Daisuke Inui

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

IntroductionFever 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.MethodsWe 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.ResultsWe 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 36.5°C to 37.4°C), MAXICU ≥ 39.5°C increased risk of 28-day mortality in septic patients (adjusted odds ratio 8.14, P = 0.01), but not in non-septic patients (adjusted odds ratio 0.47, P = 0.11).ConclusionsIn 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 registrationClinicalTrials.gov: NCT00940654

Endothelin-1-(1–31), a novel vasoactive peptide, increases [Ca2+]i in human coronary artery smooth muscle cells

We have previously found that human chymase cleaves big endothelins at the Tyr31-Gly32 bond and produces 31-amino acid long endothelins-(1-31), without any further degradation products. In this study, we investigated the effect of synthetic endothelin-1-(1-31) on the intracellular free Ca2+ concentration ([Ca2+]i) in cultured human coronary artery smooth muscle cells. Endothelin-1-(1-31) increased [Ca2+]i in a concentration-dependent manner (10(-14) to 10(-10) M). This endothelin-1-(1-31)-induced [Ca2+]i increase was not affected by phosphoramidon (N-(alpha-Rhamnopyranosyloxyhydroxyphosphinyl)-L-Leucyl-L-Tryptoph an), an inhibitor of endothelin-converting enzyme. It was, however, inhibited by 10(-10) M BQ123 (Cyclo-(-D-Trp-D-Asp(ONa)-Pro-D-Val-Leu-)), an endothelin ET(A) receptor antagonist, but not by 10(-10) M BQ788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-yMeLeu-D-Trp(COOM e)-D-Nle-ONa), an endothelin ET(B) receptor antagonist. These results suggest that endothelin-1-(1-31) by itself exhibits vasoactive properties probably through endothelin ET(A) receptors. Since human chymase has been reported to play a role in atherosclerosis, endothelin-1-(1-31) may be one of the candidate substances for its cause.

Plasma proinflammatory and anti-inflammatory cytokine and catecholamine concentrations as predictors of neurological outcome in acute stroke patients

PurposeProinflammatory and anti-inflammatory cytokines may play a pivotal role in cerebral inflammation, which is implicated in the development of brain injury. Systemic cytokine release is mediated by the sympathetic nervous system and catecholamines. The aim of this study was to investigate which parameters, among plasma levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor alpha (TNF-α) and the levels of the catecholamines, epinephrine and norepinephrine, contribute to the clinical outcome in acute stroke patients.MethodsThirty-seven acute stroke patients (ischemic, n = 19; hemorrhagic, n = 18) were enrolled. All of them were admitted to our hospital within 8 h after stroke onset. Neurological status was evaluated by a modified National Institute of Health Stroke Scale (mNIHSS) on admission and by a modified Rankin Scale (mRS) at 1 month. An mRS score of 3 or more at 1 month was considered to indicate poor outcome. Serum samples for the cytokine and catecholamine measurements were collected on admission. Plasma levels of IL-1β, IL-6, IL-10, and TNF-α were determined by an enzyme-linked immunosorbent assay (ELISA) method and epinephrine and norepinephrine concentrations were determined by high-performance liquid chromatography with electrochemical detection (HPLC-EC).ResultsIn the ischemic stroke patients, poor outcome was noted in 9 (47%). There were no significant differences in cytokine or catecholamine concentrations between patients with poor and good outcomes, and there was no association between clinical outcome and cytokine and catecholamine concentrations. In the hemorrhagic stroke patients, poor outcome was noted in 10 (56%). IL-6 and IL-10 levels were higher in patients with poor outcome. On logistic regression analysis, higher values of IL-6 were significantly associated with clinical outcome at 1 month (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.02–1.54).ConclusionIn ischemic stroke, plasma cytokines and catecholamines were not predictors of neurological outcome at 1 month. In hemorrhagic stroke, high levels of IL-6 in the early phase indicated a poor neurological outcome.

Mechanism of endothelin-1-(1—31)-induced calcium signaling in human coronary artery smooth muscle cells

We have found that human chymase produces a 31-amino acid endothelin [ET-1-(1-31)] from the 38-amino acid precursor (Big ET-1). We examined the mechanism of synthetic ET-1-(1-31)-induced intracellular Ca2+ signaling in cultured human coronary artery smooth muscle cells. ET-1-(1-31) increased the intracellular free Ca2+concentration ([Ca2+]i) in a concentration-dependent manner (10-14-10-10M). This ET-1-(1-31)-induced [Ca2+]iincrease was not affected by phosphoramidon, Bowman-Birk inhibitor, and thiorphan. The ET-1-(1-31)-induced [Ca2+]iincrease was not influenced by removal of extracellular Ca2+ but was inhibited by thapsigargin. ET-1-(1-31) at 10-12 M did not cause Ca2+ influx, whereas 10-7 M ET-1-(1-31) evoked marked Ca2+ influx, which was inhibited by nifedipine. ET-1-(1-31) also increased inositol trisphosphate formation. These results suggest that the ET-1-(1-31)-induced [Ca2+]iincrease at relatively low concentrations is attributable to the release of Ca2+ from inositol trisphosphate-sensitive intracellular stores, whereas Ca2+ influx into the cells evoked by high concentration of ET-1-(1-31) probably occurs through voltage-dependent Ca2+ channels. We concluded that the physiological activity of ET-1-(1-31) may be attributable to Ca2+ mobilization from intracellular stores rather than influx of Ca2+ from extracellular space.We have found that human chymase produces a 31-amino acid endothelin [ET-1-(1-31)] from the 38-amino acid precursor (Big ET-1). We examined the mechanism of synthetic ET-1-(1-31)-induced intracellular Ca2+ signaling in cultured human coronary artery smooth muscle cells. ET-1-(1-31) increased the intracellular free Ca2+ concentration ([Ca2+]i) in a concentration-dependent manner (10(-14)-10(-10) M). This ET-1-(1-31)-induced [Ca2+]i increase was not affected by phosphoramidon, Bowman-Birk inhibitor, and thiorphan. The ET-1-(1-31)-induced [Ca2+]i increase was not influenced by removal of extracellular Ca2+ but was inhibited by thapsigargin. ET-1-(1-31) at 10(-12) M did not cause Ca2+ influx, whereas 10(-7) M ET-1-(1-31) evoked marked Ca2+ influx, which was inhibited by nifedipine. ET-1-(1-31) also increased inositol trisphosphate formation. These results suggest that the ET-1-(1-31)-induced [Ca2+]i increase at relatively low concentrations is attributable to the release of Ca2+ from inositol trisphosphate-sensitive intracellular stores, whereas Ca2+ influx into the cells evoked by high concentration of ET-1-(1-31) probably occurs through voltage-dependent Ca2+ channels. We concluded that the physiological activity of ET-1-(1-31) may be attributable to Ca2+ mobilization from intracellular stores rather than influx of Ca2+ from extracellular space.

Effect of heat and moisture exchanger (HME) positioning on inspiratory gas humidification

BackgroundIn mechanically ventilated patients, we investigated how positioning the heat and moisture exchanger (HME) at different places on the ventilator circuit affected inspiratory gas humidification.MethodsAbsolute humidity (AH) and temperature (TEMP) at the proximal end of endotracheal tube (ETT) were measured in ten mechanically ventilated patients. The HME was connected either directly proximal to the ETT (Site 1) or at before the circuit Y-piece (Site 2: distance from proximal end of ETT and Site 2 was about 19 cm) (Figure. 1). Two devices, Hygrobac S (Mallinckrodt Dar, Mirandola, Italy) and Thermovent HEPA (Smiths Medical International Ltd., Kent, UK) were tested. AH and TEMP were measured with a hygrometer (Moiscope, MERA Co., Ltd., Tokyo, Japan).ResultsHygrobac S provided significantly higher AH and TEMP at both sites than Thermovent HEPA. Both Hygrobac S and with Thermovent HEPA provided significantly higher AH and TEMP when placed proximally to the ETT.ConclusionAlthough placement proximal to the ETT improved both AH and TEMP in both HMEs tested, one HME performed better in the distal position than the other HME in the proximal position. We conclude the both the type and placement of HME can make a significant difference in maintaining AH and TEMP during adult ventilation.

An adult patient with Kabuki syndrome presenting with Henoch-Schönlein purpura complicated with pulmonary hemorrhage

We present a case of a 33-year-old woman with Kabuki syndrome (KS) presenting with Henoch-Schönlein purpura (HSP). She was admitted to our hospital with a brain abscess in the lateral ventricle and meningitis. She had been diagnosed with KS. Skin eruptions had appeared on her lower extremities, with arthralgia, cough, and hemoptysis. She suddenly developed pulmonary hemorrhage and respiratory failure. We intubated her trachea and started mechanical ventilation in the intensive care unit (ICU). Skin biopsy revealed leukocytoclastic vasculitis with granular depositions of immunoglobulin A (IgA) in dermal vessel walls, and she was diagnosed as having HSP. Supportive management and prednisolone at 20 mg·day−1 cured the pulmonary hemorrhage and respiratory failure. On ICU day 27, she was weaned from mechanical ventilation. Pulmonary hemorrhage as a complication of HSP is rare and sometimes fatal. KS is often associated with an increased incidence of infection and congenital heart disease. Susceptibility to infection and pulmonary hypertension due to congenital heart disease in this patient may have led to the development of the pulmonary hemorrhage. Supportive care and steroid therapy appeared to be beneficial in the treatment of this patient with HSP with pulmonary hemorrhage.

Effect of endothelin-1(1-31) on p38 mitogen-activated protein kinase in cultured human mesangial cells.

It was reported that human chymase cleaves big endothelins (ETs) at the Tyr31-Gly32 bond and produces 31-amino acid ETs(1-31). In this study, we investigated the effect of ET-1(1-31) on p38 mitogen-activated protein kinase (p38-MAPK) activity in human mesangial cells (HMCs). By measuring the kinase activity, we demonstrated that ET-1 (1-31) activated the p38-MAPK dose-dependently (10(-9) M to 10(-7) M), which was inhibited by SB203580. The p38-MAPK activation induced by ET-1(1-31) peaked at 10 minutes. BQ123 almost abolished ET-1(1-31)-induced p38-MAPK activation, whereas BQ788 failed to inhibit it. These findings suggest that the stimulatory effect of ET-1(1-31) on p38-MAPK activation is mediated through ET(A) or ET(A)-like receptor. In conclusion, ET-1(1-31) induced increase in p38-MAPK activation in cultured HMCs.

EFFECT OF ENDOTHELIN-1(1-31) ON INTRACELLULAR FREE CALCIUM IN CULTURED HUMAN MESANGIAL CELLS

We found that human chymase selectively produces 31-amino-acid length endothelins (1-31) (ETs(1-31)). We investigated the effect of synthetic ET-1(1-31) on intracellular free Ca2+ concentration ([Ca2+]i) in cultured human mesangial cells. ET-1(1-31) increased [Ca2+]i in a concentration-dependent manner to a similar extent as ET-1. The ET-1 (1-31)-induced [Ca2+]i increase was not influenced by removal of extracellular Ca2+ but was inhibited by thapsigargin. ET-1(1-31)-induced [Ca2+]i increase was not affected by phosphoramidon. It was inhibited by BQ123, but not by BQ788. These results suggest that ET-1(1-31) by itself exhibits bioactive properties probably through endothelin ET(A) or ET(A)-like receptors. Since human chymase has been reported to exist in the kidney, ET-1(1-31) may be a candidate substance for mesangium-relevant diseases.

Chest computed tomography of a patient revealing severe hypoxia due to amniotic fluid embolism: a case report

IntroductionAmniotic fluid embolism is one of the most severe complications in the peripartum period. Because its onset is abrupt and fulminant, it is unlikely that there will be time to examine the condition using thoracic computed tomography (CT). We report a case of life-threatening amniotic fluid embolism, where chest CT in the acute phase was obtained.Case presentationA 22-year-old Asian Japanese primiparous woman was suspected of having an amniotic fluid embolism. After a Cesarean section for cephalopelvic disproportion, her respiratory condition deteriorated. Her chest CT images were examined. CT findings revealed diffuse homogeneous ground-glass shadow in her bilateral peripheral lung fields. She was therefore transferred to our hospital. On admission to our hospitals intensive care unit, she was found to have severe hypoxemia, with SpO2 of 50% with a reservoir mask of 15 L/min oxygen. She was intubated with the support of noninvasive positive pressure ventilation. She was successfully extubated on the sixth day, and discharged from the hospital on the twentieth day.ConclusionThis is the first case report describing amniotic fluid embolism in which CT revealed an acute respiratory distress syndrome-like shadow.

The use of continuous hemodiafiltration in a patient with diabetic ketoacidosis.

A variety of fatal complications are associated with diabetes mellitus. Among these, diabetic ketoacidosis (DKA) figures largely in fatalities in young diabetics. Although hyperosmotic diuresis in DKA causes extreme fluid loss, acute renal failure is less common than expected in DKA. We treated a case of severe DKA with associated coma, acute respiratory failure, and acute renal failure in a 24-year-old man who had been diagnosed with type 1 diabetes mellitus at age 19. The comatose patient had been intubated before transfer to our hospital for intensive care. Despite infusion with isotonic saline and insulin, metabolic acidosis was refractory. On day 2, urine output decreased and pulmonary congestion developed, so we started continuous veno-venous hemodiafiltration (CVVHDF), which was effective against the metabolic acidosis; urine output increased gradually. CVVHDF was withdrawn on day 7, and the patients renal function recovered completely. He was discharged from the intensive care unit (ICU) on day 14.