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The cardioprotective effects of glucocorticoids in the acute setting of ischemia/reperfusion have been experimentally demonstrated in animals1–7 and humans.8 Although the mechanisms underlying glucocorticoid cardioprotection are not known with certainty, glucocorticoids are reported to preserve cellular function in ischemia thereby prolonging the period of myocardial viability. In previous studies, glucocorticoids were reported to improve lactate imbalance and prevent the leakage of intracellular enzymes caused by myocardial ischemia.6,7 At the same time, deleterious effects of glucocorticoids on ischemia-induced neuronal damage have been shown in various animal models, despite the ability of glucocorticoids to alleviate cerebral edema caused by traumatic brain injury and hemorrhage.9–13 Further, steroids are not indicated for traumatic brain injury in humans, as they do not improve clinical outcomes.14 Because adenosine 5′-triphosphate (ATP) provides energy to maintain membrane functional integrity in both the heart and brain, and ATP depletion precedes loss of cellular viability, the different effects of the agents in ATP utilization in the heart and brain during ischemia could well explain differences in ischemia-induced organ injury. In the present study, therefore, we investigated the effect of dexamethasone, a glucocorticoid without mineralocorticoid activity, on ischemia-induced reduction of ATP in the mouse heart and brain. In addition, we examined the effect of metyrapone, a potent inhibitor of the synthesis of glucocorticoids, to assess the role of endogenous glucocorticoids. We hypothesized that ATP levels would be diminished in neuronal tissue subjected to dexamethasone and improved in cardiac tissue subjected to dexamethasone. In contrast, ATP levels would be improved in neuronal tissue subjected to metyrapone and diminished in cardiac tissue subjected to metyrapone.

Objective: Ischemic preconditioning (IP) has been shown to attenuate intracellular Na þ accumulation and Ca 2þ overload during ischemia and reperfusion, both of which are closely related to the outcome of myocardial damage. We compared the effects of single- and four-cycle IP in Na þ ,K þ -activated adenosine 5 0 -triphosphatase (Na þ ,K þ -ATPase) and Ca 2þ -activated adenosine 5 0 -triphosphatase (Ca 2þ -ATPase) activities in in vivo rabbit hearts, correlating these differences to the quality of protection against subsequent ischemia. Methods: The morphological outcome was evaluated in in vivo rabbit hearts subjected to 30 min of coronary occlusion and reperfusion for 180 min by assessing the ratio of infarct volume to risk zone volume. The effects of single- and four-cycle preconditioning ischemia were then examined. Another set of in vivo rabbit hearts was subjected to the measurement of ATPase activities at the conclusion of final preconditioning ischemia and at 60 min after reperfusion following 30 min of ischemia. Results: The infarct volume was reduced by single-cycle IP to 38% of that in the control group. The four-cycle IP further reduced the infarct volume, which was 11% of that in the control group. Na þ ,K þ -ATPase activity at 60 min after reperfusion in the four-cycle group was increased to 172% of that in the control group (10.8 mmol ADP/h/mg protein), whereas no difference was found in the single-cycle group. On the other hand, Ca 2þ -ATPase activity at the conclusion of IP was increased by single-cycle IP, the value being 255% of that in the control group (4.9 mmol ADP/h/mg protein). The four-cycle IP further increased the activity, and the value was 158% of that in the single-cycle group. Conclusions: Since increases in Na þ ,K þ -ATPase and Ca 2þ -ATPase activities contribute to the decrease in intracellular Ca 2þ concentration, the enhancement of these activities by four-cycle IP may be involved in the additional protection. q 2004 Elsevier B.V. All rights reserved.

A 54-year-old woman with a 21-year history of systemic lupus erythematosus (SLE) was admitted to the Matsuyama Red Cross Hospital due to subcutaneous and gingival hemorrhaging. She was diagnosed with acquired factor VIII inhibitors based on a prolonged activated partial-thromboplastin time (APTT) and factor VIII inhibitors. Steroid pulse and factor VIII plasma concentrate were administered to her, not long after which she was transferred to Ehime University Hospital due to gallbladder hematoma. Although her APTT and factor VIII activity were improved after treatment with human factor VIII, she died of multiple organ failure. The autopsy demonstrated a ruptured gallbladder.

Endotoxemia has been reported as a mechanism for the fatal sequela after heatstroke. Subsequent disseminated fungal infection in a heatstroke patient has been also described. Beta-D-glucan, a constituent of the fungal cell wall, is an early diagnostic measure for fungal infection. In a heatstroke case, we examined for the first time levels of serum beta-d-glucan and endotoxin. A 34-year-old man with a body temperature of 43.5 degrees C was admitted in a state of shock. Prior to the development of disseminated intravascular coagulopathy (DIC), a remarkable elevation of serum beta-D-glucan level to 116 pg/mL (normal level6.0 pg/mL) was revealed on the first day of admission. However, serum endotoxin was not detected when using a method that excluded beta-D-glucan contamination from endotoxin measurement (normal level1.0 pg/mL). This change of beta-D-glucan level was accompanied by a depressed neutrophil function, especially in phagocytosis of 34% (normal range 70-90%) but not in bacterocidal function (81% versus a normal range of 70-100%). After intensive care including continuous hemodiafiltration, the patient regained consciousness but remained ataxic due to cerebellar infarction, which might have resulted from DIC, and subsequent bilateral fungal oculitis were revealed 45 days after admission. This case report demonstrates the elevation of serum beta-D-glucan but normal endotoxin levels after heatstroke, which may prompt further study to re-examine the serum levels of endotoxin in such catastrophic insults.

Seigo Miyoshi,1 Ryoji Ito,1 Hitoshi Katayama,1 Kentaro Dote,2 Mayuki Aibiki,3 Hironobu Hamada,1,4 Takafumi Okura,1 Jitsuo Higaki1 1Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, 2Intensive Care Division, Ehime University Hospital, 3Department of Emergency and Critical Care Medicine, School of Medicine, Ehime University, Shitsukawa, Toon, Ehime, 4Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi, Minami-ku, Hiroshima, Japan 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. Keywords: sivelestat, recombinant human soluble thrombomodulin, disseminated intravascular coagulation, acute respiratory distress syndrome&nbsp

Fever 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. We 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. We 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). In 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. ClinicalTrials.gov: NCT00940654

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 subarachmoid 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.

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.

Objectives: Both hypothermia and ischemic preconditioning are known to provide tolerance to myocardial ischemia and reperfusion. The aim of this study was to determine whether hypothermia during the ischemic preconditioning period attenuates the protective effect of ischemic preconditioning. Methods: Experiments were performed in buffer-perfused isolated rabbit hearts. All hearts underwent 45 minutes of regional ischemia, followed by 2 hours of reperfusion. Ischemic preconditioning was elicited by either one or four periods of 5 minutes of regional ischemia. Hypothermia (25° C) was induced beginning either 20 or 50 minutes before the 45-minute period of regional ischemia; normothermia (38° C) was restored 10 minutes before the 45-minute period of regional ischemia. Except for the hypothermic periods noted, hearts were maintained at 38° C. Results: Normothermic ischemic preconditioning with either one or four cycles of 5 minutes of coronary occlusion resulted in a profound reduction of infarct size (58% reduction with one cycle, p < 0.05; 95% reduction with four cycles, p < 0.01). Hypothermic ischemic preconditioning with one cycle of 5-minute coronary occlusion resulted in no reduction of infarct size but hypothermic ischemic preconditioning with four cycles of 5-minute coronary occlusions resulted in a 94% reduction of infarct size (p < 0.01). Myocardial glycogen and lactate levels were maintained near control levels during hypothermic ischemia. Conclusions: From these data we conclude that hypothermia during the preconditioning period increases the threshold for eliciting the infarct limitation of ischemic preconditioning. (J Thorac Cardiovasc Surg 1998;116:319-26)