Tatsushi Mutoh

Adrenergic regulation of clock gene expression in mouse liver

A main oscillator in the suprachiasmatic nucleus (SCN) conveys circadian information to the peripheral clock systems for the regulation of fundamental physiological functions. Although polysynaptic autonomic neural pathways between the SCN and the liver were observed in rats, whether activation of the sympathetic nervous system entrains clock gene expression in the liver has yet to be understood. To assess sympathetic innervation from the SCN to liver tissue, we investigated whether injection of adrenaline/noradrenaline (epinephrine/norepinephrine) or sympathetic nerve stimulation could induce mPer gene expression in mouse liver. Acute administration of adrenaline or noradrenaline increased mPer1 but not mPer2 expression in the liver of mice in vivo and in hepatic slices in vitro. Electrical stimulation of the sympathetic nerves or adrenaline injection caused an elevation of bioluminescence in the liver area of transgenic mice carrying mPer1 promoter-luciferase. Under a light–dark cycle, destruction of the SCN flattened the daily rhythms of not only mPer1, mPer2, and mBmal1 genes but also noradrenaline content in the liver. Daily injection of adrenaline, administered at a fixed time for 6 days, recovered oscillations of mPer2 and mBmal1 gene expression in the liver of mice with SCN lesion on day 7. Sympathetic nerve denervation by 6-hydroxydopamine flattened the daily rhythm of mPer1 and mPer2 gene expression. Thus, on the basis of the present results, activation of the sympathetic nerves through noradrenaline and/or adrenaline release was a factor controlling the peripheral clock.

Performance of Bedside Transpulmonary Thermodilution Monitoring for Goal-Directed Hemodynamic Management After Subarachnoid Hemorrhage

Background and Purpose— Early goal-directed hemodynamic therapy is of particular importance for adequate cerebral circulation of patients with vasospasm after subarachnoid hemorrhage but is often precluded by the invasiveness of established cardiac output determination using a pulmonary artery catheter. This study was undertaken to validate the usefulness of less invasive goal-directed hemodynamic monitoring by transpulmonary thermodilution technique in patients after subarachnoid hemorrhage. Methods— One hundred sixteen patients with subarachnoid hemorrhage who underwent surgical clipping within 24 hours of ictus were investigated. Validation of transpulmonary thermodilution-derived intermittent/continuous cardiac output and cardiac preload (global end diastolic volume) were compared with pulmonary artery catheter-derived reference cardiac output and pulmonary capillary wedge pressure or central venous pressure in 16 patients diagnosed with vasospasm. In a subsequent trial of 100 consecutive cases, clinical results between the new and standard management paradigms were compared. Results— Transpulmonary thermodilution-derived intermittent cardiac output and transpulmonary thermodilution-derived continuous cardiac output showed close agreement to catheter-derived reference cardiac output with high correlation (r=0.85 and 0.77) and low percentage error (13.5% and 18.0%). Fluid responsiveness to defined volume loading was predicted better with global end diastolic volume than with pulmonary capillary wedge pressure and central venous pressure for larger receiver operating characteristic curve area. Patients receiving early goal-directed management by transpulmonary thermodilution experienced reduced frequencies of vasospasm and cardiopulmonary complications compared with those managed with standard therapy (P<0.05), whereas their functional outcomes at 3 months were not different (P=0.06). Conclusions— Goal-directed hemodynamic management guided by transpulmonary thermodilution appears to have a therapeutic advantage for optimizing the prognosis of patients with subarachnoid hemorrhage with vasospasm over conventional methods.

Goal-Directed Fluid Management by Bedside Transpulmonary Hemodynamic Monitoring After Subarachnoid Hemorrhage

Background and Purpose— Optimal monitoring of cardiac output and intravascular volume is of paramount importance for good fluid management of patients with subarachnoid hemorrhage (SAH). The aim of this study was to demonstrate the feasibility of advanced hemodynamic monitoring with transpulmonary thermodilution and to provide descriptive data early after SAH. Methods— Forty-six patients with SAH treated within 24 hours of the ictus were investigated. Specific targets for cardiac index (≥3.0 L · min−1 · m−2), global end-diastolic volume index (700 to 900 mL/m2), and extravascular lung water index (≤14 mL/kg) were established by the single-indicator transpulmonary thermodilution technique, and a fluid management protocol emphasizing supplemental colloid administration was used to attain these targets. Plasma hormones related to stress and fluid regulation were also measured. Results— A higher cardiac index (mean value of 5.3 L · min−1 · m−2) and a lower global end-diastolic volume index (555 mL/m2) were observed on initial measurement, for which elevations of plasma adrenaline, noradrenaline, and cortisol were also detected. Cardiac index was progressively decreased (3.5 L · min−1 · m−2) and global end-diastolic volume index was normalized by fluid administration aimed at normovolemia. The extent of the initial hemodynamic and hormonal profile was greater in patients with a poor clinical status (P<0.05). The extravascular lung water index was mildly elevated but within the target range throughout the study period. No patients developed pulmonary edema or congestive heart failure. Conclusions— The impact of sympathetic hyperactivity after SAH predisposes patients to a hyperdynamic and hypovolemic state, especially in those whose clinical status is poor. Bedside monitoring with the transpulmonary thermodilution system may be a powerful tool for the systemic management of such patients.

Chronic passive cigarette smoke exposure augments bronchopulmonary C‐fibre inputs to nucleus tractus solitarii neurones and reflex output in young guinea‐pigs

Children chronically exposed to environmental tobacco smoke (passive cigarette smoke) have more wheeze, cough, bronchoconstriction, airway hyper‐reactivity and mucous secretion, which may result, in part, from stimulation of the vagal bronchopulmonary C‐fibre reflex. Environmental tobacco smoke increases the sensitivity of bronchopulmonary C‐fibre endings, but the physiological relevance of this sensitization is unknown. If this exposure augments the reflex responses via a central mechanism, then the responses of higher‐order neurones in the reflex pathway and some components of the reflex output should also be augmented. Guinea‐pigs were chronically exposed to sidestream tobacco smoke (surrogate for environmental tobacco smoke) or filtered air for 5 days week−1 from age 1 to 6 weeks (age equivalent of human childhood) and were then anaesthetized, paralysed, ventilated and prepared with pneumothoraces. Baseline and left atrial capsaicin (0.5 and 2.0 μg kg−1)‐ evoked changes in the impulse activity of vagal C‐fibre‐activated neurones in nucleus tractus solitarii (NTS), phrenic nerve activity, tracheal pressure, arterial blood pressure and heart rate were compared in the two groups. Sidestream smoke exposure significantly augmented the peak (P= 0.02) and duration (P= 0.01) of the NTS neuronal responses and the prolongation of expiratory time (P= 0.003) at the higher capsaicin dose. Thus, the sensitization of the bronchopulmonary C‐fibre endings by chronic exposure to sidestream tobacco smoke is transmitted to the NTS and is associated with a prolonged reflexively evoked expiratory apnoea. The findings may help to explain some related respiratory symptoms in children and be a factor in sudden infant death syndrome.

Melatonin modulates the light-induced sympathoexcitation and vagal suppression with participation of the suprachiasmatic nucleus in mice

In mammals, the autonomic nervous system mediates the central circadian clock oscillation from the suprachiasmatic nucleus (SCN) to the peripheral organs, and controls cardiovascular, respiratory and gastrointestinal functions. The present study was conducted in mice to address whether light signals conveyed to the SCN can control peripheral autonomic functions, and further examined the impact of centrally administered melatonin on peripheral autonomic functions via activation of melatonin receptor signalling. In vivo electrophysiological techniques were performed in anaesthetised, open‐chest and artificially ventilated mice whilst monitoring the arterial blood pressure and heart rate. Light induced an increase of the renal sympathetic nerve activity, arterial blood pressure and heart rate immediately after lights on. Conversely, light rapidly suppressed the gastric vagal parasympathetic nerve activity, which was affected neither by hepatic vagotomy nor by total subdiaphragmatic vagotomy. These autonomic responses were mediated by the SCN since bilateral SCN lesion totally abolished the light‐evoked neuronal and cardiovascular responses. Melatonin administered intracerebroventricularly (i.c.v.) attenuated the sympathetic and vagal nerve activities in a dose‐dependent manner with a threshold of 0.1 ng and these effects were blocked by i.c.v. pre‐treatment of the competitive melatonin receptor antagonist luzindole. These results suggest that light induces sympathoexcitation and vagal suppression through the SCN and that melatonin modulates the light‐induced autonomic responses via activation of the central melatonin receptor signalling.

Early Intensive Versus Minimally Invasive Approach to Postoperative Hemodynamic Management After Subarachnoid Hemorrhage

Background and Purpose— The results of previous studies suggest that early goal-directed fluid therapy (EGDT) reduces delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage, but the effects of EGDT on clinical outcomes are still unclear. This study aimed to determine whether EGDT improves outcomes compared with standard less-invasive hemodynamic therapy. Methods— This study included 160 patients treated within 24 hours after subarachnoid hemorrhage, randomized to receive either (1) EGDT guided by preload volume and cardiac output monitored by transpulmonary thermodilution (treatment group) or (2) standard therapy guided by fluid balance or central venous pressure, assisted by uncalibrated less-invasive cardiac output monitoring during hyperdynamic therapy in patients with clinical or radiological indications of DCI (control group). DCI determined by clinical or radiological findings and functional outcome determined by the modified Rankin Scale score at 3 months were compared between groups. Results— For all clinical grades combined, there were no significant differences in the rates of DCI (33% versus 42%; P=0.33) or modified Rankin Scale score of 0 to 3 at 3 months (67% versus 57%; P=0.22) between the 2 groups. For patients with poor clinical grade, those who received EGDT had a significantly lower rate of DCI (5% versus 14%; P=0.036), modified Rankin Scale score of 0 to 3 at 3 months (52% versus 36%; P=0.026), and shorter length of intensive care unit stay (14 versus 17 days; P=0.043) than those who received standard therapy. Conclusions— EGDT is beneficial for reducing DCI and improving postoperative functional outcome in patients with poor clinical grade. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: UMIN000007509.

Evaluation of the FloTrac uncalibrated continuous cardiac output system for perioperative hemodynamic monitoring after subarachnoid hemorrhage.

Early hemodynamic assessment is of particular importance for adequate cerebral circulation in patients with aneurysmal subarachnoid hemorrhage (SAH), but is often precluded by the invasiveness and complexity of the established cardiac output determination techniques. We examined the utility of an uncalibrated arterial pressure-based cardiac output monitor (FloTrac) for intraoperative and postoperative hemodynamic management after SAH. In 16 SAH patients undergoing surgical clipping, arterial pulse contour cardiac index, and stroke volume variation (SVV) were analyzed via the radial FloTrac system. The hemodynamic values after induction of anesthesia until 12 hours after surgery were compared with reference transpulmonary thermodilution cardiac index (TPCI), calibrated pulse contour CI, and global end-diastolic volume index determined by the PiCCO system and central venous pressure. Arterial pulse contour cardiac index underestimated CI as overall bias±SD of 0.57±0.44 L/min/m2 and 0.54±0.46 L/min/m2 compared with TPCI and calibrated pulse contour CI, resulting in a percentage error of 24.8% and 26.6%, respectively. Subgroup analysis revealed a percentage error of 29.3% for values obtained intraoperatively and 20.4% for values measured under spontaneously breathing after tracheal extubation. Better prediction of cardiac responsiveness to defined volume loading for increasing stroke volume index >10% was observed for SVV under mechanical ventilation with greater area under the receiver operating characteristics curve than that for global end-diastolic volume index or central venous pressure. These data suggest that the FloTrac underestimates the reference CI, and is not as reliable as transpulmonary thermodilution for perioperative hemodynamic monitoring after SAH. SVV is considered to be an acceptable preload indicator under mechanical ventilation.

Responses of laryngeal capsaicin-sensitive receptors to volatile anesthetics in anesthetized dogs

The responses of laryngeal capsaicin (CAPS)-sensitive receptors to halothane, enflurane, isoflurane and sevoflurane were evaluated in anesthetized spontaneously breathing dogs from the afferent activity of the internal branch of the superior laryngeal nerve. The CAPS-sensitive receptors were clearly distinguished from irritant receptors by their responsiveness to CAPS and their lack of responsiveness to water. All the CAPS-sensitive receptors were significantly stimulated by all volatile anesthetics in a concentration-related manner, and the activation by halothane, enflurane, and isoflurane was significantly greater than by sevoflurane. In contrast, responses of irritant receptors to the volatile anesthetics were divided into three types (stimulation, inhibition or non-response), and did not differ among anesthetics. In conclusion, the present study demonstrated that the CAPS-sensitive receptors were consistently stimulated by halogenated volatile anesthetics and especially by halothane, enflurane, and isoflurane, and that these responses were dissimilar to the variable responses of irritant receptors.

Effects of volatile anesthetics on vagal C-fiber activities and their reflexes in anesthetized dogs

Effects of halothane, enflurane, isoflurane, and sevoflurane on vagal capsaicin (CAPS)-sensitive C-fibers were elucidated in anesthetized dogs. The CAPS-sensitive C-fibers were significantly stimulated by all volatile anesthetics with a significantly greater response to halothane than with sevoflurane. A significant increase in respiratory frequency (fR) and a significant decrease in tidal volume (VT) were observed with halothane and isoflurane, and a significant increase in fR was observed with sevoflurane. In contrast, a significant decrease in fR was induced by enflurane. The tachypnea induced by halothane, isoflurane, and sevoflurane was significantly reduced or no longer observed after perineural CAPS-treatment or bilateral vagotomy, whereas the slowing of respiration observed with enflurane was not affected by either of these treatments. These results suggest that vagal C-fibers play an important role in the reflex tachypnea that occurs with halothane, isoflurane, and sevoflurane.

Performance of Third-generation FloTrac/Vigileo system during hyperdynamic therapy for delayed cerebral ischemia after subarachnoid hemorrhage.

Background: Monitoring of cardiac output (CO) is important for promising safe approach to goal-directed hemodynamic therapy for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH), but is often precluded by the invasiveness and complexity of ongoing monitoring modalities. We examined the clinical utility of less-invasive management using an uncalibrated arterial pressure waveform-derived cardiac output (APCO) monitor with refined algorithm (Third-generation FloTrac/Vigileo, Edwards, Irvine, CA, USA) during hyperdynamic therapy for post-SAH DCI, compared with transpulmonary thermodilution (PiCCO, Pulsion, Munich, Germany) as a reference technique. Methods: Forty-five patients who underwent surgical clipping within 24 h of SAH onset and subsequently developed clinical deterioration attributable to DCI were investigated. Validation of the APCO-derived cardiac index (CI) during dobutamine-induced hyperdynamic therapy was compared with a reference CI analyzed by transpulmonary thermodilution in 20 patients. In a subsequent trial of 48 cases, the overall clinical results from patients managed with each device were compared. Results: The APCO underestimated CI with an overall bias ± SD of 0.33 ± 0.26 L/min/m2 compared with transpulmonary thermodilution, resulting in an error of 14.9%. The trends of CI for both techniques at each dobutamine dose were similar (r2= 0.77; P < 0.0001). No statistically significant differences were observed between the device groups for frequencies of neurological improvement, cerebral infarction, cardiopulmonary complications, or functional outcomes at 3 months. Conclusions: These data suggest that the refined APCO tends to underestimate CI compared with reference transpulmonary thermodilution during hyperdynamic therapy with dobutamine for reversing DCI, but may be acceptable in this select category of patients to obtain comparable clinical results.