The optimal glycemic target in critically ill patients: an updated network meta-analysis.

Acute glycemic control significantly affects the clinical outcomes of critically ill patients. This updated network meta-analysis examines the benefits and harms of four target blood glucose levels (< 110, 110-144, 144-180, and > 180 mg/dL). Analyzing data of 27,541 patients from 37 trials, the surface under the cumulative ranking curve for mortality and hypoglycemia was highest at a target blood glucose level of 144-180 mg/dL, while for infection and acute kidney injury at 110-144 mg/dL. Further evidence is needed to determine whether 110-144 or 144-180 mg/dL is superior as an optimal glucose target, considering prioritized outcomes.

The role of ferroptosis in cell-to-cell propagation of cell death initiated from focal injury in cardiomyocytes.

AIMS: Ferroptosis has grown in importance as a key factor in ischemia-reperfusion (I/R) injury. This study explores the mechanism underlying fibrotic scarring extending along myofibers in cardiac ischemic injury and demonstrates the integral role of ferroptosis in causing a unique cell death pattern linked to I/R injury. MAIN METHODS: Cadaveric hearts from individuals who had ischemic injury were examined by histological assays. We created a novel model of inducing cell death in H9c2 cells, and used it to demonstrate ferroptotic cell death extending in a cell-to-cell manner. Ex vivo Langendorff-perfused hearts were used alongside the model to replicate cell death extension along myofibers while also demonstrating protective effects of a ferroptosis inhibitor, ferrostatin-1 (Fer-1). KEY FINDINGS: Human hearts from individuals who had I/R injury demonstrated scarring along myofibers that was consistent with mouse models, suggesting that cell death extended from cell-to-cell. Treatment with Ras-selective lethal 3 (RSL3), a ferroptosis inducer, and exposure to excess iron exacerbated cell death propagation in in vitro models, and inhibition of ferroptosis by Fer-1 blunted this effect in both settings. In ex vivo models, Fer-1 was sufficient to reduce cell death along the myofibers caused by external injury. SIGNIFICANCE: The unique I/R injury-induced pattern of cell death along myofibers requires novel injury models that mimic this phenomenon, thus we established new methods to replicate it. Ferroptosis is important in propagating injury between cells and better understanding this mechanism may lead to therapeutic responses that limit I/R injury.

Early intubation and decreased in-hospital mortality in patients with coronavirus disease 2019.

BACKGROUND: Some academic organizations recommended that physicians intubate patients with COVID-19 with a relatively lower threshold of oxygen usage particularly in the early phase of pandemic. We aimed to elucidate whether early intubation is associated with decreased in-hospital mortality among patients with novel coronavirus disease 2019 (COVID-19) who required intubation. METHODS: A multicenter, retrospective, observational study was conducted at 66 hospitals in Japan where patients with moderate-to-severe COVID-19 were treated between January and September 2020. Patients who were diagnosed as COVID-19 with a positive reverse-transcription polymerase chain reaction test and intubated during admission were included. Early intubation was defined as intubation conducted in the setting of ≤ 6 L/min of oxygen usage. In-hospital mortality was compared between patients with early and non-early intubation. Inverse probability weighting analyses with propensity scores were performed to adjust patient demographics, comorbidities, hemodynamic status on admission and time at intubation, medications before intubation, severity of COVID-19, and institution characteristics. Subgroup analyses were conducted on the basis of age, severity of hypoxemia at intubation, and days from admission to intubation. RESULTS: Among 412 patients eligible for the study, 110 underwent early intubation. In-hospital mortality was lower in patients with early intubation than those with non-early intubation (18 [16.4%] vs. 88 [29.1%]; odds ratio, 0.48 [95% confidence interval 0.27-0.84]; p = 0.009, and adjusted odds ratio, 0.28 [95% confidence interval 0.19-0.42]; p < 0.001). The beneficial effects of early intubation were observed regardless of age and severity of hypoxemia at time of intubation; however, early intubation was associated with lower in-hospital mortality only among patients who were intubated later than 2 days after admission. CONCLUSIONS: Early intubation in the setting of ≤ 6 L/min of oxygen usage was associated with decreased in-hospital mortality among patients with COVID-19 who required intubation. Trial Registration None.

COVID-19 shares clinical features with anti-melanoma differentiation-associated protein 5 positive dermatomyositis and adult Still's disease.

OBJECTIVES: To investigate the similarities and differences between Coronavirus disease 2019 (COVID-19) and autoimmune and autoinflammatory rheumatic diseases characterised by hyperferritinaemia, such as antimelanoma differentiation-associated protein 5 (MDA5) autoantibody-positive dermatomyositis and adult Still's disease. METHODS: We reviewed consecutive, newly diagnosed, untreated patients with COVID-19, anti-MDA5 dermatomyositis, or adult Still's disease. We compared their clinical, laboratory, and radiological characteristics, including the prevalence of macrophage activation syndrome and lung involvement in each disease. RESULTS: The numbers of patients with COVID-19, anti-MDA5 dermatomyositis, and adult-onset Still's disease with hyperferritinaemia (serum ferritin ≥500ng/dL) who were included for main analysis were 22, 14, and 59, respectively. COVID-19 and adult Still's disease both featured hyperinflammatory status, such as high fever and elevated serum C-reactive protein, whereas COVID-19 and anti-MDA5 dermatomyositis both presented with severe interstitial lung disease and hypoxaemia. While two-thirds of the patients in each group met the criteria for macrophage-activated syndrome that is used in systemic juvenile idiopathic arthritis, the HScore, an indicator of haemophagocytic lymphohistiocytosis, was low in anti-MDA5 dermatomyositis and COVID-19 even in severe or critical cases. The findings of chest computed tomography were similar between COVID-19 and anti-MDA5 dermatomyositis. CONCLUSIONS: COVID-19 shared clinical features with rheumatic diseases characterised by hyperferritinaemia, including anti-MDA5 dermatomyositis and adult Still's disease. These findings should be investigated further in order to shed light on the pathogenesis of not only COVID-19 but also the aforementioned rheumatic diseases.

mTOR-mediated calcium transients affect cardiac function in ex vivo ischemia-reperfusion injury.

The mechanistic target of rapamycin (mTOR) is a key mediator of energy metabolism, cell growth, and survival. While previous studies using transgenic mice with cardiac-specific overexpression of mTOR (mTOR-Tg) demonstrated the protective effects of cardiac mTOR against ischemia-reperfusion (I/R) injury in both ex vivo and in vivo models, the mechanisms underlying the role of cardiac mTOR in cardiac function following I/R injury are not well-understood. Torin1, a pharmacological inhibitor of mTOR complex (mTORC) 1 and mTORC2, significantly decreased functional recovery of LV developed pressure in ex vivo I/R models (p < 0.05). To confirm the role of mTOR complexes in I/R injury, we generated cardiac-specific mTOR-knockout (CKO) mice. In contrast to the effects of Torin1, CKO hearts recovered better after I/R injury than control hearts (p < 0.05). Interestingly, the CKO hearts had exhibited irregular contractions during the reperfusion phase. Calcium is a major factor in Excitation-Contraction (EC) coupling via Sarcoplasmic Reticulum (SR) calcium release. Calcium is also key in opening the mitochondrial permeability transition pore (mPTP) and cell death following I/R injury. Caffeine-induced SR calcium release in isolated CMs showed that total SR calcium content was lower in CKO than in control CMs. Western blotting showed that a significant amount of mTOR localizes to the SR/mitochondria and that GSK3-ß phosphorylation, a key factor in SR calcium mobilization, was decreased. These findings suggest that cardiac mTOR located to the SR/mitochondria plays a vital role in EC coupling and cell survival in I/R injury.

The real-time reverse transcription-polymerase chain reaction threshold cycle values for severe acute respiratory syndrome coronavirus 2 predict the prognosis of coronavirus disease 2019 pneumonia.

The clinical course of coronavirus disease 2019 (COVID-19) varies from mild to critical. We retrospectively examined whether clinical and laboratory findings on admission could predict COVID-19 prognosis. Among various factors associated with COVID-19 severity, our results indicated that the real-time reverse transcription-polymerase chain reaction (RT-PCR) threshold cycle (Ct) values for severe acute respiratory syndrome coronavirus 2 were the most useful predictor of COVID-19 prognosis.

Life-threatening rocuronium-induced anaphylactic shock without cutaneous manifestations successfully reversed with sugammadex: a case report.

BACKGROUND: Recognition of rocuronium-induced anaphylaxis is often challenging, owing to its diverse clinical manifestations. Regarding treatment, several reports have described the efficacy of sugammadex, while conflicting reports have also been published. CASE: A 71-year-old man was scheduled to undergo split-thickness skin grafting surgery on his hip. During the induction of general anesthesia, the patient developed profound circulatory collapse without any cutaneous manifestations, which required 40 min of cardiopulmonary resuscitation. Later, the patient developed circulatory collapse again during the induction of anesthesia for tracheostomy surgery, which apparently coincided with the administration of rocuronium. Rocuronium-induced anaphylactic shock was suspected, and the administration of sugammadex resulted in swift recovery of hemodynamics. The basophil activation test revealed a positive reaction to rocuronium. CONCLUSION: The possibility of rocuronium-induced anaphylaxis should be considered when the circulatory collapse coincides with rocuronium administration, even though cutaneous manifestation is absent. Sugammadex can be a treatment option in such atypical cases.

Evaluation of the Safety of Percutaneous Dilational Tracheostomy Compared with Surgical Tracheostomy in the Intensive Care Unit.

BACKGROUND: Tracheostomy is a necessary procedure for patients who require long-term mechanical ventilation support. There are two methods for tracheostomy in current use: surgical tracheostomy (ST) and percutaneous dilational tracheostomy (PDT). In the current study, we retrospectively compared the safety of both procedures performed in our intensive care unit (ICU). METHODS: In this study, we enrolled subjects who underwent tracheostomy in our ICU between January 2012 and March 2016. We excluded subjects who were <20 years old and underwent tracheostomy in the operating room. As a primary outcome, we evaluated the rate of complications between ST and PDT groups. The length of ICU stay, time to tracheostomy from intubation, and the rate of mechanical ventilation and mortality at 28 postoperative days were also examined as secondary outcomes. RESULTS: Compared with the ST group, the rate of all complications was lower in the PDT group (13.4% vs. 38.8%, p=0.007). Although the rate of intraoperative complications did not differ between the two groups (3.8% vs. 8.1%, p=0.62), relative to the ST procedure, the PDT procedure was associated with fewer postoperative complications (34.6% vs. 9.6%, p=0.003). Among postoperative complications, accidental removal of the tracheostomy tube and an air leak from the tracheostomy fistula were less frequent in the PDT group than the ST group. Between the two groups, there were no significant differences in their secondary outcomes. CONCLUSION: This retrospective study indicates that relative to ST, PDT is a safer procedure to be performed in the ICU. Fewer postoperative complications following PDT might be attributed to the small skin incision made during this procedure.

Pathological Roles of Iron in Cardiovascular Disease.

Iron is an essential mineral required for a variety of vital biological functions. Despite being vital for life, iron also has potentially toxic aspects. Iron has been investigated as a risk factor for coronary artery disease (CAD), however, iron's toxicity in CAD patients still remains controversial. One possible mechanism behind the toxicity of iron is "ferroptosis", a newly described form of irondependent cell death. Ferroptosis is an iron-dependent form of regulated cell death that is distinct from apoptosis, necroptosis, and other types of cell death. Ferroptosis has been reported in ischemiareperfusion (I/R) injury and several other diseases. Recently, we reported that ferroptosis is a significant form of cell death in cardiomyocytes. Moreover, myocardial hemorrhage, a major event in the pathogenesis of heart failure, could trigger the release of free iron into cardiac muscle and is an independent predictor of adverse left ventricular remodeling after myocardial infarction. Iron deposition in the heart can now be detected with advanced imaging methods, such as T2 star (T2*) cardiac magnetic resonance imaging, which can non-invasively predict iron levels in the myocardium and detect myocardial hemorrhage, thus existing technology could be used to assess myocardial iron. We will discuss the role of iron in cardiovascular diseases and especially with regard to myocardial I/R injury.

Protective effects of the mechanistic target of rapamycin against excess iron and ferroptosis in cardiomyocytes.

Clinical studies have suggested that myocardial iron is a risk factor for left ventricular remodeling in patients after myocardial infarction. Ferroptosis has recently been reported as a mechanism of iron-dependent nonapoptotic cell death. However, ferroptosis in the heart is not well understood. Mechanistic target of rapamycin (mTOR) protects the heart against pathological stimuli such as ischemia. To define the role of cardiac mTOR on cell survival in iron-mediated cell death, we examined cardiomyocyte (CM) cell viability under excess iron and ferroptosis conditions. Adult mouse CMs were isolated from cardiac-specific mTOR transgenic mice, cardiac-specific mTOR knockout mice, or control mice. CMs were treated with ferric iron [Fe(III)]-citrate, erastin, a class 1 ferroptosis inducer, or Ras-selective lethal 3 (RSL3), a class 2 ferroptosis inducer. Live/dead cell viability assays revealed that Fe(III)-citrate, erastin, and RSL3 induced cell death. Cotreatment with ferrostatin-1, a ferroptosis inhibitor, inhibited cell death in all conditions. mTOR overexpression suppressed Fe(III)-citrate, erastin, and RSL3-induced cell death, whereas mTOR deletion exaggerated cell death in these conditions. 2',7'-Dichlorodihydrofluorescein diacetate measurement of reactive oxygen species (ROS) production showed that erastin-induced ROS production was significantly lower in mTOR transgenic versus control CMs. These findings suggest that ferroptosis is a significant type of cell death in CMs and that mTOR plays an important role in protecting CMs against excess iron and ferroptosis, at least in part, by regulating ROS production. Understanding the effects of mTOR in preventing iron-mediated cell death will provide a new therapy for patients with myocardial infarction. NEW & NOTEWORTHY Ferroptosis has recently been reported as a new form of iron-dependent nonapoptotic cell death. However, ferroptosis in the heart is not well characterized. Using cultured adult mouse cardiomyocytes, we demonstrated that the mechanistic target of rapamycin plays an important role in protecting cardiomyocytes against excess iron and ferroptosis.

Targeting Oxygen-Sensing Prolyl Hydroxylase for Metformin-Associated Lactic Acidosis Treatment.

Metformin is one of the most widely used therapeutics for type 2 diabetes mellitus and also has anticancer and antiaging properties. However, it is known to induce metformin-associated lactic acidosis (MALA), a severe medical condition with poor prognosis, especially in individuals with renal dysfunction. Inhibition of prolyl hydroxylase (PHD) is known to activate the transcription factor hypoxia-inducible factor (HIF) that increases lactate efflux as a result of enhanced glycolysis, but it also enhances gluconeogenesis from lactate in the liver that contributes to reducing circulating lactate levels. Here, we investigated the outcome of pharmaceutical inhibition of PHD in mice with MALA induced through the administration of metformin per os and an intraperitoneal injection of lactic acid. We found that the PHD inhibitors significantly increased the expression levels of genes involved in gluconeogenesis in the liver and the kidney and significantly improved the survival of mice with MALA. Furthermore, the PHD inhibitor also improved the rate of survival of MALA induced in mice with chronic kidney disease (CKD). Thus, PHD represents a new therapeutic target for MALA, which is a critical complication of metformin therapy.

The mTOR Signaling Pathway in Myocardial Dysfunction in Type 2 Diabetes Mellitus.

PURPOSE OF REVIEW: T2DM (type 2 diabetes mellitus) is a risk factor for heart failure. The mTOR (mechanistic target of rapamycin) is a key mediator of the insulin signaling pathway. We will discuss the role of mTOR in myocardial dysfunction in T2DM. RECENT FINDINGS: In T2DM, chronically activated mTOR induces multiple pathological events, including a negative feedback loop that suppresses IRS (insulin receptor substrate)-1. While short-term treatment with rapamycin, an mTOR inhibitor, is a promising strategy for cardiac diseases such as acute myocardial infarction and cardiac hypertrophy in T2DM, there are many concerns about chronic usage of rapamycin. Two mTOR complexes, mTORC1 and mTORC2, affect many molecules and processes via distinct signaling pathways that regulate cardiomyocyte function and survival. Understanding mechanisms underlying mTOR-mediated pathophysiological features in the heart is essential for developing effective therapies for cardiac diseases in the context of T2DM.

Sepsis-induced cardiac dysfunction and ß-adrenergic blockade therapy for sepsis.

Despite recent advances in medical care, mortality due to sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, remains high. Fluid resuscitation and vasopressors are the first-line treatment for sepsis in order to optimize hemodynamic instability caused by vasodilation and increased vascular permeability. However, these therapies, aimed at maintaining blood pressure and blood flow to vital organs, could have deleterious cardiac effects, as cardiomyocyte damage occurs in the early stages of sepsis. Recent experimental and clinical studies have demonstrated that a number of factors contribute to sepsis-induced cardiac dysfunction and the degree of cardiac dysfunction is one of the major prognostic factors of sepsis. Therefore, strategies to prevent further cardiomyocyte damage could be of crucial importance in improving the outcome of sepsis. Among many factors causing sepsis-induced cardiac dysfunction, sympathetic nerve overstimulation, due to endogenous elevated catecholamine levels and exogenous catecholamine administration, is thought to play a major role. ß-adrenergic blockade therapy is widely used for ischemic heart disease and chronic heart failure and in the prevention of cardiovascular events in high-risk perioperative patients undergoing major surgery. It has also been shown to restore cardiac function in experimental septic animal models. In a single-center randomized controlled trial, esmolol infusion in patients with septic shock with persistent tachycardia reduced the 28-day mortality. Furthermore, it is likely that ß-adrenergic blockade therapy may result in further beneficial effects in patients with sepsis, such as the reduction of inflammatory cytokine production, suppression of hypermetabolic status, maintenance of glucose homeostasis, and improvement of coagulation disorders. Recent accumulating evidence suggests that ß-adrenergic blockade could be an attractive therapy to improve the prognosis of sepsis. We await a large multicenter randomized clinical trial to confirm the beneficial effects of ß-adrenergic blockade therapy in sepsis, of which mortality is still high.

Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle.

Loss of prolyl hydroxylase 2 (PHD2) activates the hypoxia-inducible factor-dependent hypoxic response, including anaerobic glycolysis, which causes large amounts of lactate to be released from cells into the circulation. We found that Phd2-null mouse embryonic fibroblasts (MEFs) produced more lactate than wild-type MEFs, as expected, whereas systemic inactivation of PHD2 in mice did not cause hyperlacticacidemia. This unexpected observation led us to hypothesize that the hypoxic response activated in the liver enhances the Cori cycle, a lactate-glucose carbon recycling system between muscle and liver, and thereby decreases circulating lactate. Consistent with this hypothesis, blood lactate levels measured after a treadmill or lactate tolerance test were significantly lower in Phd2-liver-specific knockout (Phd2-LKO) mice than in control mice. An in vivo (13)C-labeled lactate incorporation assay revealed that the livers of Phd2-LKO mice produce significantly more glucose derived from (13)C-labeled lactate than control mice, suggesting that blockade of PHD2 in the liver ameliorates lactic acidosis by activating gluconeogenesis from lactate. Phd2-LKO mice were resistant to lactic acidosis induced by injection of a lethal dose of lactate, displaying a significant elongation of survival. Moreover, oral administration of a PHD inhibitor improved survival in an endotoxin shock mice model. These data suggest that PHD2 is a potentially novel drug target for the treatment of lactic acidosis, which is a serious and often fatal complication observed in some critically ill patients.

[Perioperative anticoagulant therapy in a patient with congenital antithrombin III deficiency undergoing posterior spinal fusion].

A 22-year-old female was scheduled to undergo posterior thoracolumbar spinal fusion. She had been diagnosed with congenital antithrombin III (AT-III) deficiency by the onset of pulmonary embolism and deep vein thrombosis after the first operation at the age of 18. Thereafter she had taken warfarin, 5 mg daily, until 4 days before the surgery. Preoperatively, we administered AT-III products to regulate AT-III activity. The posterior spinal fusion was performed successfully without surgical complications. Postoperatively, we continued administration of AT-III products to maintain AT-III activity above 75%. We also used low dose unfractionated heparin with AT-III by continuous intravenous infusion. Heparin was administered with dose adjustment to achieve a target activated partial thromboplastin time of 45 to 60 seconds. After the activated partial thromboplastin time was stabilized in the target range, we started warfarin therapy (target international normalized ratio, 1.5 to 2.5) on postoperative day 16 and stopped administration of heparin on postoperative day 19. There was no thrombosis complications during the perioperative period. Good anticoagulant management was achieved in a patient with congenital AT-III deficiency undergoing posterior spinal fusion.

[Airway management in a patient with cavernous hemangioma of the hypopharynx and larynx].

A 48-year-old woman was diagnosed with cavernous hemangioma of hypopharynx and larynx, which extended to the trachea and mediastinum. She was scheduled for tracheostomy and open surgical excision of hypopharynx hemangioma under general anesthesia. On induction of anesthesia, we planned awake fiberoptic intubation according to the difficult airway algorithm of the American Society of Anesthesiologists. Under continuous infusion of remifentanil at 0.1-0.2 microg x kg(-1) x min(-1), the patient became sedated while spontaneously breathing, and her pain and laryngeal reflexes were reduced. Although tracheal intubation was successfully accomplished without injuring the hypopharynx hemangioma, tracheostomy was difficult because of bleeding from the surgical site. After 3 hr of surgery with 1880 g of blood loss, the surgeons quitted tracheostomy and the patient was transferred to the intensive care unit. Her airway was managed with endotracheal tube for 7 days, and open surgical excision of hypopharynx hemangioma was performed on day 7. The patient was successfully extubated on day 9 with the support of non-invansive positive pressure ventilation. Awake fiberoptic intubation under remifentanil infusion is safe and useful approach for patients with airway hemangioma.