Disease Outcome and Brain Metabolomics of Cyclophilin-D Knockout Mice in Sepsis.

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction resulting from a systemic inflammatory response to infection, but the mechanism remains unclear. The mitochondrial permeability transition pore (MPTP) could play a central role in the neuronal dysfunction, induction of apoptosis, and cell death in SAE. The mitochondrial isomerase cyclophilin D (CypD) is known to control the sensitivity of MPTP induction. We, therefore, established a cecal ligation and puncture (CLP) model, which is the gold standard in sepsis research, using CypD knockout (CypD KO) mice, and analyzed the disease phenotype and the possible molecular mechanism of SAE through metabolomic analyses of brain tissue. A comparison of adult, male wild-type, and CypD KO mice demonstrated statistically significant differences in body temperature, mortality, and histological changes. In the metabolomic analysis, the main finding was the maintenance of reduced glutathione (GSH) levels and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio in the KO animals following CLP. In conclusion, we demonstrate that CypD is implicated in the pathogenesis of SAE, possibly related to the inhibition of MPTP induction and, as a consequence, the decreased production of ROS and other free radicals, thereby protecting mitochondrial and cellular function.

Postoperative malignant hyperthermia confirmed by calcium-induced calcium release rate after breast cancer surgery, in which prompt recognition and immediate dantrolene administration were life-saving: a case report.

BACKGROUND: Malignant hyperthermia (MH) is a rare genetic disease characterized by the development of very serious symptoms, and hence prompt and appropriate treatment is required. However, postoperative MH is very rare, representing only 1.9% of cases as reported in the North American Malignant Hyperthermia Registry (NAMHR). We report a rare case of a patient who developed sudden postoperative hyperthermia after mastectomy, which was definitively diagnosed as MH by the calcium-induced calcium release rate (CICR) measurement test. CASE PRESENTATION: A 61-year-old Japanese woman with a history of stroke was hospitalized for breast cancer surgery. General anesthesia was introduced by propofol, remifentanil, and rocuronium. After intubation, anesthesia was maintained using propofol and remifentanil, and mastectomy and muscle flap reconstruction surgery was performed and completed without any major problems. After confirming her spontaneous breathing, sugammadex was administered and she was extubated. Thereafter, systemic shivering and masseter spasm appeared, and a rapid increase in body temperature (maximum: 38.9 °C) and end-tidal carbon dioxide (ETCO2) (maximum: 59 mmHg) was noted. We suspected MH and started cooling the body surface of the axilla, cervix, and body trunk, and administered chilled potassium-free fluid and dantrolene. After her body temperature dropped and her shivering improved, dantrolene administration was ended, and finally she was taken to the intensive care unit (ICU). Body cooling was continued within the target range of 36-37 °C in the ICU. No consciousness disorder, hypotension, increased serum potassium level, metabolic acidosis, or cola-colored urine was observed during her ICU stay. Subsequently, her general condition improved and she was discharged on day 12. Muscle biopsy after discharge was performed and provided a definitive diagnosis of MH. CONCLUSIONS: The occurrence of MH can be life-threatening, but its frequency is very low, and genetic testing and muscle biopsy are required to confirm the diagnosis. On retrospective evaluation using the malignant hyperthermia scale, the present case was almost certainly that of a patient with MH. Prompt recognition and immediate treatment with dantrolene administration and body cooling effectively reversed a potentially fatal syndrome. This was hence a valuable case of a patient with postoperative MH that led to a confirmed diagnosis by CICR.

The NRF2­PGC­1ß pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, synoviolin, in a cecal ligation/perforation­induced septic mouse model.

Sepsis­associated encephalopathy (SAE) is a systemic inflammatory response syndrome of which the precise associated mechanisms remain unclear. Synoviolin (Syvn1) is an E3 ubiquitin ligase involved in conditions associated with chronic inflammation, including rheumatoid arthritis, obesity, fibrosis and liver cirrhosis. However, the role of Syvn1 in acute inflammation is not clear. The aim of the present study was to investigate the role of Syvn1 in a septic mouse model induced by cecal ligation/perforation (CLP). Metabolome analysis revealed that kynurenine (KYN), a key factor for the development of neuroinflammation, was increased in CLP­induced septic mice. Notably, KYN was not detected in CLP­induced septic Syvn1­deficient mice. KYN is converted to kynurenic acid (KYNA) by kynurenine aminotransferases (KATs), which has a neuroprotective effect. The expression of KAT4 was significantly increased in Syvn1­deficient mice compared to that in wild­type mice. Promoter analysis demonstrated that Syvn1 knockdown induced the KAT4 promoter activity, as assessed by luciferase reporter activity, whereas Syvn1 overexpression repressed this activity in a dose­dependent manner. Furthermore, the KAT4 promoter was significantly activated by the transcriptional factors, NF­E2­related factor 2 and peroxisome proliferator­activated receptor coactivator 1ß, which are targets of Syvn1­induced degradation. In conclusion, the results of the current study demonstrates that the repression of Syvn1 expression induces the conversion of neurotoxic KYN to neuroprotective KYNA in a CLP­induced mouse model of sepsis, and that Syvn1 is a potential novel target for the treatment of SAE.

Effect of pressure-controlled inverse ratio ventilation on dead space during robot-assisted laparoscopic radical prostatectomy: A randomised crossover study of three different ventilator modes.

BACKGROUND: Pressure-controlled inverse inspiratory to expiratory ratio ventilation (PC-IRV) is thought to be beneficial for reducing the dead space volume. OBJECTIVE: To investigate the effects of PC-IRV on the components of dead space during robot-assisted laparoscopic radical prostatectomy (RLRP). DESIGN: A randomised crossover study of three different ventilator modes. SETTING: A single university hospital from September 2014 to April 2015. PATIENTS: Twenty consecutive study participants undergoing RLRP. INTERVENTIONS: Patients were ventilated sequentially with three different modes in random order for 30 min: volume control ventilation (VCV; inspiratory to expiratory ratio 0.5), pressure control ventilation (PCV; inspiratory to expiratory ratio 0.5) and PC-IRV. Inverse inspiratory to expiratory ratio was adjusted individually by observing the expiratory flow-time wave to prevent the risk of dynamic pulmonary hyperinflation. MAIN OUTCOME MEASURES: The primary outcome included physiological dead space (VDphys), airway dead space (VDaw), alveolar dead space (VDalv) and shunt dead space (VDshunt). VDphys was calculated by Enghoff's method. We also analysed respiratory dead space (VDresp) and VDaw using a novel analytical method. Then, VDalv and VDshunt were calculated by VDalv = VDresp - VDaw and VDshunt = VDphys - VDresp, respectively. RESULTS: The VDphys/expired tidal volume (VTE) ratio in PC-IRV (29.2 ±â€Š4.7%) was significantly reduced compared with that in VCV (43 ±â€Š8.5%) and in PCV (35.9 ±â€Š3.9%). The VDshunt/VTE in PC-IRV was significantly smaller than that in VCV and PCV. VDaw/VTE in PC-IRV was also significantly smaller than that in VCV but not that in PCV. There was no significant change in VDalv/VTE. CONCLUSION: PC-IRV with the inspiratory to expiratory ratio individually adjusted by the expiratory flow-time wave decreased VDphys/VTE in patients undergoing RLRP. TRIAL REGISTRATION: University Hospital Medical Information Network in Japan 000014004.

Retraction Note: Brain injury following cardiac arrest: pathophysiology for neurocritical care.

[This retracts the article DOI: 10.1186/s40560-016-0140-9.].

Brain injury following cardiac arrest: pathophysiology for neurocritical care.

Cardiac arrest induces the cessation of cerebral blood flow, which can result in brain damage. The primary intervention to salvage the brain under such a pathological condition is to restore the cerebral blood flow to the ischemic region. Ischemia is defined as a reduction in blood flow to a level that is sufficient to alter normal cellular function. Brain tissue is highly sensitive to ischemia, such that even brief ischemic periods in neurons can initiate a complex sequence of events that may ultimately culminate in cell death. However, paradoxically, restoration of blood flow can cause additional damage and exacerbate the neurocognitive deficits in patients who suffered a brain ischemic event, which is a phenomenon referred to as "reperfusion injury." Transient brain ischemia following cardiac arrest results from the complex interplay of multiple pathways including excitotoxicity, acidotoxicity, ionic imbalance, peri-infarct depolarization, oxidative and nitrative stress, inflammation, and apoptosis. The pathophysiology of post-cardiac arrest brain injury involves a complex cascade of molecular events, most of which remain unknown. Many lines of evidence have shown that mitochondria suffer severe damage in response to ischemic injury. Mitochondrial dysfunction based on the mitochondrial permeability transition after reperfusion, particularly involving the calcineurin/immunophilin signal transduction pathway, appears to play a pivotal role in the induction of neuronal cell death. The aim of this article is to discuss the underlying pathophysiology of brain damage, which is a devastating pathological condition, and highlight the central signal transduction pathway involved in brain damage, which reveals potential targets for therapeutic intervention.

Inadequate gas supply to patients with an adjustable pressure-limiting valve in the fully opened position.

With spontaneous ventilation, sufficient exhaust resistance at the adjustable pressure-limiting (APL) valve when fully opened ensures that the reservoir bag fills and adequately supplies gas to patients. A lack of exhaust resistance with the APL valve fully open caused inadequate gas supply to patients with four types of anesthesia machines: SA2 (Dräger), Excel-210 SE (GE), Fabius (Dräger), and Cato (Dräger). Mechanically, the SA2 and Excel-210 SE APL valve systems, which are of the spring-loaded disc type positioned horizontally, cannot maintain sufficient exhaust resistance with the APL valve fully open. As for the Fabius and Cato, an exhaust valve independent of the APL valve should maintain sufficient exhaust resistance continuously. However, accumulated viscous substances on the thin diaphragm of the exhaust valve contributed to hindrance of diaphragm closure.

Effects of temperature gradient reduction in three different carbon dioxide absorbents.

BACKGROUND AND OBJECTIVE: Temperature gradients in CO2 absorbents may locally increase the water content by condensation. We hypothesized that temperature gradient reduction (TGR) would prevent increased water content, thus preserving the reactivity of the CO2 absorbent and thereby increasing its time to exhaustion (longevity). The purpose of this study was to compare the effects of TGR on the longevity of CO2 absorbent with three different types of CO2 absorbents. METHODS: We constructed a novel TGR canister. Experiments were conducted using three different types of CO2 absorbents: Drägersorb 800 Plus (D800), Drägersorb Free and Amsorb Plus. One kilogram of fresh CO2 absorbent of each type was placed into two types of canister: the conventional control canister (n = 6) and the TGR canister (n = 6). RESULTS: In the case of Drägersorb Free, the TGR canister most effectively and specifically prevented local increase in water content of the CO2 absorbent and markedly increased the longevity (30% increase) compared with the control canister. In the case of Amsorb Plus, the TGR canister also prevented local excessive water content, but the increase in longevity was smaller (17% increase). In the case of D800, the TGR canister markedly increased the longevity (27% increase), but its prevention of local excessive water content was smaller. CONCLUSIONS: TGR is a useful method to prevent local increase in water content and improve the longevity of CO2 absorbent. The effectiveness of TGR on longevity and water content changes varied in the different types of CO2 absorbent.

Nicorandil decreases cardiac events during and after noncardiac surgery.

STUDY OBJECTIVE: To assess whether nicorandil reduces the likelihood of cardiac events during and after intermediate risk surgery. DESIGN: Multicenter study. SETTING: 13 hospitals in Japan. PATIENTS: Intermediate-risk patients were identified by the presence of risk factors such as angina, a history of myocardial infarction, heart failure, diabetes mellitus, and abnormal electrocardiography (ECG). INTERVENTIONS: Nicorandil was given to these patients during the operation. MEASUREMENTS AND MAIN RESULTS: Cardiac events during the operation and the following 5 days were monitored. The frequency of cardiac events in nicorandil-treated patients was compared with those in nontreated patients. Eighty-four patients received nicorandil during surgery and 237 patients received standard care. Cardiac events in the nicorandil-treated group occurred less frequently both during the operation (odds ratio, 0.15; 95% confidence interval, 0.03-0.76; P=0.02) and after it (odds ratio, 0.24; 95% confidence interval, 0.06-0.90; P=0.04). CONCLUSIONS: Nicorandil reduces the frequency of cardiac events in patients undergoing noncardiac surgery, both during and after the operation.

[General anesthesia for thyroplasty employing voice test].

BACKGROUND: We reported an anesthetic technique for thyroplasty employing voice test. Thyroplasty is performed to improve voice quality in patients with unilateral vocal cord paralysis. Correct displacement of the vocal cord is assessed by asking the patient to phonate. At this point all patients should have recovered from general anesthesia and cooperate to phonation, facilitating correct displacement of the vocal cords. METHODS: Anesthesia was induced with i.v. pentazocine 15-30 mg and continuous propofol infusion 10 mg x kg(-1) x hr(-1). The patients received propofol infusion 4-6 mg x kg(-1) x hr(-1) with spontaneous ventilation. At the point of correct displacement of the vocal cords, we stopped propofol infusion and all the patients woke up immediately and cooperated. After determining the voice propofol was given at a rate of 4-6 mg x kg(-1) x hr(-1). RESULTS: The average times of surgery and anesthesia were 98 +/- 23 min and 139 +/- 22 min, respectively. At the point of correct displacement of the vocal cords, the average time from the end of propofol infusion until awakening with good quality of recovery was 313 +/- 93 sec. No patients complained of pain during or after CONCLUSIONS: This anesthetic technique provided both optimal operating conditions and patient comfort without serious complications.

Are the incidences of cardiac events during noncardiac surgery in Japan the same as in the United States and Europe?

In Japan, an ever-present problem in the preoperative evaluation of patients with ischemic heart disease is that although such evaluations are based on Western data, these data serve as the basis for determining perioperative risk in Japanese patients. To remedy this problem, the Cardiac Ischemia and Anesthesia Research Committee was formed in 1997 and has conducted studies of perioperative complications in noncardiac surgery in Japan. In two retrospective studies in 1997, the proportions of patients with ischemic heart disease were 3.9% and 3.1%, approximately one tenth the rates reported in Europe and the United States. The incidences of perioperative cardiac complications in patients with ischemic heart disease were 16.4% and 13.2%, not widely divergent from rates reported in Europe and the United States. To investigate the baseline characteristics involved in perioperative complications, we conducted a prospective study of 237 patients classified as having intermediate risk for perioperative cardiac complications according to the American College of Cardiology/American Heart Association Guidelines for Perioperative Cardiovascular Evaluation for Noncardiac Surgery. We found that the prominent factor in intraoperative cardiac complications was the presence of hypertension (odds ratio = 2.911). Factors contributing to postoperative cardiac complications included those reflecting coronary lesion severity and cardiac dysfunction (history of heart failure; odds ratio = 6.884, coronary risk index grade; odds ratio = 2.884, and a history of intervention; odds ratio = 4.774).

Novel radiator for carbon dioxide absorbents in low-flow anesthesia.

During long-term low-flow sevoflurane anesthesia, dew formation and the generation of compound A are increased in the anesthesia circuit because of elevated soda lime temperature. The object of this study was to develop a novel radiator for carbon dioxide absorbents used for long durations of low-flow sevoflurane anesthesia. Eleven female swine were divided into two groups comprising a "radiator" group (n = 5) that used a novel radiator for carbon dioxide absorbents and a "control" group (n = 6) that used a conventional canister. Anesthesia was maintained with N2O, O2, and sevoflurane, and low-flow anesthesia was performed with fresh gas flow at 0.6 L/min for 12 hr. In the "control" group, the soda lime temperature reached more than 40 degrees C and soda lime dried up with severe dew formation in the inspiratory valve. In the "radiator" group, the temperature of soda lime stayed at 30 degrees C, and the water content of soda lime was retained with no dew formation in the inspiratory valve. In addition, compound A concentration was reduced. In conclusion, radiation of soda lime reduced the amounts of condensation formed and the concentration of compound A in the anesthetic circuit, and allowed long term low-flow anesthesia without equipment malfunction.