NS group were not fully restored, whereas those in the LD and HD groups were completely restored to the pre-ischemic values. There were no significant differences between the HD and LD groups. There were no differences between any groups in cardiopulmonary parameters. CONCLUSION: Because UTI improved renal oxygenation after reperfusion without changing cardiopulmonary parameters, the pharmacological properties of UTI, such as its renal protection and anti-shock activity, may be explained in part, by this improvement in tissue oxygenation.

Inhibitory effect of d-allose on neutrophil activation after rat renal ischemia/reperfusion.

D-Allose is one of the rare sugars produced from D-psicose. We examined whether d-allose reduces the extent of rat renal ischemia/reperfusion (I/R) injury by suppressing the activation of neutrophils. The renal concentrations of cytokine-induced neutrophil chemoattractant (CINC)-1 and myeloperoxidase were significantly increased after renal I/R. These increases were significantly inhibited by D-allose administration. Furthermore, D-allose significantly inhibited the increase in the concentrations of blood urea nitrogen (BUN), creatinine, N-acetyl beta-D-glucosaminidase (NAG) and histopathologic changes after renal I/R. These findings strongly suggest that D-allose protects against I/R-induced renal injury by inhibiting the activation of neutrophils that play an important role in I/R-induced renal injury. These findings may have important implications in understanding the biologic functions of D-allose. D-Allose may prove useful in renal surgery and transplantation.

Urinary trypsin inhibitor reduces inflammatory response in kidney induced by lipopolysaccharide.

Human urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely used in Japan as a drug for patients with acute inflammatory disorders such as septic shock and pancreatitis. Lipopolysaccharide (LPS) triggers the sepsis syndrome by activating monocytes to produce proinflammatory cytokines, including tumor necrosis factor alpha (TNFalpha), which potently stimulate the activation of neutrophils. The inhibitory mechanism of UTI on the systemic inflammatory response induced by the intraperitoneal injection of LPS in the kidney is unclear. This study was undertaken to examine the inhibitory effects of UTI on renal injury associated with the systemic inflammatory response induced by LPS stimulation, with emphasis on systemic TNFalpha and the activation of neutrophils in rat kidney. The systemic inflammatory response syndrome was induced by LPS treatment. Serum and renal TNFalpha, renal cytokine-induced neutrophil chemoattractant-1 (CINC-1) and myeloperoxidase (MPO) levels, as well as renal function after LPS stimulation, were evaluated. UTI (50,000 U/kg) inhibited LPS-induced increases in the serum and renal tissue levels of TNFalpha, as well as the renal tissue levels of CINC-1 and MPO after LPS stimulation. UTI (50,000 U/kg) also inhibited the production of serum TNFalpha associated with the systemic inflammatory response syndrome induced by LPS stimulation, thereby attenuating neutrophil infiltration into renal tissues and subsequent neutrophil-mediated renal injury. These findings may have important implications in understanding the biologic functions of UTI. UTI may prove useful in protecting against acute renal injury associated with a systemic inflammatory response.