Study of usefulness of low-dose IgG for patients with septic disseminated intravascular coagulation.

Aim: Improving prognosis with intravenous IgG (IVIG) has been ruled out in a large, multicenter, randomized controlled trial in patients with sepsis. However, its efficacy in the case of septic disseminated intravascular coagulation (DIC) has not been well studied. Results, materials & methods: We retrospectively evaluated the effects of IVIG on severity scores and 28-day survival in patients with septic DIC. A total of 80 patients with septic DIC were enrolled. Changes in infection-related markers, coagulation-related markers, severity scores and 28-day survival were compared between IVIG-treated and untreated groups. Discussion & conclusion: IVIG treatment significantly reduced the Sequential Organ Failure Assessment scores and DIC scores and increased platelet counts, but the 28-day mortality rate did not decrease significantly.

Association of type II secretory phospholipase A2 and surfactant protein D with the pulmonary oxygenation potential in patients with septic shock during polymyxin-B immobilized fiber-direct hemoperfusion.

This study was undertaken to analyze the association of type II secretory phospholipase A2 (sPLA2 -II) and surfactant protein D (SP-D) with the pulmonary oxygenation potential in patients with septic shock during polymyxin-B immobilized fiber-direct hemoperfusion (PMX-DHP). The study was conducted in 25 patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). PMX-DHP lowered the blood endotoxin level in all patients. Following PMX-DHP, there were decreases from day 0 → day 1 → day 2 in both the mean plasma sPLA2 -II level (340 → 260 → 189 ng/mL) and plasma SP-D level (483 → 363 → 252 ng/mL). The PaO2/FiO2 ratio (P/F ratio) rose (210 → 237 → 262) in all patients. Upon the onset of ALI or ARDS, there was a significant negative correlation between the sPLA2 -II level and the P/F ratio. Furthermore, there was a significant positive correlation between the sPLA2 -II and TNF-α levels. The results suggest that as the blood endotoxin levels were lowered by the PMX-DHP, the inflammatory reactions were suppressed, with suppressed formation of sPLA2 -II and improved pulmonary oxygenation potential. The results also suggested possible involvement of TNF-α in the production of sPLA2 -II.

Diagnostic accuracy of procalcitonin and presepsin for infectious disease in patients with acute kidney injury.

Procalcitonin (PCT) and presepsin (PSEP) are sepsis markers, but their diagnostic accuracy may be compromised in acute kidney injury (AKI). We evaluated their diagnostic accuracy in patients with/without AKI. This retrospective study comprised 91 patients with at least one criterion of systematic inflammatory response syndrome. AKI markers plasma neutrophil gelatinase-associated lipocalin (NGAL), plasma cystatin C (CysC), and estimated glomerular filtration rate (eGFR) were measured upon hospital admission and on days 1, 3, 5, and 7. Patients were divided into non-AKI and AKI groups. APACHE II severity scores were determined. PCT and PSEP levels were increased significantly in non-AKI and AKI patients with infection. NGAL, CysC, and eGFR in patients with infection were associated with PCT, PSEP, and APACHE II score, and levels of PCT and PSEP were correlated significantly with disease severity. PCT and PSEP are useful markers of bacterial infections in AKI but different thresholds should be applied.

Age-related effects of dexmedetomidine on myocardial contraction and coronary circulation in isolated guinea pig hearts.

Dexmedetomidine is a selective α2 adrenergic agonist. Although dexmedetomidine is widely used for sedation and analgesia, it frequently produces hypotension and bradycardia. The present study aimed to evaluate the effects of dexmedetomidine on cardiac function and coronary circulation using Langendorff-perfused guinea pig hearts. Coronary perfusion pressure (CPP) and left ventricular pressure (LVP) were continuously monitored, and electric field stimulation (EFS) was applied to stimulate sympathetic nerve terminals. Dexmedetomidine almost completely inhibited the EFS-induced increase in LVP at all ages. The effect of dexmedetomidine on coronary artery resistance varied according to postnatal age, i.e., dexmedetomidine had little effect on CPP in young hearts (<4 weeks) but increased CPP by 10 mmHg at 4-8 weeks and by 15 mmHg at >8 weeks. The increase in CPP in adult hearts was inhibited by imiloxan, an α2B antagonist, and prazosin, an α1 antagonist. The results suggest that dexmedetomidine acts on α2 adrenergic receptors at sympathetic nerve terminals to suppress the release of norepinephrine. In addition, the findings suggest that dexmedetomidine directly affects α1 adrenoceptors and/or α2B adrenoceptors on coronary smooth muscles to increase CPP. The age-related changes in α adrenoceptor subtypes may be linked to the cardiodepressant effects of dexmedetomidine.

Clinical Performance of a New Soluble CD14-Subtype Immunochromatographic Test for Whole Blood Compared with Chemiluminescent Enzyme Immunoassay: Use of Quantitative Soluble CD14-Subtype Immunochromatographic Tests for the Diagnosis of Sepsis.

We previously reported that a soluble CD14-subtype (sCD14-ST) immunochromatographic test (ICT) for plasma is more convenient than chemiluminescent enzyme immunoassay (CLEIA), but plasma separation makes bedside measurements difficult. We developed a new sCD14-ST ICT for whole blood and investigated whether quantitative determinations of sCD14-ST by ICT were useful for diagnosing sepsis and severe sepsis/septic shock. We studied 20 patients who fulfilled two or more systemic inflammatory response syndrome (SIRS) criteria and 32 patients who had been diagnosed with sepsis or severe sepsis/septic shock. Whole blood was collected on day 0 (on admission) and day 7, and the sCD14-ST concentration was quantitatively measured by CLEIA and ICT for whole blood. The patients' Acute Physiology and Chronic Health Evaluation (APACHE) II, Sequential Organ Failure Assessment (SOFA), and Mortality in Emergency Department Sepsis (MEDS) scores were also calculated. The cut-off values obtained by the quantitative measurements made by ICT were 464.5 pg/mL for sepsis and 762.7 pg/mL for severe sepsis/septic shock (P < 0.0001). A Bland-Altman plot showed that no fixed bias or proportional bias was detected between CLEIA and quantitative ICT for whole blood. sCD14-ST concentrations were significantly correlated with APACHE II, SOFA, and MEDS scores (P < 0.0001). These results suggest that the new sCD14-ST ICT for whole blood may be a useful tool for the convenient, rapid bedside diagnosis and treatment of sepsis.

[Effect of Human Serum Albumin on Endotoxin Scattering Photometry].

PURPOSE: Laser scattering photometry (ESP) is a newly developed plasma endotoxin assay method using horseshoe crab amebocyte lysate (AL) that recognizes small particles produced by polymerization of coagulin under the stirring conditions at 1000rpm. We elucidated the effect of human serum album (HSA) in the ESP method. METHODS: AL was dissolved with 630µL of the specimen and a 200-µL aliquot was used for ESP; this conventional protocol was regarded as the ESP630 method. The ESP210 method was also used, i. e. AL was dissolved with 210µL of the specimen and a 200-µL aliquot was used for ESP. RESULTS: Water induced the agglutination, and HSA prolonged the agglutination time depending on its concentration especially in the ESP630 method. The water-induced agglutination was not inhibited by the addition of anti-factor C monoclonal antibody, and amidinophenyl benzoate hydrochloride, used as a clotting enzyme inhibitor, intensively inhibited the water-induced agglutination. Therefore, the water-induced agglutination was suggested to be a false-positive reaction to non-specific activation of the clotting enzyme. The HSA-induced prolongation of the reaction in the national health insurance-covered turbidimetric kinetic assay was not observed. CONCLUSION: HSA or plasma protein seemed to affect the result, especially in the ESP630 method, and a non-specific reaction was found to occur in the ESP methods.

Determination of ß-d-glucan and endotoxin levels in Kampo extracts.

Aims: Kampo medicine is based on the use of established formulations combining natural extracts with no "brand-name" products or corresponding "generic" formulation. Due to differences in manufacturing practices, products of different pharmaceutical companies may contain different concentrations of ß-d-glucan and endotoxins. The aim of this study was to compare the concentrations of ß-d-glucan and endotoxins in five Kampo extracts from four pharmaceutical companies. Methods: Packages of Kampo extracts were dissolved in distilled water. ß-d-Glucan and endotoxin concentrations were measured using high-sensitivity kinetic turbidimetric Limulus assay. Results: All Kampo extracts examined in this study were found to contain detectable concentrations of ß-d-glucan and endotoxins. Significant differences in the concentration of ß-d-glucan and endotoxins (P = 0.0024 and P = 0.0013, respectively) were observed between products of different pharmaceutical companies. Conclusions: High ß-d-glucan and endotoxin contents were detected in Kampo extracts, with a large variability in the concentrations of both ß-d-glucan and endotoxins among extracts from different pharmaceutical companies.

Presepsin in the prognosis of infectious diseases and diagnosis of infectious disseminated intravascular coagulation: a prospective, multicentre, observational study.

BACKGROUND: Few prospective studies have described the prognostic accuracy of presepsin for 28-day mortality during days 0 to 7, or its role in the diagnosis of disseminated intravascular coagulation (DIC) in patients with infection. OBJECTIVE: We aimed to evaluate the clinical usefulness of presepsin levels by comparing infection markers such as procalcitonin, interleukin-6 and C-reactive protein, as well as markers of DIC such as fibrin degradation products (FDPs) and D-dimer, from days 0 to 7. DESIGN: A prospective, multicentre, observational study. SETTING: Four medical institutions between June 2010 and June 2011. PATIENTS: A total of 191 patients who fulfilled at least one of the systemic inflammatory response syndrome (SIRS) criteria were enrolled in the study. MAIN OUTCOME MEASURES: The presepsin levels were evaluated for their diagnostic accuracy in discriminating between SIRS and sepsis, the prognostic accuracy for 28-day mortality from days 0 to 7 and the diagnostic accuracy for DIC in patients with infection by comparison with other infection markers. RESULTS: The diagnostic accuracy for discriminating between SIRS and sepsis from combining the presepsin and procalcitonin measurements [area under the curve (AUC), 0.91; likelihood ratio, 4.96] was higher than that of presepsin (AUC, 0.89; likelihood ratio, 4.75) or procalcitonin (AUC, 0.85; likelihood ratio, 3.18) alone. Not only the correlation coefficient between the presepsin level and the sequential organ failure assessment (SOFA) score but also the prognostic accuracy of presepsin for 28-day mortality increased with the elapsed time, and both were highest at day 7. The diagnostic accuracy for DIC generated by combining presepsin and FDP (AUC, 0.84; likelihood ratio, 3.57) was higher than that of FDP (AUC, 0.82; likelihood ratio, 2.64) or presepsin (AUC, 0.80; likelihood ratio, 2.94) alone. CONCLUSION: The prognosis and severity of infection may be assessed more accurately by measuring the presepsin levels until day 7. Presepsin is a useful diagnostic tool for DIC with infection.

The mechanism of increased postnatal heart rate and sinoatrial node pacemaker activity in mice.

Heart rate (HR) of mammalian species changes postnatally, i.e., HR of large animals including humans decreases, while HR in small animals such as mice and rats increases. To clarify cellular mechanisms underlying the postnatal HR changes, we performed in vivo HR measurement and electrophysiological analysis on sinoatrial node (SAN) cells in mice. The in vivo HR was ~320 beats min(-1) (bpm) immediately after birth, and increased with age to ~690 bpm at postnatal day 14. Under blockage of autonomic nervous systems, HR remained constant until postnatal day 5 and then increased day by day. The spontaneous beating rate of SAN preparation showed a similar postnatal change. The density of the L-type Ca(2+) current (LCC) was smaller in neonatal SAN cells than in adult cells, accompanied by a positive shift of voltage-dependent activation. Thus, the postnatal increase in HR is caused by both the increased sympathetic influence and the intrinsic activity of SAN cells. The different conductance and kinetics of LCC may be involved in the postnatal increase in pacemaker activity.

Interleukin-18 levels reflect the long-term prognosis of acute lung injury and acute respiratory distress syndrome.

PURPOSE: The purpose of this study was to investigate the relationship between the blood levels of interleukin (IL)-18 measured in the early stage of acute respiratory failure and the prognosis for patient survival. METHODS: The study subjects were 38 patients with acute respiratory failure treated at our institution during the 4-year period from April 2004 to March 2008. The underlying clinical condition was defined as acute respiratory distress syndrome (ARDS; n = 12) or acute lung injury (ALI; n = 26). The serum levels of interleukin (IL)-18, IL-12, and tumor necrosis factor (TNF)-α were measured by enzyme-linked immunosorbent assays. RESULTS: The ARDS group showed significantly higher serum levels of IL-18, IL-12, and TNF-α even at an early stage after disease onset compared with the ALI group. A negative correlation was noted between the PaO(2)/FIO(2) ratio (P/F ratio) and serum IL-18 level. Analysis of all 38 patients with ALI/ARDS revealed a 30-day mortality rate of 7.9 %, 60-day mortality rate of 15.8 %, and 90-day mortality rate of 18.4 %. The early-stage serum levels of IL-18, IL-12, and TNF-α were significantly higher in the non-survivors at 60 and 90 days, but not at 30 days, than in the corresponding survivors. CONCLUSION: The present data demonstrate an inverse correlation between serum IL-18 level and the P/F ratio, suggesting the possible involvement of IL-18 in the pathogenesis of respiratory failure in patients with ALI/ARDS. Early-stage serum IL-18, IL-12, and TNF-α levels appear to reflect the >60-day prognosis in patients with ALI/ARDS.

Direct effects of esmolol and landiolol on cardiac function, coronary vasoactivity, and ventricular electrophysiology in guinea-pig hearts.

The ultra-short acting, selective ß(1)-adrenergic antagonists landiolol and esmolol are widely used perioperatively; however, little is known about their acute direct actions on the heart. The current study utilized the Langendorff perfused heart system to measure changes in cardiac function and hemodynamics in response to each drug. Furthermore, electrophysiological analysis was performed on isolated ventricular myocytes. Direct application of esmolol significantly decreased systolic left ventricular pressure and heart rate at concentrations > 10 µM, while it dose-dependently increased coronary perfusion pressure. Esmolol also shortened the action potential duration (APD) in a concentration-dependent manner, an action maintained even when the delayed rectifier K(+) current or ATP sensitive K(+) current was blocked. Moreover, esmolol inhibited both the inward rectifier K(+) current (I(K1)) and the L-type Ca(2+) current (I(CaL)) and increased the outward current dose-dependently. In contrast, landiolol had minimal cardiac effects. In the Kyoto Model computer simulation, inhibition of either I(K1) or I(CaL) alone failed to shorten the APD; however, an additional increase in the time-independent outward current caused shortening of the APD, equal to that induced by esmolol. In conclusion, esmolol directly inhibits cardiac performance significantly more so than landiolol, an effect revealed to be at least in part mediated by esmolol-induced APD shortening.

Green Urine Discoloration due to Propofol Infusion: A Case Report.

We present a 19-year-old man who excreted green urine after propofol infusion. The patient was admitted to our hospital for injuries sustained in a traffic accident and underwent surgery. After starting continuous infusion of propofol for postoperative sedation, his urine became dark green. Serum total bilirubin and urine bilirubin were both elevated. We believe that the green discoloration of the urine was caused by propofol infusion and was related to impaired enterohepatic circulation and extrahepatic glucuronidation in the kidneys.

Multiple transverse colonic perforations associated with slow-release nonsteroidal anti-inflammatory drugs and corticosteroids: a case report.

The patient was a 36-year-old woman with sarcoidosis and Sjogren's syndrome, and had been prescribed slow-release diclofenac sodium and prednisolone for the treatment of pain associated with uveitis and erythema nodosum. She was admitted to our emergency center with abdominal pain and distention. A chest X-ray showed free air under the diaphragm on both sides, and an emergency laparotomy was performed for suspected panperitonitis associated with intestinal perforation. Laparotomy revealed several perforations on the antimesenteric aspect of the transverse colon. The resected specimen showed 11 punched-out ulcerations, many of which were up to 10 mm in diameter. The microscopic findings were non-specific, with leukocytic infiltration around the perforations. She showed good postoperative recovery, as evaluated on day 42. The present case highlights the need for exercising caution while prescribing slow-release nonsteroidal anti-inflammatory drugs with corticosteroids to patients with autoimmune diseases, as such treatment may exacerbate intestinal epithelial abnormalities.

Suppressive effects of sivelestat on interleukin 8 and TNF-α production from LPS-stimulated granulocytes in whole blood culture.

PURPOSE: The goal of the study was to examine the effects of sivelestat sodium hydrate (sivelestat), a neutrophil elastase inhibitor, on production of cytokines in granulocytes and monocytes, using flow cytometry after cytokine staining in whole blood culture. METHODS: Blood samples were collected from healthy volunteers. Vehicle (control group), lipopolysaccharide (LPS) (LPS group), or LPS + sivelestat (sivelestat group) were added to the whole blood, followed by addition of a protein transport inhibitor in each group. After incubation, staining for cytokines retained in the cells was performed by addition of an anti-interleukin 8 (IL-8) or anti-tumor necrosis factor-α (TNF-α) antibody. The cells were then analyzed using flow cytometry. RESULTS: Granulocytic production of IL-8 induced by 1 ng/ml LPS was significantly (P < 0.05) inhibited by treatment with 1 µg/ml sivelestat, and upregulation of IL-8 by 10 ng/ml LPS was also significantly (P < 0.05) suppressed by 1 and 10 µg/ml sivelestat. Addition of 10 or 100 µg/ml sivelestat significantly (P < 0.05) inhibited the production of TNF-α from granulocytes induced by 10 ng/ml LPS. Sivelestat did not significantly inhibit LPS-induced monocytic production of TNF-α and IL-8. CONCLUSION: Suppression of granulocytic production of IL-8 and TNF-α by sivelestat suggests that this drug may be useful for treatment of morbid conditions involving IL-8 and TNF-α at onset.

A prospective cohort study of ALI/ARDS in the Tohoku district of Japan (second report).

PURPOSE: We previously reported a study of systemic inflammatory response syndrome (SIRS) cases in the Tohoku district of Japan in which the patients showed a 30-day mortality from acute lung injury/acute respiratory distress syndrome (ALI/ARDS) of about 20%. Cases in which chest X-ray findings did not meet ALI/ARDS criteria were diagnosed as acute hypoxemic respiratory failure (AHRF), but about 50% of these patients progressed to ALI/ARDS. The objective of this study was to verify the findings obtained in the earlier study and to gain further insights into the pathognomonic symptoms of AHRF associated with SIRS. METHODS: A prospective cohort study was performed in SIRS patients admitted to the intensive care unit (ICU) with PaO(2)/fractional inspired oxygen (FIO(2)) < or = 300 mmHg. Patients were assigned to ALI or ARDS groups based on symptoms at ICU entry. Cases in which chest X-ray showed no infiltration shadows in bilateral lung fields were classified as AHRF. RESULTS: A total of 240 patients were enrolled in the study. The 30-day mortalities were 21.6% and 20.0% in the ALI and ARDS groups, respectively. Of the 88 AHRF patients, 49 progressed to ALI/ARDS, with progression occurring within 3 days after ICU entry in most cases; 39 patients recovered with no progression. Chest X-ray and computed tomography (CT) showed no findings indicating ALI/ARDS in 20 AHRF patients at ICU entry, but 7 of these patients progressed to ALI/ARDS. CONCLUSION: The mortality rates of ALI and ARDS were 21.6% and 20.5%, respectively. More than half of the AHRF patients progressed to ALI or ARDS. Some AHRF patients had normal findings on chest CT, but subsequently showed a bilateral shadow on a chest X-ray. This indicates that mild pathologic lesions may not show imaging abnormalities.

Use of the bispectral index during the early postresuscitative phase after out-of-hospital cardiac arrest.

Non-invasive and real-time measures of neurological status after cardiac arrest are needed to be able to make an early determination of the postresuscitative outcome. We investigated whether the bispectral index (BIS) predicts the postresuscitative outcome in 10 patients with out-of-hospital cardiac arrest. We measured the BIS after return of spontaneous circulation (ROSC) in the emergency room and on admission to the intensive care unit (ICU). We determined the Glasgow Coma Scale (GCS) on admission to the emergency room and the ICU and the Glasgow Outcome Scale (GOS) on discharge from the ICU. The BIS increased after about 30 min of ROSC or reached a plateau in patients rated as achieving a good recovery or moderate disability, but it did not increase to >80 in patients rated as being in a permanent vegetative state/dead. The GCS on admission to the ICU was the same as that on admission to the emergency room. The BIS values were significantly lower in the nonsurviving group than in the surviving group. There was a positive correlation between the BIS on admission to the ICU and the GOS on discharge from the ICU. The BIS can thus be used to predict the postresuscitative outcome of patients with out-of-hospital cardiac arrest.

Nitrous oxide administration during washout of sevoflurane improves postanesthetic agitation in children.

The use of sevoflurane in pediatric patients, which could enable a more rapid emergence and recovery, is complicated by a high incidence of postanesthetic agitation, probably due to residual sevoflurane during washout. The present study was designed to investigate whether administration of nitrous oxide (N2O) reduces sevoflurane concentration at awakening and suppresses postanesthetic agitation. The study enrolled 20 children classified as ASA physical status I. Anesthesia was induced with 5% sevoflurane and maintained with 2.5% end-tidal sevoflurane and N2O in oxygen. In the control group, sevoflurane and N2O were discontinued immediately after completion of surgery. In the N2O group, inspired N2O was replaced with oxygen after the bispectral index (BIS) had reached 80. The end-tidal concentrations of sevoflurane at awakening were significantly lower (P < 0.05) in the N2O group than in the control group. The BIS at awakening was higher (P < 0.01) in the N2O group than in the control group. The point scores of postanesthetic agitation were significantly lower (P < 0.01) in the N2O group than in the control group. Using N2O during washing out of sevoflurane may improve postanesthetic agitation at awakening in children.

Sevoflurane inhibition of the slowly activating delayed rectifier K+ current in guinea pig ventricular cells.

Single ventricular cells were enzymatically isolated from guinea pig hearts and the effects of sevoflurane on the delayed rectifier K(+) current were investigated by the patch clamp method. The rapidly (I(Kr)) and slowly activating delayed rectifier K(+) current (I(Ks)) were isolated using chromanol 293B, a selective blocker for I(Ks) or E4031 (N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide dihydrochloride), a blocker for I(Kr). Sevoflurane and halothane decreased I(Ks) in a concentration-dependent manner with an IC(50) value of 0.38 mM for sevoflurane and 1.05 mM for halothane. I(Ks) inhibition was characterized by suppression of maximum conductance with little effect on activation kinetics. Inhibition occurred immediately after anesthetic application and recovered upon wash-out. In contrast to the marked inhibition of I(Ks), I(Kr) was hardly affected by sevoflurane. Under the current clamp, sevoflurane prolonged the action potential duration in a reversible manner and this effect was more marked when I(Kr) was inhibited by E4031. The results suggest that sevoflurane inhibits I(Ks), and not I(Kr), in a concentration-dependent manner at clinically relevant concentrations. The resulting prolongation of ventricular repolarization may partly account for the clinical observation of excessive QT prolongation by these anesthetics.

Pacemaker mechanism of porcine sino-atrial node cells.

In cardiac sino-atrial node (SAN) cells, time- and voltage-dependent changes in the gating of various ionic currents provide spontaneous, stable and repetitive firing of action potentials. To address the ionic nature of the species-dependent heart rate, action potentials and membrane currents were recorded in single cells dissociated from the porcine SAN, and compared with those from SAN cells of rabbits, guinea-pigs and mice. The porcine SAN cells exhibited spontaneous activity with a frequency of 60-80 min(-1), which was much slower than that of rabbit SAN cells. Under voltage clamp conditions, depolarization activated the L-type Ca2+ current (I(CaL)) followed by a gradual activation of the delayed rectifier K+ current (I(K)) while hyperpolarization activated the hyperpolarization-activated cation current (I(h)). It was found that the major component of I(K) in porcine SAN is the slowly activating I(K) (I(Ks)), in contrast to SAN cells of the rabbit and other species in which the rapid I(K) (I(Kr)) plays an active role in repolarization and the subsequent pacemaker depolarization. Replacement of rabbit I(Kr) with porcine I(Ks) and a slight modification in the gating parameters and amplitudes of other current systems in the 'Kyoto Model' gave an adequate reconstruction of spontaneous action potentials as well as of the voltage clamp recordings. We conclude that the density and the kinetics of I(K) contribute, in part, to the different heart rates of various species.