Inhibition of QDPR synergistically modulates intracellular tetrahydrobiopterin profiles in cooperation with methotrexate.

Tetrahydrobiopterin (BH4) is an essential cofactor for dopamine and serotonin synthesis in monoaminergic neurons, phenylalanine metabolism in hepatocytes, and nitric oxide synthesis in endothelial and immune cells. BH4 is consumed as a cofactor or is readily oxidized by autooxidation. Quinonoid dihydropteridine reductase (QDPR) is an enzyme that reduces quinonoid dihydrobiopterin (qBH2) back to BH4, and we have previously demonstrated the significance of QDPR in maintaining BH4 in vivo using Qdpr-KO mice. In addition to the levels of BH4 in the cells, the ratios of oxidized to reduced forms of BH4 are supposed to be important for regulating nitric oxide synthase (NOS) via the so-called uncoupling of NOS. However, previous studies were limited due to the absence of specific and high-affinity inhibitors against QDPR. Here, we performed a high-throughput screening for a QDPR inhibitor and identified Compound 9b with an IC50 of 0.72 µM. To understand the inhibition mechanism, we performed kinetic analyses and molecular dynamics simulations. Treatment with 9b combined with methotrexate (MTX), an inhibitor of another BH4-reducing enzyme, dihydrofolate reductase (DHFR), significantly oxidized intracellular redox states in HepG2, Jurkat, SH-SY5Y, and PC12D cells. Collectively, these findings suggest that 9b may enhance the anticancer and anti-autoimmune effects of MTX.

Damage-associated molecular patterns and fibrinolysis perturbation are associated with lethal outcomes in traumatic injury.

BACKGROUND: Upon cellular injury, damage-associated molecular patterns (DAMPs) are released into the extracellular space and evoke proinflammatory and prothrombotic responses in animal models of sterile inflammation. However, in clinical settings, the dynamics of DAMP levels after trauma and links between DAMPs and trauma-associated coagulopathy remain largely undetermined. METHODS: Thirty-one patients with severe trauma, who were transferred to Kagoshima City Hospital between June 2018 and December 2019, were consecutively enrolled in this study. Blood samples were taken at the time of delivery, and 6 and 12 h after the injury, and once daily thereafter. The time-dependent changes of coagulation/fibrinolysis markers, including thrombin-antithrombin complex, α2-plasmin inhibitor (α2-PI), plasmin-α2-PI complex, and plasminogen activator inhibitor-1 (PAI-1), and DAMPs, including high mobility group box 1 and histone H3, were analyzed. The relationship between coagulation/fibrinolysis markers, DAMPs, Injury Severity Score, in-hospital death, and amount of blood transfusion were analyzed. RESULTS: The activation of coagulation/fibrinolysis pathways was evident at the time of delivery. In contrast, PAI-1 levels remained low at the time of delivery, and then were elevated at 6-12 h after traumatic injury. Histone H3 and high mobility group box 1 levels were elevated at admission, and gradually subsided over time. PAI-1 levels at 6 h were associated with serum histone H3 levels at admission. Increased histone H3 levels and plasmin-α2-PI complex levels were associated with in-hospital mortality. α2-PI levels at admission showed the strongest negative correlation with the amount of blood transfusion. CONCLUSION: The elevation of histone H3 levels and fibrinolysis perturbation are associated with fatal outcomes in patients with traumatic injury. Patients with low α2-PI levels at admission tend to require blood transfusion.

An evaluation of circulating activated TAFI in septic DIC: a case series and review of the literature.

BACKGROUND: Administration of recombinant human soluble thrombomodulin (rTM) is often used in Japan to treat septic disseminated intravascular coagulation (DIC). Thrombin-activatable fibrinolysis inhibitor (TAFI) is a fibrinolysis inhibitor activated by the thrombin-thrombomodulin complex, however, it is unknown whether circulating activated TAFI is increased after rTM administration in patients with DIC. Furthermore, the relationship between TAFI activation and the prognosis of septic DIC is not defined yet. CASE PRESENTATION: We report a series of 8 patient's TAFI activation with septic DIC treated by rTM. We sought to investigate the effect of rTM on TAFI activation and the association of plasma activated TAFI (TAFIa/ai) levels with the prognosis of septic DIC. Using plasma samples from clinical studies conducted from May 2016-March 2017 on eight patients with septic DIC at Kagoshima University Hospital, we measured plasma levels of total TAFI, TAFIa/ai, thrombin-antithrombin complex (TAT), prothrombin fragment 1 + 2 (F1 + 2), soluble fibrin (SF), antithrombin (AT), protein C (PC), protein S (PS), and plasminogen activator inhibitor-1 (PAI-1) before and after intravenous rTM administration. Then, we evaluated the relationship of these marker levels to prognosis. The thrombin-rTM complex activated TAFI in vitro in plasma from a healthy volunteer. However, TAFIa/ai levels did not significantly increase over baseline in the septic DIC patients after intravenous rTM administration. Baseline TAFIa/ai levels in non-survivors were significantly higher than those in survivors. CONCLUSIONS: Plasma TAFIa/ai did not increase with rTM administration. Elevated baseline TAFIa/ai concentration may be a negative prognostic indicator in septic DIC. Larger studies are needed to confirm the in vivo effect of rTM on TAFI activation.

A modified microchip-based flow chamber system for evaluating thrombogenicity in patients with thrombocytopenia.

BACKGROUND: In the intensive care unit (ICU), patients with thrombocytopenia are at high risk for bleeding and should be assessed for their thrombogenic potential. However, the analytical conditions of conventional hemostatic tests are unsuitable for the evaluation of low-platelet samples. Here we aimed to establish suitable analytical conditions with the Total Thrombus-formation Analysis System (T-TAS) for quantitative assessment of thrombogenic potential in patients with thrombocytopenia and to investigate how T-TAS values relate to bleeding symptoms and the effects of platelet transfusion. METHODS: Modified chips with a different chamber depth were developed for the analysis of low-platelet samples in the T-TAS. We included 10 adult patients admitted to the ICU of Kagoshima University Hospital who required platelet transfusion. Patients were divided into major and minor bleeding groups according to their bleeding scale before platelet transfusion. The thrombogenic potential of these patients before and after platelet transfusion was assessed with hemostatic function tests, including rotational thromboelastometry, multiplate aggregometry, and the T-TAS. RESULTS: Analysis of low-platelet samples revealed that, compared with the conventional chip (80-µm-deep chamber), the modified chip (50-µm-deep chamber) achieved higher sensitivity in detecting elevation of flow pressure caused by growth of an occlusive thrombus in the T-TAS analytical chamber. All patients in the minor bleeding group retained thrombogenic potential that occluded the modified chip (occlusion time 16.3 ± 3.3 min), whereas most patients in the major bleeding group were unable to occlude the modified chip during the 30-min measurement (P <  0.01). The recovery of thrombogenic potential after platelet transfusion was confirmed with the T-TAS and correlated with the function, rather than the count, of transfused platelets. Among all evaluated parameters in hemostatic function tests, only the T-TAS showed significant differences in occlusion time and area under the curve both between the minor and major bleeding groups and between pre- and post-platelet transfusion. CONCLUSIONS: We developed a modified microchip-based flow chamber system that reflects the hemostatic function of patients with thrombocytopenia.

Fulminant myocarditis associated with severe fever with thrombocytopenia syndrome: a case report.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral infectious disease with high mortality. It causes multiple organ dysfunction; however, myocarditis has never been reported as a complication with SFTS. CASE PRESENTATION: A 62-year-old previously healthy woman developed fever, fatigue, diarrhea, and a mild consciousness disorder. She visited a local clinic, and laboratory data showed leukocytopenia, thrombocytopenia, and elevation of the aspartate aminotransferase level. She was transferred to Kagoshima University Hospital and diagnosed as having SFTS by real-time reverse transcription polymerase chain reaction. Subsequently, her blood pressure gradually decreased despite fluid resuscitation and vasopressor administration. Based on elevated toroponin I levels in serum, a transient diffuse left ventricular hypokinesis and wall thickening in echocardiography, diffuse ST elevation in electrocardiography, and exclusion of other heart diseases, she was diagnosed as having fulminant myocarditis. After hemodynamic support with inotropic agents, she recovered near normal cardiac function. She was discharged to home on day 28. CONCLUSIONS: We report the first case of fulminant myocarditis associated with SFTS.

Circulating histone H3 levels in septic patients are associated with coagulopathy, multiple organ failure, and death: a single-center observational study.

BACKGROUND: Nuclear histone proteins are released into the extracellular space, and act as major mediators of coagulopathy and remote organ failure in septic animals. However, the circulating histone levels in septic patients have not been precisely quantified. METHODS: Using a novel enzyme-linked immunosorbent assay for histone H3 detection, we measured the serum histone H3 levels in 85 patients admitted to the intensive care unit because of infectious diseases. We then evaluated the associations of circulating histone H3 levels with organ failure, coagulopathy, and mortality. RESULTS: Circulating histone H3 levels were significantly higher in patients with coagulopathy, and were positively correlated with numbers of organ failures. Circulating histone H3 levels were also associated with fatal outcome. Receiver-operating characteristic analyses revealed that the predictive performance of circulating histone H3 levels for mortality was higher than that of conventional inflammatory markers, including white blood cell count, C-reactive protein, and cell-free DNA. CONCLUSIONS: Circulating histone H3 levels are associated with coagulopathy, multiple organ failure, and death in patients requiring intensive care because of infectious diseases.

Circulating activated protein C levels are not increased in septic patients treated with recombinant human soluble thrombomodulin.

BACKGROUND: Recombinant human soluble thrombomodulin (rTM) has been used for the treatment of disseminated intravascular coagulation in Japan, and an international phase III clinical trial for rTM is currently in progress. rTM mainly exerts its anticoagulant effects through an activated protein C (APC)-dependent mechanism, but the circulating APC levels after rTM treatment have not been clarified. This prospective observational study investigated plasma APC levels after rTM treatment. METHODS: Plasma levels of soluble thrombomodulin, thrombin-antithrombin complex (TAT), protein C, and APC were measured in eight septic patients treated with rTM. APC generation in vitro was assessed in the presence or absence of rTM. RESULTS: rTM significantly increased thrombin-mediated APC generation in vitro. In septic patients, soluble thrombomodulin levels were significantly increased during a 30-60-min period of rTM treatment and TAT levels were decreased. However, APC activity was not increased during the treatment period. CONCLUSIONS: Plasma APC activity is not increased in septic patients treated with rTM. It is possible that APC acts locally and does not circulate systemically.

Monitoring of Brain Oxygenation During and After Cardiopulmonary Resuscitation: A Prospective Porcine Study.

This study aimed to evaluate the usefulness of near-infrared time-resolved spectroscopy (TRS) for the monitoring of post-resuscitation encephalopathy. Cardiac arrest (CA) was induced in pigs by electrical stimuli; then, return of spontaneous circulation (ROSC) was achieved by direct current. The changes in cerebral oxygenation were analyzed by two methods: (1) the time-independent calculation based on the modified Beer-Lambert law (MBL), and (2) the curve-fitting method based on the photon diffusion theory (DT). The changes in reduced scattering coefficient (µs') in DT were also calculated. Post-resuscitation encephalopathy was evaluated by MRI findings. During CA, cerebral oxygen saturation (ScO2) decreased to the lowest level, and then gradually increased during the chest compression period. When ROSC was achieved, ScO2 (DT) increased further, but ScO2 (MBL) decreased transiently. This strange phenomenon disappeared when the scalp was peeled off and the probes were directly fixed to the cranial bone. In some cases, a sustained decrease in µs' was observed several hours after ROSC and, in such cases, MRI Diffusion Enhancement Image (DWI) showed findings suggestive of post-resuscitation encephalopathy. In conclusion, simultaneous monitoring of cerebral oxygenation with MBL and DT may provide more information about the vascular response of different layers. Also, the monitoring of µs' may help us to recognize the occurrence of post-resuscitation encephalopathy in real time.

Non-invasive Monitoring of Hepatic Oxygenation Using Time-Resolved Spectroscopy.

UNLABELLED: The aim of the present study was to investigate whether changes in hepatic oxygenation can be detected by time-resolved spectroscopy (TRS) placed on the skin surface above the liver. METHODS: With approval of the local Hospital Ethics Committee and informed consent, six healthy volunteers aged 28.8 (25-36) years, and five patients with chronic renal failure aged 70.6 (58-81) years were studied. In six healthy volunteers, following echography, TRS (TRS-10, Hamamatsu Photonics K.K., Hamamatsu, Japan) probes consisting of a near-infrared light (at 760, 800, 835 nm) emitter and a receiver optode, were placed 4 cm apart on the abdominal skin surface above the liver or at least 10 cm distant from the liver. In five patients with chronic renal failure, following echography, TRS probes were placed 4 cm apart on the skin surface above the liver during hemodialysis (HD). RESULTS: In six healthy volunteers, the values of abdominal total hemoglobin concentration (tHb) were significantly higher in the liver area than in the other area (80.6±26.81 vs 44.6±23.1 µM, p=0.0017), while the value of abdominal SO2 in the liver area was nearly the same as that in the other area (71.5±3.6 vs 73.6±4.6%, p=0.19). The values of mean optical pathlength and scattering coefficient (µ's) at 800 nm in the liver area were significantly different from those in the other area (21.3±4.9 vs 29.2±5 cm, p=0.0004, and 7.97±1.14 vs 9.02±0.51 cm(-1), p=0.015). One of five patients with chronic renal failure complained of severe abdominal pain during HD, and abdominal SO2 decreased from 53 to 22%; however, pain relief occurred following cessation of HD, and SO2 recovered to the baseline level. CONCLUSIONS: Our data suggest that the optical properties of the liver may be measured by the TRS placed on the skin surface, and the hepatic oxygenation may act as a non-invasive monitoring for early detection of intestinal ischemia.

Two autopsy cases of severe fever with thrombocytopenia syndrome (SFTS) in Japan: a pathognomonic histological feature and unique complication of SFTS.

We report two autopsy cases of severe fever with thrombocytopenia syndrome (SFTS) with a high fatality rate in aged Japanese patients. Both cases were caused by a tick-bite. The pathognomonic histological feature was necrotizing lymphadenitis of systemic lymphoid tissue with SFTS viruses and SFTSV-RNA copies. Marked fungal infections were also observed in the lungs of both patients. Since cellular immune function may be suppressed in SFTS patients, physicians should be aware of possible fungal infections.

Safety and efficacy of dexmedetomidine for long-term sedation in critically ill patients.

PURPOSE: We evaluated the safety and efficacy of long-term administration of dexmedetomidine in patients in the intensive care unit (ICU). Primary endpoint was the incidence of hypotension, hypertension, and bradycardia. Secondary endpoints were withdrawal symptoms, rebound effects, the duration of sedation with Richmond Agitation-Sedation Scale (RASS) ≤ 0 relative to the total infusion time of dexmedetomidine, and the dose of additional sedatives or analgesics. METHODS: Dexmedetomidine 0.2-0.7 µg/kg/h was continuously infused for maintaining RASS ≤ 0 in patients requiring sedation in the ICU. Safety and efficacy of short-term (≤ 24 h) and long-term (>24 h) dexmedetomidine administration were compared. RESULTS: Seventy-five surgical and medical ICU patients were administered dexmedetomidine. The incidence of hypotension, hypertension, and bradycardia that occurred after 24 h (long-term) was not significantly different from that occurring within 24 h (short-term) (P = 0.546, 0.513, and 0.486, respectively). Regarding withdrawal symptoms, one event each of hypertension and headache occurred after the end of infusion, but both were mild in severity. Increases of mean arterial blood pressure and heart rate after terminating the infusion of dexmedetomidine were not associated with the increasing duration of its infusion. The ratio of duration with RASS ≤ 0 was ≥ 85 % until day 20, except day 9 (70 %) and day 10 (75 %). There was no increase in the dose of additional sedatives or analgesics after the first 24-h treatment period. CONCLUSIONS: Long-term safety of dexmedetomidine compared to its use for 24 h was confirmed. Dexmedetomidine was useful to maintain an adequate sedation level (RASS ≤ 0) during long-term infusion.

[Spinal instrumentation and spinal fusion surgery].

In this article, we review the potential complications of spinal instrumentation discussing various types of postoperative complications. Surgical implants in spinal surgeries are used to stabilize the spine, replace the defective parts and maintain anatomic reduction. Internal spinal instrumentation has undergone considerable advances during the last century. However, the spinal instrumentation is an invasive surgery, and postoperative complications occur frequently after the spinal deformity surgery. Elderly patients, who may have many histories of medical complications and osteoporosis, have a higher complication rate. Pulmonary complications are the most common life-threatening postoperative complications. The acute onset of neurologic symptoms in the immediate postoperative period should arouse clinical suspicion about the possible formation of a hematoma. Such occurrences require urgent surgical decompression. Better recognition of postoperative risk factors and early detection of urgent signs may lead to decrease complication rates and may improve outcomes. Although the latest monitoring system is very useful we should recognize that the observation of the patients by the five senses is the most important way to detect the postoperative medical complications early.

Type III Kounis Syndrome Caused by Iodine Contrast Media After Improvement of Allergic Symptoms.

Kounis syndrome is an acute coronary syndrome (ACS) caused by an allergic reaction that almost always occurs immediately and simultaneously with allergic symptoms. We present a case of Kounis syndrome type III that developed after complete resolution of contrast-induced anaphylaxis in a 60-year-old man with a coronary stent placed in the proximal left anterior descending (LAD) artery branch for ischemic heart disease. Contrast-enhanced computed tomography revealed anaphylactic shock. Symptoms quickly improved with intramuscular adrenaline injection; however, chest pain appeared after approximately 30 min. ECG revealed ST-wave elevation in the precordial leads. Coronary angiography revealed acute stent thrombosis with total occlusion of the proximal LAD, and percutaneous coronary angioplasty was performed. We diagnosed Kounis syndrome based on the allergic symptoms and ACS. Because some cases of Kounis syndrome develop after anaphylactic symptoms have resolved, it is advisable to follow-up patients with allergic symptoms and pay attention to chest symptoms and ECG changes, especially when they have a history of noted or treated coronary artery disease.

Observation of blood motion in the internal jugular vein by contact and contactless photoplethysmography during physiological testing: case studies.

Central venous pressure is an estimate of right atrial pressure and is often used to assess hemodynamic status. However, since it is measured invasively, non-invasive alternatives would be of great utility. The aim of this preliminary study was a) to investigate whether photoplethysmography (PPG) can be used to characterize venous system fluid motion and b) to find the model for venous blood volume modulations. For this purpose, we monitored the internal jugular veins using contact (cPPG) and video PPG during clinically validated physiological tests: abdominojugular test (AJT) and breath holding (BH). Video PPG and cPPG signals were captured simultaneously on the left and right sides of the neck, respectively. ECG was also captured using the same clinical monitor as cPPG. Two volunteers underwent AJT and BH with head up/down, each with: baseline (15s), experiment (15s), and recovery (15s). Video PPG was split into remote PPG (rPPG) and micromotion detection. All signal modalities were significantly affected by physiological testing. Moreover, cPPG and micromotion waveforms exhibited primary features of jugular vein waveforms and, therefore, have great potential for venous blood flow monitoring. Specifically, remote patient monitoring applications may be enabled by this methodology, facilitating physical collection without a specially trained care provider.

Survival trends of extracorporeal membrane oxygenation support for pediatric emergency patients in regional and metropolitan areas in Japan.

BACKGROUND: To assess the performance of pediatric extracorporeal membrane oxygenation (ECMO) centers, outcomes were compared between metropolitan and other areas. METHODS: A retrospective cohort study was conducted at three regional centers on Kyushu Island and the largest center in the Tokyo metropolitan area of Japan. The clinical outcomes of patients of ≤15 years of age who received ECMO during 2010-2019 were investigated, targeting the survival and performance at discharge from intensive care units (ICUs), using medical charts. RESULTS: One hundred and fifty-five patients were analyzed (regional, n = 70; metropolitan, n = 85). Survival rates at ICU discharge were similar between the two areas (64%). In regional centers, deterioration of Pediatric Cerebral Performance Category (PCPC) scores were more frequent (65.7% vs. 49.4%; p = 0.042), but survival rates and ΔPCPC scores (PCPC at ICU discharge-PCPC before admission) improved in the second half of the study period (p = 0.005 and p = 0.046, respectively). Veno-arterial ECMO (odds ratio [OR], 3.00; p < 0.03), extracorporeal cardiopulmonary resuscitation (OR, 8.98; p < 0.01), and absence of myocarditis (OR, 5.47; p < 0.01) were independent risk factors for deterioration of the PCPC score. A sub-analysis of patients with acute myocarditis (n = 51), the main indicator for ECMO, revealed a significantly higher proportion of cases with deteriorated PCPC scores in regional centers (51.9% vs. 25.0%; p = 0.049). CONCLUSIONS: The survival rates of pediatric patients supported by ECMO in regional centers were similar to those in a metropolitan center. However, neurological outcomes must be improved, particularly in patients with acute myocarditis.

Development of initial loading procedure for teicoplanin in critically ill patients with severe infections.

Methicillin-resistant Staphylococcus aureus (MRSA) is now endemic in many hospitals. Infection with MRSA is more frequent in the intensive care unit (ICU) than in general wards. Therefore, appropriate treatments for MRSA infections will lead to good outcomes in the ICU. Teicoplanin is an anti-MRSA agent. Recently, it was recommended at a new target trough concentration of 15-30 µg/mL. However, the initial loading procedure for teicoplanin to allow it to reach the target concentration promptly remains uncertain. Therefore, this study aimed to determine the appropriate initial loading procedure for teicoplanin in critically ill patients with severe infections. We performed a retrospective study in patients given teicoplanin in the ICU in order to determine the initial loading procedure to promptly reach the target trough concentration. We then evaluated the trough concentration on the third day after commencement of teicoplanin therapy. The mean loading dose and trough concentration were 11.5±1.0 mg/kg and 18.9±5.9 µg/mL, respectively. A correlation (r=0.45, p=0.046) was shown between teicoplanin loading dose and trough concentration. The correlation equation was trough concentration=2.563·loading dose -10.672. In the cases of 11.0 and 15.0 mg/kg for the loading dose, respectively, trough concentrations were 17.5 and 27.8 µg/mL. We suggested that an initial loading dose of 11-15 mg/kg every 12 h for 3 doses should be administered to promptly achieve the target trough concentration of 15-30 µg/mL on the third day after commencement of teicoplanin therapy in the ICU.

[Naloxone].

Naloxone hydrochloride is an agent capable of antagonizing respiratory depression and analgesic actions which are inherent to the opioid by competitively acting at opioid receptors. It greatly contributed to basic research on antagonistic action of opioid receptors due to its high affinity to opioid receptors, in particular, micro-receptor. Naloxone has been recommended as an analeptic agent at a guideline level for patients with revealed or suspicious opioid addiction. Further, it has also been used as a preventive and treatment agent for spinal cord ischemia. Moreover, even though it has been confirmed in 1980's that naloxone has vasopressor effect in septic shock, further clinical trials are required for its wide clinical application.

Prognostic predictors in patients with cardiopulmonary arrest: A novel equation for evaluating the 30-day mortality.

BACKGROUND: Early prediction of outcomes after cardiopulmonary arrest (CPA) is important for considering the best support. Our purpose was to evaluate predictors of the 30-day mortality in patients with CPA after return of spontaneous circulation (ROSC) and to assess an equation for calculating the 30-day mortality using clinical parameters. METHODS: We retrospectively analyzed the data of 194 consecutive patients with CPA and ROSC in a derivation study (2015-2022). We compared clinical parameters between the survived (n = 78) and dead (n = 116) patients. We derived an equation for estimated probability of death based on clinical parameters, using multivariate logistic regression analysis. The reliability of the equation was validated in 80 additional patients with CPA. RESULTS: The 30-day mortality was associated with sex, witnessed cardiac arrest, bystander cardiopulmonary resuscitation (CPR), CPA due to acute myocardial infarction, pupil diameter, Glasgow Coma Scale score (GCS), presence of light reflex, arterial or venous pH, lactate levels, initial ventricular fibrillation (VF), CPA time, and age. The derived logistic regression equation was as follows: Estimated probability of death = 1 / (1 + e-x), x = (0.25 × bystander CPR) + (0.44 × pupil diameter) - (0.14 × GCS) + (0.09 × lactate) - (1.87 × initial VF) + (0.07 × CPA time) + (0.05 × age) - 7.03. The cut-off value for estimated probability of death calculated by this equation was 54.5 %, yielding a sensitivity, specificity, and accuracy of 86.2 %, 80.8 %, and 84.5 %, respectively. In the validation model, these values were 81.8 %, 85.7 %, and 82.5 %, respectively. CONCLUSIONS: The 30-day mortality may be calculated after ROSC in patients with CPA using simple clinical parameters. This equation may facilitate further best support for patients with CPA.

Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study.

INTRODUCTION: Fever is frequently observed in critically ill patients. An independent association of fever with increased mortality has been observed in non-neurological critically ill patients with mixed febrile etiology. The association of fever and antipyretics with mortality, however, may be different between infective and non-infective illness. METHODS: We designed a prospective observational study to investigate the independent association of fever and the use of antipyretic treatments with mortality in critically ill patients with and without sepsis. We included 1,425 consecutive adult critically ill patients (without neurological injury) requiring >48 hours intensive care admitted in 25 ICUs. We recorded four-hourly body temperature and all antipyretic treatments until ICU discharge or 28 days after ICU admission, whichever occurred first. For septic and non-septic patients, we separately assessed the association of maximum body temperature during ICU stay (MAXICU) and the use of antipyretic treatments with 28-day mortality. RESULTS: We recorded body temperature 63,441 times. Antipyretic treatment was given 4,863 times to 737 patients (51.7%). We found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen independently increased 28-day mortality for septic patients (adjusted odds ratio: NSAIDs: 2.61, P=0.028, acetaminophen: 2.05, P=0.01), but not for non-septic patients (adjusted odds ratio: NSAIDs: 0.22, P=0.15, acetaminophen: 0.58, P=0.63). Application of physical cooling did not associate with mortality in either group. Relative to the reference range (MAXICU ≥ 39.5°C increased risk of 28-day mortality in non-septic patients (adjusted odds ratio 8.14, P=0.01), but not in septic patients (adjusted odds ratio 0.47, P=0.11) [corrected]. CONCLUSIONS: In non-septic patients, high fever (≥39.5°C) independently associated with mortality, without association of administration of NSAIDs or acetaminophen with mortality. In contrast, in septic patients, administration of NSAIDs or acetaminophen independently associated with 28-day mortality, without association of fever with mortality. These findings suggest that fever and antipyretics may have different biological or clinical or both implications for patients with and without sepsis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00940654.

Early ascorbic acid administration prevents vascular endothelial cell damage in septic mice.

Oxidation of BH4, a cofactor of nitric oxide synthase (NOS), produces reactive oxygen species (ROS) through uncoupling of NOS and affects vascular endothelial dysfunction. Ascorbic acid (AsA) inhibits the oxidation of BH4 and reduces ROS. However, the kinetic changes of BH4 in sepsis and its effect on the kinetic changes in AsA administration therapy, as well as the appropriate timing of AsA administration for AsA therapy to be effective, are unclear. Mice with sepsis, induced by cecal ligation and puncture (CLP), were examined for the effect of AsA administration (200 mg/kg) on vascular endothelial cell dysfunction at two administration timings: early group (AsA administered immediately after CLP) and late group (AsA administered 12 h after CLP). Survival rates were compared between the early and late administration groups, and vascular endothelial cell damage, indicated by the dihydrobiopterin/tetrahydrobiopterin ratio, serum syndecan-1, and endothelial nitric oxide synthase, as well as liver damage, were examined. The early group showed significantly improved survival compared to the non-treatment group (p < 0.05), while the late group showed no improved survival compared to the non-treatment group. Compared to the non-treated group, the early AsA group showed less oxidation of BH4 in sepsis. Syndecan1, a marker of vascular endothelial cell damage, was less elevated and organ damage was reduced in the early AsA-treated group. In septic mice, early AsA administration immediately after CLP may protect vascular endothelial cells by inhibiting BH4 oxidation, thereby reducing organ dysfunction and improving survival.