Koji Hosokawa

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

Expression and intracellular distribution of the G protein-coupled receptor 30 in rat hippocampal formation

Although the expression and distribution of nuclear estrogen receptors in the hippocampus has been described, it has been proposed that the nuclear receptors may not explain all aspects of estrogen function in the hippocampus. Recently, a G protein-coupled receptor for estrogen, GPR30, was identified as a membrane-localized estrogen receptor in several cancer cell lines. In this study, we examined the expression and intracellular distribution of GPR30 in the rat hippocampal formation. We found expression of GPR30 in pyramidal cells of CA1-3 and granule cells of the dentate gyrus at both mRNA and protein levels. Specific markers for intracellular organelles and immunoelectron microscopy revealed that GPR30 was mainly localized to the Golgi apparatus and partially in the endoplasmic reticulum of the neuron but could not detect the protein at the cell surface. Expression levels were not different among male, female in proestrus and female in estrus at the adult stage, but were higher in newborn male than newborn female.

Expression of G protein-coupled receptor 30 in the spinal somatosensory system

Estrogens were originally identified as the primary sex steroid hormones in females and regulators of reproductive function and sexual behavior, but it has long been suggested that estrogens also have local effects on the somatosensory system at the spinal cord level. It is well known that the effects of estrogens are mediated by nuclear estrogen receptors (ERs) through genomic action, but recently a membrane-bound G protein-coupled receptor, GPR30, was identified as a non-genomic estrogen receptor. In this study we investigated the presence and localization of GPR30 in the rat spinal cord and dorsal root ganglion (DRG) in comparison with ERalpha. Using immunohistochemistry and in situ hybridization, we showed the expression of GPR30 in DRG neurons in male and female rats at mRNA and protein levels without specific sexual difference. A dense accumulation of GPR30 immunoreactivity was observed in the outer layer of the spinal dorsal horn, and selective spinal dorsal rhizotomy revealed that GPR30 was transported from the DRG to terminals located in the spinal dorsal horn. GPR30 expression was downregulated in DRG neurons of ovariectomized female rats. The spinal somatosensory system might be modulated by estradiol via putative membrane ER, GPR30-mediated mechanism.

Regional distribution of importin subtype mRNA expression in the nervous system: study of early postnatal and adult mouse.

Importin-alpha and beta1 mediate the translocation of macromolecules bearing nuclear localization signals across the nuclear pore complex. Five importin-alpha isoforms have been identified in mice and six in human. Some of these importins play an important role in neural activity such as long term potentiation, but the functional differences of each isoform in the CNS are still unclear. We performed in situ hybridization (ISH) using non-isotopic probes to clarify the expression patterns of importin-alpha subtypes (alpha5, alpha7, alpha1, alpha4, alpha3) and importin-beta1 in the mouse CNS of adult and early postnatal stages. The mRNAs of the importin-alpha subtypes and importin beta1 were expressed throughout the CNS with specific patterns; importin-alpha5, alpha7, alpha3, and beta1 showed moderate to high expression levels throughout the brain and spinal cord; importin-alpha4 showed a lack of expression in limited regions; and importin-alpha1 showed a low expression level throughout the brain and spinal cord but with a moderate expression level in the olfactory bulb and reticular system. We also demonstrated that importin-alphas and beta1 mRNAs were predominantly expressed in neurons in the adult mouse brain by using double-labeling fluorescence ISH and immunohistochemistry. Moreover, importin-alphas and beta1 mRNAs were detected throughout the CNS of postnatal mice and were highly expressed in the external granule layer of the cerebellar cortex on postnatal days 0, 4, and 10. This is the first report of importin-alphas and beta1 expression throughout the CNS of adult mice, as well as in the developing brain, including cell type specific localization.

Direct visualization of glucocorticoid receptor positive cells in the hippocampal regions using green fluorescent protein transgenic mice.

The hippocampal formation is a plastic brain structure important for certain types of learning and memory, and also vulnerable to the effects of stress and trauma. Since hippocampal neurons express high levels of corticosteroid receptor, the morphological changes, including alterations in the size of soma, and the length and number of neurites and spines, in response to glucocorticoids released as a result of stress are intriguing. In order to highlight the morphology of neurons that express glucocorticoid receptor (GR), we have generated a transgenic mouse line expressing green fluorescent protein (GFP) under the control of the GR promoter. We found strong green fluorescence in the pyramidal cell layer of the CA1 and CA2 regions and the granule cell layer of the dentate gyrus of the hippocampus in brain sections of the transgenic mice. GFP fluorescence was observed not only in somas, but also in neurites including both dendrites and axons. In dissociated culture, we also observed GFP fluorescence in the soma, neurites including both dendrites and axons, and dendritic spines. Microtubule-associated protein 2 immunopositive pyramidal-shaped neurons clearly showed two different populations, GFP positive and GFP negative neurons. These results indicate that this transgenic mouse line should be useful for live imaging of neuronal structure in animals as well as GR-positive cultured cells using GFP as a specific indicator.

Ultrasound evidence of the optimal wrist position for radial artery cannulation

PurposeRadial artery cannulation is a common medical procedure for anesthesia and critical care. To establish the ideal wrist position for radial artery cannulation, we performed ultrasound examinations of the radial artery to investigate the effect of the angle of wrist extension on radial artery dimensions.Clinical featuresMeasurements were performed in 17 healthy subjects and 17 surgical patients scheduled for coronary artery bypass graft (CABG) surgery. The radial artery was echographically visualized near the styloid process of the radius at the wrist. Radial artery dimensions were measured at wrist joint angles of 0, 15, 30, 45, 60 and 75°.ObservationsIn both groups, radial artery height was affected by the wrist joint angle. Vessel height was decreased at 60° (one way ANOVA Pxa0=xa00.027 vs 0°) and 75° (Pxa0<xa00.001 vs 0, 15, 45°) in healthy subject and at 75° in CABG patients (Pxa0<xa00.001 vs 0°). The mean differences in radial artery height at 0 and 75° were 0.33xa0±xa00.09xa0mm and 0.20xa0±xa00.06xa0mm for healthy and CABG patients, respectively. Vessel width was not affected by wrist joint angulation up to 75° of extension.ConclusionOur results demonstrate that in healthy subjects, radial artery dimensions are unaltered when the wrist joint is extended up to an angle of 45°. Extension at 60° for healthy subjects and 75° for CABG patients, however, results in a decrease in the height of the radial artery, which could possibly render arterial catheterization more difficult.RésuméObjectifLa canulation de l’artère radiale est un geste médical courant en anesthésie et aux soins intensifs. Afin de déterminer la position optimale du poignet pour canuler de l’artère radiale, nous avons réalisé des examens échographiques de l’artère radiale pour examiner l’effet de l’angle d’extension du poignet sur les dimensions de l’artère radiale.Éléments cliniquesLes mesures ont été réalisées chez 17 patients sains et 17 patients devant subir des pontages aortocoronariens (PAC). L’artère radiale a été visualisée par échographie au niveau du poignet, près de l’apophyse styloïde du radius. Les dimensions de l’artère radiale ont été mesurées à des angles du poignet de 0°, 15°, 30°, 45°, 60° et 75°.ObservationsLa hauteur de l’artère radiale a été affectée par l’angle du poignet dans les deux groupes. La hauteur des vaisseaux était réduite à un angle de 60° (ANOVA simple Pxa0=xa00,027 versus 0°) et 75° (Pxa0<xa00,001 versus 0°, 15°, 45°) chez les patients sains et à 75° chez les patients subissant un PAC (Pxa0<xa00,001 versus 0°). Les différences moyennes des hauteurs de l’artère radiale à 0° et 75° étaient de 0,33xa0±xa00,09xa0mm et 0,20xa0±xa00,06xa0mm chez les patients sains et les patients subissant un PAC, respectivement. La largeur des vaisseaux n’a pas été affectée par l’angulation du poignet jusqu’à 75° d’extension.ConclusionNos résultats démontrent que chez les patients sains, les dimensions de l’artère radiale ne changent pas lorsque l’articulation du poignet est étendue jusqu’à un angle de 45°. Une extension à 60° chez les patients sains et à 75° chez les patients subissant un PAC a toutefois pour résultat une réduction de la hauteur de l’artère radiale, ce qui pourrait possiblement rendre la canulation artérielle plus difficile.

An Evaluation of Acute Cardiac Tamponade by Transesophageal Echocardiography

A 63-yr-old man with femoral venous thrombosis presented to the interventional radiology suite for prophylactic placement of an inferior vena cava (IVC) filter from the right internal jugular approach. During the procedure, he became hypotensive and developed pulseless electrical activity. Cardiopulmonary resuscitation, fluids, vasopressors and, ultimately, femorofemoral veno-arterial cardiopulmonary bypass assistance were required to resuscitate the patient. Pulmonary embolism and coronary artery occlusion were excluded using angiographic methods. Transthoracic echocardiography (TTE) revealed a large pericardial effusion suggesting a cardiac rupture. TTE-guided pericardiocentesis was performed, but his hemodynamics were not substantially improved and TTE images were suboptimal. To more thoroughly evaluate cardiac tamponade, transesophageal echocardiography (TEE) was performed, demonstrating a large pericardial echo-free space containing large echodense masses that were suspected to be hemorrhagic effusion and pericardial thrombus, respectively. (Figs. 1A–C; please see video clips available at www. anesthesia-analgesia.org). The large pericardial effusion and pericardial thrombus compressed the right atrium and right ventricle, worsening the patient’s hemodynamics. Severe global hypokinesis was believed to be secondary to the ischemic effects related to his cardiac arrest. The patient was taken to the operating room, where a large hematoma was evacuated from the pericardium and a laceration of the right ventricle was repaired. The patient was uneventfully weaned from cardiopulmonary bypass and recovered without any neurological sequelae.

Five-day pain management regimen using patient-controlled analgesia facilitates early ambulation after cardiac surgery

PurposeExcessive pain may interrupt early rehabilitation after cardiac surgery. The purpose of this study was to evaluate the efficacy of a longer patient-controlled analgesia (PCA) regimen for early ambulation after cardiac surgery.MethodsThis study was designed to be a retrospective, single-institutional (focusing on an urban, university-affiliated hospital), pre-post intervention survey. Fifty-nine patients undergoing elective cardiac surgery were included. A long pain management regimen (subcutaneous fentanyl PCA for up to 120xa0h) protocol was implemented for the postoperative care for adult cardiac surgery patients. Before implementing this extended protocol, the same PCA regimen was used for up to 40xa0h. Perioperative and postoperative management was similar for all patients. The number of days required to walk more than 100xa0m without assistance was recorded. Additional usage of analgesic drugs and pain intensity on movement were documented up to POD 5.ResultsTime required to walk more than 100xa0m without assistance was significantly shorter in the 120xa0h PCA group. Need for another analgesic regimen and pain score during the ambulation phase were significantly lower in the 120xa0h PCA than in the 40xa0h PCA group. Frequency of side effects was similar for both groups.ConclusionPain management using a PCA system can be recommended for patients during the ambulation period after cardiac surgery. Subcutaneous PCA with fentanyl is a safe and effective analgesic regimen for this purpose.

Signal transport from synapse to the nucleus

High-affinity choline transporter (CHT) is efficiently transported to cholinergic axon terminals. We have previously shown that most of the CHT is associated with synaptic vesicles rather than synaptic plasma membrane. Here, we analyzed intracellular distribution of CHT in adaptor protein-3 (AP-3) deficient mouse (mocha mouse). In the mouse, endosomal granular structures were intensely labeled with CHT antibody, indicating possible deficit in CHT trafficking. Western blot analysis revealed that CHT on synaptic vesicle in mocha mice was decreased by 70% compared with wild-type mice. However no significant difference in synaptosomal choline uptake activity was detected, implicating the existence of large pool for CHT. Furthermore most of CHT is found associated with synaptic-like micro-vesicles (SLMV) in CHT-overexpressed PC12 cells. The amounts of CHT detected on SLMV were greatly reduced by treating the cell with agents which halt AP-3, demonstrating AP-3 involvement in CHT trafficking.