Kentaro Dote

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

Cerebral blood flow during conventional, new and open-chest cardio-pulmonary resuscitation in dogs.

The following parameters were monitored simultaneously in 15 dogs, in order to evaluate the efficacy of conventional CPR (C-CPR), new CPR (N-CPR), and open-chest CPR (O-CPR) on cerebral perfusion: arterial blood pressure (BP), central venous pressure (CVP), intrathoracic airway pressure, blood flow in carotid artery, intracranial pressure (ICP), sagittal sinus blood flow (sinus BF) and pressure (sinus P), and blood flow in cerebral cortex (cortical BF). The sinus blood flow was measured by the direct-method and with a cannulating electromagnetic flowmeter. The cortical blood flow was measured with a termocouple tissue flowmeter. Intracranial pressure was obtained by measuring subarachnoid cerebrospinal fluid pressure. Ventricular fibrillation was induced electrically. Chest compression and ventilation were always done manually in all cardiopulmonary resuscitation. The mean blood pressures during C-CPR, N-CPR and O-CPR were 52, 68 and 95 mmHg, respectively, and mean carotid blood flows per stroke were 36, 71 and 131% of the control values, respectively. The intracranial pressures were 30, 42 and 36 mmHg, respectively, giving the calculated cerebral perfusion pressures (BP-ICP) of 22, 27 and 60 mmHg, respectively. This should have been reflected in cerebral blood flow. Sinus blood flows/min were 18, 18 and 42%, and sinus blood flows per stroke were 55, 45 and 127% of control values, respectively; the differences between C-CPR and N-CPR were not significant. This was also true for cortical blood flow. From this we conclude that, firstly, N-CPR is not significantly better than C-CPR in cerebral perfusion because of its accompanying high intracranial pressure, secondly, O-CPR is far superior to the other two methods in respect of cerebral perfusion.

Usefulness of a selective neutrophil elastase inhibitor, sivelestat, in acute lung injury patients with sepsis.

Background Neutrophil elastase plays a crucial role in the development of acute lung injury (ALI) in patients with systemic inflammatory response syndrome (SIRS). The clinical efficacy of the neutrophil elastase inhibitor, sivelestat, for patients with ALI associated with SIRS has not been convincingly demonstrated. The aim of this study was to determine if there are clinical features of patients with this condition that affect the efficacy of sivelestat. Methods This was a retrospective study of 110 ALI patients with SIRS. Clinical information, including the etiology of ALI, the number of organs failing, scoring systems for assessing the severity of illness, and laboratory data, was collected at the time of diagnosis. Information on the number of ventilator-free days (VFDs) and changes in PaO2/FIO2 (ΔP/F) before and 7 days after the time of ALI diagnosis was also collected. The effect of sivelestat on ALI patients was also examined based on whether they had sepsis and whether their initial serum procalcitonin level was ≥0.5 ng/mL. Results There were 70 patients who were treated with sivelestat and 40 control patients. VFDs and ΔP/F were significantly higher in the treated patients than in the control patients. However, there was no significant difference in the patient survival rate between the two groups. Sivelestat was more effective in ALI patients with a PaO2/FIO2 ratio ≥ 140 mmHg or sepsis. Sivelestat significantly prolonged survival and led to higher VFDs and increased ΔP/F in septic patients and patients with initial serum procalcitonin levels ≥ 0.5 ng/mL. Conclusion The results may facilitate a future randomized controlled trial to determine whether sivelestat is beneficial for ALI patients with sepsis.

Survey of patients whose lungs could not be ventilated and whose trachea could not be intubated in university hospitals in Japan

AbstractPurpose. We conducted a survey to clarify the actual circumstances in which the lungs could not be ventilated and the trachea could not be intubated (CVCI). Methods. A questionnaire was mailed to all the university hospitals in Japan, asking about CVCI they had experienced during induction of anesthesia in 1998, and before 1997. Results. Answers were obtained from 60 of 83 institutes. CVCI occurred in 26 of 151 900 cases of general anesthesia (0.017%) in 1998. Eighteen cases occurred after induction of anesthesia by several induction methods. Five cases occurred after repeated attempts at tracheal intubation by laryngoscopy and fiberscopy in patients under awake or anesthetized conditions. In the remaining 3 cases, the situation of occurrence was not documented. Patients with CVCI had anatomical abnormalities around the upper airways, mostly from acquired diseases. CVCIs after induction of anesthesia were successfully treated by restoration of spontaneous respiration, blind intubation, laryngeal mask airway, and transtracheal approaches, and CVCIs after repeated attempts at intubation were treated mostly by transtracheal approaches. No serious consequences occurred in any patients in 1998. Twenty cases were reported before 1997, and 2 were specific, in which CVCI followed malplacement of a tracheal tube, and serious consequences, death and brain damage, respectively, followed. In other patients, no serious consequences occurred, although cardiac arrest occurred in 1 patient. Conclusion. This survey demonstrates that CVCI can occur in any situation in which the airway is not established. Furthermore, effective treatments may be different depending on the situation, and delayed recognition of tracheal tube misplacement may lead to a serious outcome.

Ischemic preconditioning suppresses the noradrenaline turnover in the rat heart

OBJECTIVE The mechanism by which ischemic preconditioning protects the heart is presumed to be related to the reduction of energy consumption during a subsequent myocardial infarction. Since the sympathetic nervous system enhances cardiac function and energy consumption, we investigated the relation between ischemic preconditioning and the turnover rate of noradrenaline (NA) in the rat heart. METHODS The effect of 3 cycles of 5-min occlusions of the rat left coronary artery on changes in arterial blood pressure and heart rate provoked by a subsequent 30 min of ischemia were examined until 60 min after reperfusion. The effect of 3 cycles of occlusions on the infarct size was also evaluated 60 min after reperfusion by comparing the infarcted area with the area at risk in these animals (6 per preconditioned and sham-operated group). The tissue concentration of NA during sustained ischemia was determined in the left ventricle, the intraventricular septum, and the right ventricle in the preconditioned and sham-operated groups. Changes in the turnover rate of NA after 3 cycles of occlusions were also evaluated by assessing the alpha-methyl-p-tyrosine-induced depletion of NA (n = 7 per group). RESULTS A series of transient occlusions reduced the infarct size 60 min after a sustained ischemia for 30 min. Arterial pressure and heart rate were not affected. The concentration of NA was decreased in the left ventricle 60 min after the onset of sustained ischemia in both the preconditioned and sham-operated groups. The treatment with alpha-methyl-p-tyrosine decreased the NA concentration in all regions of the heart in the sham-operated group after 60 min. However, the treatment with alpha-methyl-p-tyrosine did not deplete the NA concentration in both the occluded and nonoccluded regions in the preconditioned group. CONCLUSIONS Transient ischemia ameliorated the heart injury induced by a subsequent sustained ischemia, as assessed histologically. The activity of the sympathetic nervous system in all regions of the heart was reduced by transient ischemia in the left coronary vascular bed. These findings suggest that the inhibition of the sympathetic nervous system by the treatment of ischemic preconditioning takes part in the cardiac protection.

Mafutsuto-Ron: The First Anesthesia Textbook in the World. Bibliographic Review and English Translation

On October 13, 1804, Seishu Hanaoka performed a mastectomy on Kan Aiya in Hirayama, Kii Province Japan, in what is considered to be the first operation under general anesthesia. She was anesthetized with a mixture of herbs known as Mafutsuto. Although Seishu did not record his anesthetic practices, his student, Gendai Kamada, documented the use of Mafutsuto in Mafutsuto-Ron. Written in 1839, Mafutsuto-Ron is 10 pages and covers six topics, including preoperative management, dosing and administering Mafutsuto, induction of general anesthesia, common errors, and postoperative precautions. Mafutsuto-Ron, therefore, meets the requirements to be considered the first extant anesthesia textbook. We present a complete English translation of Mafutsuto-Ron.

A new model for total cerebral ischemia in dogs.

We have developed a new method producing total cerebral ischemia (TCI) in dogs; clamping ascending aorta with aorto-atrial bypass formation. Clamping ascending aorta provides TCI, the duration of which can be controlled up to the periods of 10 min. Beyond this interval, it is difficult to maintain TCI because of heart failure from high afterload. Blood outflow from left ventricle is completely obstructed except for coronary circulation which is small relative to the blood volume expelled from left ventricle, even if venous return to the heart is reduced. Aorto-atrial bypass formation during aortic clamping provides two distinctive advantages. First, adjusting aortic pressure in an appropriate level low enough not to overload myocardium but still high enough to maintain sufficient coronary blood flow is possible by regulating the blood flow through the bypass tubing, and secondly drug administration and blood volume control is possible through the tubing. These result in better preservation of myocardium, enabling longer TCI and longer survivals after TCI. We were successful in having up to 18 min of TCI with this method. Seventy-five percent of dogs of 12 min TCI and 40% of 15 min TCI survived 7 days, limit of experiment, after TCI, but no dogs of 18 min TCI survived for more than 3 days.

combination therapy with sivelestat and recombinant human soluble thrombomodulin for arDs and Dic patients

Background Neutrophil elastase, alveolar thrombin generation, and fibrin deposition play crucial roles in the development of acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC). However, the usefulness of combination therapy with a selective neutrophil elastase inhibitor, sivelestat, and recombinant human soluble thrombomodulin (rhTM) for patients with ARDS and DIC remains unknown. Methods We conducted a retrospective data analysis of 142 ARDS patients with DIC to assess the effects of sivelestat combined with rhTM. Patients were divided into four groups: control (no sivelestat or rhTM treatment), sivelestat treatment alone, rhTM treatment alone, and combined treatment with sivelestat and rhTM. A Cox proportional hazard model was used to assess subject mortality rates. The efficacy of these drugs was evaluated based on survival rate, number of ventilator-free days, and change in PaO2/FIO2 (P/F) ratios and DIC scores before and at 7 days after a diagnosis of ARDS with DIC. Results Multivariate analysis showed that patient age, combination therapy, gas exchange, organ failure, cause, associated disease score, and serum C-reactive protein levels were predictors of mortality for patients with ARDS and DIC. As compared with untreated controls, combination therapy significantly improved the 60-day survival rate of patients with ARDS and DIC. There were significantly more ventilator-free days for those who received combination therapy than for untreated controls. P/F ratios and DIC scores were significantly improved with sivelestat alone, rhTM alone, or their combination as compared with untreated controls. Conclusion Our results suggest that combined treatment with sivelestat and rhTM has beneficial effects on survival and the respiratory and DIC status of patients with ARDS and DIC.

Two Japanese Pioneers in Anesthesiology: Seishū Hanaoka and Gendai Kamada

Seishū Hanaoka and Gendai Kamada are two Japanese pioneers in anesthesiology. Seishū Hanaoka was the worlds first surgeon on record to successfully perform surgery under general anesthesia in 1804. Seishū discovered that six medicinal herbs containing Datura, stramonium, and Aconitum had anesthetic properties. From these, he developed Mafutsusan. His fame spread across Japan, and he was inundated with requests from patients and prospective students. He founded a private medical school (Shunrinken) and trained more than 1000 students. Gendai Kamada was an outstanding pupil of Seishū Hanaoka. From the perspective of the history of anesthesiology, three of Gendais achievements had a global impact. (1) In 1839, he wrote the first textbook of clinical anesthesiology, Mafutsuto-ron; (2) in 1840, he authored Gekakihai-zufu, which included some of the oldest illustrations of surgery under general anesthesia; and (3) he trained Gensei Matsuoka, the worlds second anesthesiologist.

Management of patients under general anesthesia with mafutsu-san in Hanaoka-style surgery: comparisons of illustrations from Geka-Kihai-Zufu with descriptions from Mafutsuto-Ron and Yohka-Hiroku

IntroductionSeishu Hanaoka (1760–1835) left behind no books that he himself had written. This is why many aspects of Hanaoka-style general anesthesia using a mixture of herbal extracts, which he called mafutsu-san, remain unknown. We are able to learn about this technique today because there are several descriptions of it in books written by his students, such as Mafutsuto-Ron (“Treatise on Mafutsuto”) by Gendai Kamata (1794–1854) and Yohka-Hiroku (“Secret Records of Surgery”) by Gencho Homma (1804–1872). On the other hand, Geka-Kihai-Zufu (“Illustrations of Surgical Cases”), a surgical textbook, by Gendai Kamata, containing one of the oldest illustrations of general anesthesia published in 1840, was recently rediscovered (2011). For the first time, this book revealed, in the form of a picture image, the actual circumstances of Hanaoka-style general anesthesia.MethodsWe therefore compared the descriptions of general anesthesia featured in these three documents, and thereby investigated the actual anesthetic management and the procedures used.Results and conclusionsWe found that the circumstances under which Hanaoka-style general anesthesia, using fabrics and futon mattresses, as well as blindfolding and constraining the patient’s body during surgery, were exactly as described in Mafutsuto-Ron and Yohka-Hiroku. In addition, besides a surgeon conducting an operation, there was a physician who observed the patient’s general condition. Gendai Kamata, the author of Geka-Kihai-Zufu, is believed to have recognized the importance of anesthetic care of surgical patients.