Risk of Out-of-Hospital Cardiac Arrest in Aged Individuals in Relation to Cold Ambient Temperature　- A Report From North Tochigi Experience.

BACKGROUND: The impact of cold ambient temperature on out-of-hospital cardiac arrest (OHCA) in aged individuals caused by cardiovascular events in indoor environments has not been investigated sufficiently.Methods and Results:We conducted a case-crossover study. The relationship between OHCA caused by cardiovascular events and exposure to minimum temperature <0℃ was analyzed. Conditional logistic regression analysis was performed to estimate the odds ratios for the relationship between exposure to minimum temperature <0℃ and the risk of OHCA. Between January 1, 2011, and December 31, 2015, a total of 1,452 cases of OHCA were documented, and patients were screened for enrollment. A total of 458 individuals were enrolled in this analysis, and were divided into 2 groups of 110 (elderly group: 65-74 years old) and 348 (aged group: ≥75 years old). The aged individuals had a significant increased risk of OHCA after exposure to minimum temperature <0℃ (odds ratio [OR]: 1.528, 95% confidence interval [CI] 1.009-2.315, P=0.045). Cold ambient temperature was an especially significant increased risk for OHCA occurrence for males (OR: 1.997, 95% CI 1.036-3.773, P=0.039) and during winter (OR: 2.391, 95% CI 1.312-4.360, P=0.004) in the aged group. CONCLUSIONS: Cold ambient temperature significantly affected aged individuals (≥75 years old) experiencing an OHCA caused by cardiovascular events in indoor environments.

Efficacy of a high FFP:PRBC transfusion ratio on the survival of severely injured patients: a retrospective study in a single tertiary emergency center in Japan.

PURPOSE: Recent studies have shown increased survival benefits when a high fresh frozen plasma (FFP) to packed red blood cell (PRBC) ratio is used during trauma resuscitation. However, some reports have raised questions about the effect of higher FFP:PRBC transfusion ratios. The aim of this study was to examine the efficacy of high FFP:PRBC ratios in injured patients with regard to survival and morbidity in a single tertiary emergency center in Japan. METHODS: This study examined severe trauma patients who received 10 or more PRBC units during the first 24 h of admission. We examined the relationship between the FFP:PRBC ratios during the first 6 h and the patient outcome. RESULTS: The severity was similar among all groups. The mortality rate was 44.4% in the high (>1:1.5), 16.7% in the middle (1:1.5-1:2) and 33.3% in the low (<1:2) F:P ratio groups. Only one patient in the high group developed sepsis, and none of the patients developed ARDS. CONCLUSIONS: The current results indicate that the FFP:PRBC ratios during the first 6 h after admission might not affect the mortality or morbidity. However, differences between trauma care systems in Japan and other countries, along with other study limitations, necessitate that a subsequent prospective multicenter study be undertaken before any definitive conclusions can be made.

Penetration of micafungin into the burn eschar in patients with severe burns.

Micafungin (MCFG) concentrations in the plasma and in burn eschar were investigated after daily intravenous infusion (1 h) of MCFG (200 mg) in three patients with severe burns. MCFG treatment was initiated more than 72 h after the burn injuries. The MCFG concentrations in the plasma were determined at the end of the first administration of MCFG, immediately before the second dosing, at the end of the MCFG infusion after at least 4 days from the initial treatment, and immediately before the subsequent dosing using high-performance liquid chromatography. In addition, the trough levels in burn eschar after both the initial administration and repeated administration were measured. The peak and trough levels in the plasma were comparable to or slightly lower than the reported values in healthy volunteers. The mean (range) MCFG concentrations in the burn eschar after initial administration and repeated administration were 1.41 µg/mL (<0.1-3.98 µg/mL) and 6.65 µg/mL (1.10-14.81 µg/mL), respectively. In most cases, the MCFG concentrations in the burn eschar, especially after repeated administration, were higher than the reported MIC90 of MCFG against the clinically important pathogenic species of Candida and Aspergillus. These results suggest that MCFG is capable of penetrating burn eschar.

Micafungin concentrations in the plasma and burn eschar of severely burned patients.

Micafungin concentrations in plasma and burn eschar after daily intravenous infusion (1 h) of micafungin (200 to 300 mg) were investigated for six patients with severe burns. Micafungin treatment was initiated more than 72 h after the burn injuries. The peak and trough levels in the plasma after the initial administration and repeated administrations for more than 4 days were comparable with or slightly lower than the reported values for healthy volunteers. Micafungin concentrations in the plasma and burn eschar were between 3.6 and >1,000 times higher than the reported MIC(90)s of micafungin against clinically important Candida and Aspergillus species.

Blood N-terminal proBNP as a potential indicator of cardiac preload in patients with high volume load.

Stroke volume is mainly determined by preload, afterload and contractility. Accordingly, measuring cardiac preload provides essential information for treatment of hemodynamically unstable patients. Hemodynamic monitoring is widely used to measure cardiac preload, but the monitoring method is time-consuming and invasive. It is therefore important to establish a simple and non-invasive test for monitoring cardiac preload. Brain natriuretic peptide (BNP), which lowers systemic vascular resistance, is synthesized as proBNP in response to myocardial wall stretch, and blood BNP has been used as an indicator of preload. Here, we measured blood level of N-terminal proBNP (NT-proBNP), which is generated during processing of proBNP, because NT-proBNP is stable and easily measured at the bedside. To assess the correlation between blood NT-proBNP and preload, we also measured the global end-diastolic volume index (GEDVI) that reflects the cardiac preload. GEDVI was calculated with the volumes in all chambers of the heart at the time of end-diastole. Eight male patients (57.6 +/- 25.3 years old) with high volume load (1,000 ml within 4 hours) were included in the present study: 3 subjects with burn, 3 subjects with sepsis, a patient with alcoholic ketoacidosis and a resuscitated patient. Blood levels of NT-proBNP were 1,316.3 +/- 1,154.5 pg/ml (47 blood samples from the eight patients; the normal range, < 125 pg/ml). Notably, the increase in the NT-proBNP levels was associated with the increased GEDVI (r = 0.61, p < 0.0001). Therefore, blood NT-proBNP may be a good indicator of cardiac preload in patients with high volume load.

Induction of lipocalin-type prostaglandin D synthase in mouse heart under hypoxemia.

Hypoxemia is a common manifestation of various disorders and generates pressure overload to the heart. Here we analyzed the expression of lipocalin-type prostaglandin D synthase (L-PGDS) in the heart of C57BL/6 mice kept under normobaric hypoxia (10% O2) that generates hemodynamic stress. Northern and Western blot analyses revealed that the expression levels of L-PGDS mRNA and protein were significantly increased (> twofold) after 14 days of hypoxia, compared to the mice kept under normoxia. Immunohistochemical analysis indicated that L-PGDS was increased in the myocardium of auricles and ventricles and the pulmonary venous myocardium at 28 days of hypoxia. Moreover, using C57BL/6 mice lacking heme oxygenase-2 (HO-2(-/-)), a model of chronic hypoxemia, we showed that the expression level of L-PGDS protein was twofold higher in the heart than that of wild-type mouse. L-PGDS expression is induced in the myocardium under hypoxemia, which may reflect the adaptation to the hemodynamic stress.

[Fluid management and care for multiple organ dysfunction syndrome in patients with extensive burns].

Burn shock and multiple organ dysfunction syndrome (MODS) are the main causes of death in patients with extensive burns, and thus fluid management and care for MODS are crucial in the treatment of these patients. Several fluid formulas have been developed, although there is still controversy over the best formula. The important point is to understand how to deal with the different side effects inevitable with each fluid therapy: fluid restriction and/or diuretic administration in the refilling phase in fluid therapy with crystalloid, care for hypernatremia and/or a hyperosmolar state in fluid therapy with hypertonic lactated solution (HLS), etc. Precise fluid management is needed for aged patients, patients with extensive inhalation injury, extensive electric injury, and myocardial dysfunction, or patients in whom the start of fluid treatment was delayed. MODS in extensively burned patients is attributed to overwhelming burn stress and complicated sepsis, including bacterial translocation (BT). A dysfunctioning organ impairs another organ (organ interrelationships), and therefore substitution and/or recovery of a dysfunctioning organ are crucial. Debridement of skin with third-degree burns, suppression of BT, sanitary airway management, avoidance of unnecessary stress, and mediator modulation to stop the mediator cascade inducing MODS are also crucial.

[Pathophysiologies of ischemic/reperfusion injuries associating with hemorrhagic shock and up-to-date treatment].

During the ischemic state, hypoxanthine and xanthine oxidase are accumulated in the ischemic cells, and thereafter when oxygen is reperfused into ischemic cells, hypoxanthine and xanthine oxidase work to change oxygen into oxygen radicals. Oxygen radicals themselves damage various cells and they also injure cells by activating the transcription factors of inflammatory cells to induce special protein synthesis depending on individual cells. These processes are considered to be related to the systemic inflammatory response syndrome (SIRS) and multiple-organ dysfunction syndrome (MODS). Hemorrhagic shock is a generalized ischemic state and intestinal ischemia is more profound and more severely damaging than in other vital organs because of luxurious flow to the latter organs. The lack of microcirculation in large areas of the intestinal mucosa and in high-density areas of intestinal immune cells results in the synthesis of various inflammatory mediators, in the appearance of adhesion molecules, in the induction of tissue factors, and finally in the development of impairment of remote vital organs and MODS when oxygen is reperfused. There is no therapy for reperfusion injury after a prolonged ischemic state, and thus it is most important to reduce the intestinal ischemic time by supplying sufficient oxygen to preserve intestinal circulation and to commence early enteral nutrition. The development of new treatments to interrupt the vicious pathological cascade inducing MODS after ischemic reperfusion injury is mandatory.

[Animal models for sepsis].

When new immunomodulatory agents are developed for the treatment of sepsis, the efficacy is usually tested in animal models before going to clinical trials. However, despite promising preclinical evidence, dozens of new agents have failed to demonstrate clinical efficacy. One of the reasons may be that the preclinical trials were conducted using animal models that did not adequately reflect clinical realities. Various kinds of experiments utilized for the development of new agents were carried where bolus or short term continuous infusions of large doses of bacteria or endotoxin were administered intravenously. Massive i.v. bolus models using bacteria or endotoxin generally produce a rapid hypodynamic cardiovascular response with the animals dying within hours. The serum cytokine response is transient and is much greater in magnitude than that observed in septic patients. For the preclinical testing of agents, 1) i.v. bacteria and endotoxin models in which the total challenge dose of adequate bacteria or endotoxin is reduced and/or the length of administration time is increased, and 2) peritonitis models, e.g., cecal ligation and puncture and peritoneal implantation of bacteria or endotoxin, will become reasonable choices. The animals are also required to receive volume resuscitation and adjuvant antibiotic therapy.

[Correlation between intravascular coagulation/fibrinolysis system and cytokines].

Bacterial factors stimulate the release of tissue factor as well as proinflammatory and antiinflammatory cytokines. TNF augments inflammation, TNF and IFN-gamma induce coagulation, and IL-1beta induces coagulation and fibrinolysis. IL-8 augments synergistic inflammation and coagulation. IL-6 augments coagulation and inhibits fibrinolysis. IL-10 inhibits inflammatory process and inhibits fibrinolysis. IL-4, IL-13, and TGF-beta act for anticoagulation. Administration of IL-2, G-CSF or IFN-gamma has been reported to have side effect of induction of coagulation. IL-12 induces coagulation first and fibrinolysis later. On the other, tissue factor induces proinflammatory (except TNF) and antiinflammatory cytokines, and thrombin enhances inflammation. Patients who died of SIRS/sepsis have been complicated with hypercoagulopathy and impaired fibrinolysis correlated with increased IL-10 production. Inhibition of IL-10 production or administration of fiblynolitic agents may be useful. Recently, activated protein C (APC) which has antiinflammatory effect has been paid attention in the treatment of SIRS/sepsis.

Oxygen free radical and antioxidant status in necrotizing soft tissue infection of the lower extremity; a report of two cases with opposite outcomes.

Two cases of necrotizing soft tissue infection of the lower extremity were treated concurrently but independently. Multimodal therapy including hip joint disarticulation and hyperbaric oxygen therapy was administered, resulting in opposite outcomes: survival and death. Analysis of the relationships between patient outcome and time-course changes in serum diacron-reactive oxygen metabolites (d-ROMs; an index of oxidative stress), antioxidative potential, and cytokines revealed that serum d-ROMs levels decreased with time, but high serum levels of interleukin-10 (anti-inflammatory cytokine) persisted in the patient who died. These findings may reflect an immunosuppressive status unfavorable to infection prevention. Serum d-ROMs may be a prognostic predictor in necrotizing soft tissue infections.

Hypoxemia induces expression of heme oxygenase-1 and heme oxygenase-2 proteins in the mouse myocardium.

Heme oxygenase (HO) catalyzes oxidative breakdown of heme, and constitutes two isozymes, HO-1 and HO-2. Here, we explored the tissue-specific regulation of expression of HO-1 and HO-2 under hypoxemia. There was no significant change in the overall expression levels of HO-1 and HO-2 mRNAs and proteins in the lung during adaptation of C57BL/6 mice to normobaric hypoxia (10% O(2)). However, immunohistochemical analysis revealed the increased expression of HO-1 and HO-2 proteins after 28 days of normobaric hypoxia in the pulmonary venous myocardium that is the extension of the left atrial myocardium into pulmonary venous walls. Moreover, the expression of HO-2 protein was increased in the sub-endocardial myocardium of ventricles under hypoxia, while HO-1 protein level was increased in the full-thickness walls. Thus, hypoxemia induces expression of both HO-1 and HO-2 proteins in the myocardium. Using C57BL/6 mice lacking HO-2 (HO-2(-/-)), which manifest chronic hypoxemia, we also showed that the HO-1 protein level in the lung was similar between HO-2(-/-) mice and wild-type mice. Unexpectedly, HO-1 protein level was lower by 35% in the HO-2(-/-) mouse liver than the wild-type liver. These results indicate that the expression of HO-1 protein is regulated in a tissue-specific manner under hypoxemia.

Experiences in organizing Advanced Burn Life Support (ABLS) provider courses in Japan.

The ABLS course sponsored by the ABA has not yet been made available in Japan, although it is strongly desired. During the 3 years between 2006 and 2008, authorized ABLS provider courses were given once a year in Japan as part of preparations to reach an agreement between the ABA and the JSBI for the continuation of ABLS provider courses in Japan. These courses were provided as one of the programs available at the annual meeting of the JSBI. Nine Japanese registered ABLS instructors (including some candidates) acted as lecturers. Two national faculty members and one course coordinator, acting as ABA observers, participated in the first and second courses. In total, 64 physicians (37 emergency physicians, 20 plastic surgeons, 4 intensivists and 3 general surgeons) attended the courses. Course management and instructor behavior were reviewed by the ABA observers and the 64 physicians in attendance using questionnaires. The ABA observers rated the courses as "outstanding" in every aspect (course faculty, facilities, course organization, course conduct, and adherence to ABLS philosophies). The pre-course planning, course conduct, and course evaluations were professional and adhered to the highest educational standards. However, several areas of the ABLS course content may require revision to accommodate differences in standard medical treatment between the United States and Japan. Two percent of the physicians rated the courses as easy, 59% rated the course as moderate, 22% rated the course as slightly difficult, and 6% rated the course as difficult. The courses were generally evaluated as very good by 28% of the physicians and good by 56%. The major opinion regarding the organization of the course in Japan was that the course should have undergone appropriate curriculum changes to accommodate societal differences (including the translation of the course into Japanese) as well as modifications to the disaster management and patient transport sections. Regarding the organization of future ABLS courses in Japan, the active involvement of the JSBI is inevitable. Several areas of the ABLS course content may need to be revised to accommodate differences in standard medical treatment between the United States and Japan. A joint effort between the ABA and the JSBI regarding appropriate curriculum changes to accommodate societal differences as well as modifications to some sections would increase the applicability of the course in Japan.

The effects of arginine and selective inducible nitric oxide synthase inhibitor on pathophysiology of sepsis in a CLP model.

BACKGROUND: Sepsis is an arginine-deficient state and is associated with overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS). It has been indicated that low plasma levels of arginine are related to high mortality rates in sepsis. Arginine, however, is also known to be a precursor of NO. Therefore, administration of arginine in septic patients remains controversial. We examined the effects of co-administration of arginine and aminoguanidine, a selective iNOS inhibitor, on sepsis, using rat models. METHOD: Sepsis was induced in rats by cecal ligation and puncture (CLP). Effects of separate and combined administration of arginine and aminoguanidine were investigated by comparing plasma levels of arginine, expressions of heme oxygenase (HO)-1 and HO-2 in liver and lung, and nitrite + nitrate (NOx) excretion in urine, as well as neuroendocrine responses in urine in the early phase of sepsis. Seven-day survival rates were also examined. RESULTS: A combination of arginine and aminoguanidine recovered the plasma level of arginine at 6 h post-CLP, decreased expression of HO-1 in liver and lung at 24 h post-CLP, decreased urinary excretion of epinephrine, norepinephrine, dopamine, and 17-hydroxycorticosteroid in the first 24 h post-CLP, and increased 7-d survival. CONCLUSION: It is demonstrated that administration of arginine together with the selective iNOS inhibitor in the early phase of sepsis restores plasma arginine, reduces oxidative stress by probably maintaining NO derived from constitutive NOS, and attenuates neuroendocrine stress responses. This co-administration may be a beneficial treatment approach against sepsis.

Neuroendocrine system response modulates oxidative cellular damage in burn patients.

Oxygen-derived free radicals play important roles in pathophysiological processes in critically ill patients, but the data characterizing relationships between radicals and neuroendocrine system response are sparse. To search the cue to reduce the oxidative cellular damage from the point of view of neuroendocrine system response, we studied the indicators of neuroendocrine and inflammatory responses excreted in urine in 14 burn patients (42.3 +/- 31.4 years old, and 32.3 +/- 27.6% burn of total body surface area [%TBSA]) during the first seven days post burn. The daily mean amounts of urinary excretion of 8-hydroxy-2'-deoxy-guanosine (8-OHdG), a marker of oxidative cellular damage, were above the upper limit of the standard value during the studied period. The total amount of urinary excretion of 8-OHdG in the first day post burn correlated with burn severity indices: %TBSA (r = 0.63, p = 0.021) and burn index (r = 0.70, p = 0.008). The daily urinary excretion of 8-OHdG correlated with the daily urinary excretion of norepinephrine and nitrite plus nitrate (NOx) during the studied period except day 2 post burn, and correlated with the daily urinary excretion of 17-hydroxycorticosteriod (17-OHCS) in days 2, 3, and 7 post burn. These data suggest that oxidative cellular damage correlates with burn severity and neuroendocrine system response modulates inflammation and oxidative cellular damage. Modulation of neuroendocrine system response and inflammation in the treatment in the early phase of burn may be useful to reduce the oxidative cellular damage and to prevent multiple organ failures in patients with extensive burn.

Dynamic changes in expression of heme oxygenases in mouse heart and liver during hypoxia.

Heme oxygenase cleaves heme to form biliverdin, carbon monoxide (CO), and iron, and consists of two structurally related isozymes, HO-1 and HO-2. HO-2 is also known as a potential oxygen sensor. Here we show that the relative CO content in arterial blood, which reflects the total amount of endogenous heme degradation, dynamically changes in mice during acclimatization to normobaric hypoxia (10% O2), with the two peaks at 1 day and 21 days of hypoxia. The expression levels of HO-1 and HO-2 proteins were decreased by 20% and 40%, respectively, in the mouse liver at 7 days of hypoxia, which returned to the basal levels at 14 days. On the other hand, HO-1 and HO-2 proteins were increased 2-fold and 1.3-fold, respectively, in the heart at 28 days of hypoxia. Thus, hypoxia induces or represses the expression of HO-1 and HO-2 in vivo, depending on cellular microenvironments.

Correlation of glomerular permeability, endothelial injury, and postoperative multiple organ dysfunction.

PURPOSE: To determine whether the degree of microalbuminuria correlates with the extent of endothelial cell injury, the severity of illness, and the magnitude of multiple organ dysfunction in patients who undergo emergency surgery. METHODS: We measured the urinary albumin : creatinine ratio (ACR) within 24 h after surgery in 31 patients and examined its relationship with various clinical measurements. RESULTS: The ACR increased during the first 24 h postoperatively. The log ACR correlated with the serum thrombomodulin concentration measured on the same day, but not with the level of plasma von Willebrand factor antigen. The increase in the log ACR correlated with the acute physiology and chronic health evaluation score (APACHE III), the simplified acute physiology score, the multiple organ dysfunction score, and the score of sequential organ failure assessment (SOFA) calculated on the same day, and the blood volume lost during the operation. The log ACR did not correlate with the white blood cell count or the serum C-reactive protein measured at the same time. The log ACR correlated with SOFA on postoperative days 3, 7, and 10, and mortality increased in accordance with the increase in log ACR. CONCLUSIONS: The urinary ACR correlated with the extent of endothelial cell injury, the severity of illness, and the magnitude of multiple organ dysfunction.

Recombinant human interleukin-1alpha increases serum albumin, Gc-globulin, and alpha1-antitrypsin levels in burned mice.

The response to thermal injury is a complex physiologic process requiring communication between sites of injury and distant target organs. The liver, one of these target organs, synthesizes a family of secretory proteins, the acute phase proteins, that carries out specific immunoprotective functions. In this study we investigated the effects of daily recombinant human interleukin-1alpha (rhIL-1alpha) administration on the serum levels of negatively regulated, i.e., albumin and Gc-globulin and positively regulated, i.e., alpha1-antitrypsin, acute phase proteins in a murine model of thermal injury. Adult CF-1 female mice underwent a 6.5-seconds, 20% total burn surface area, full thickness steam injury, and received either intraperitoneal rhIL-1alpha (20 microg x kg(-1) x day(-1)) or diluent for 10 days. Seven and 14 days after injury, mice were sacrificed, and serum albumin, Gc-globulin and alpha1-antitrypsin levels were measured by crossed immunoelectrophoresis technique. Thermal injury significantly lowered serum albumin levels, tended to decrease Gc-globulin levels, and increased serum alpha1-antitrypsin levels. Daily rhIL-1alpha administration after burn injury prevented hypoalbuminemia, and increased serum levels of Gc-globulin and alpha1-antitrypsin. IL-1 therapy might be helpful to maintain the homeostasis and immunity of the host after thermal injury.