Yasuyuki Kuwagata

Analysis of 372 patients with Crush syndrome caused by the Hanshin-Awaji earthquake

OBJECTIVE To clarify clinical features and determine the severity of injuries in patients with crush syndrome in Hanshin-Awaji earthquake. METHODS We retrospectively reviewed medical records of 6,107 patients hospitalized in 95 hospitals, and identified 372 patients with crush syndrome. RESULTS The major sites of crush injury were in the lower extremities (74%), followed by the upper extremities (10%), and the trunk (9%). Pelvic fractures, limb fractures, and abdominal injuries were the most frequently associated injury. Patients with trunk compression and/or with abdominal injury had a higher mortality rate. A total of 50 patients (13.4%) died. The causes of death within 5 days after the earthquake were hypovolemia and hyperkalemia. Peak serum creatine kinase concentration increased with the number of crushed extremities. Mortality and the risk of acute renal failure were higher in patients with creatine kinase concentration more than 75,000 micro/L. CONCLUSIONS Peak serum concentration of creatine kinase as well as the number of injured extremities serve to estimate the severity of crush syndrome.

Activated platelets enhance microparticle formation and platelet-leukocyte interaction in severe trauma and sepsis.

BACKGROUND Activated platelets have been recently reported to produce platelet microparticles and to enhance platelet-leukocyte interaction. The precise role of platelets in systemic inflammatory response syndrome (SIRS) has not been clarified. The objective of this study was to evaluate microparticle formation and platelet-leukocyte interaction in severe trauma and sepsis. METHODS Twenty-six patients with severe SIRS (SIRS criteria and serum C-reactive protein > 10 mg/dL) and 12 healthy volunteers were studied. The severe SIRS was caused by trauma in 12 patients and sepsis in 14. Microparticle formation, P-selectin expression on platelets, platelet-monocyte binding, and platelet-polymorphonuclear leukocyte (PMNL) binding were measured by flow cytometry in the presence or absence of ionomycin, N-formyl-methionyl-leucyl-phenylalanine, or anti-CD62p monoclonal antibody. Soluble P-selectin, thrombomodulin, neopterin, and PMNL elastase in blood were also measured. RESULTS Microparticle formation, P-selectin expression on platelets, platelet-monocyte binding with or without ionomycin, and platelet-PMNL binding with ionomycin significantly increased in patients with severe SIRS in comparison with values in normal volunteers. The increased platelet-leukocyte binding in severe SIRS patients was markedly inhibited by P-selectin blockade and was not enhanced by N-formyl-methionyl-leucyl-phenylalanine. Soluble P-selectin, thrombomodulin, neopterin, and PMNL elastase in blood also increased in these patients. CONCLUSION Activated platelets enhance microparticle formation and platelet-leukocyte interaction in severe trauma and sepsis. Enhanced platelet-leukocyte interaction is dependent on P-selectin expression and may be involved in the systemic inflammatory response after severe inflammatory insult.

Priming, second-hit priming, and apoptosis in leukocytes from trauma patients

BACKGROUND Polymorphonuclear leukocytes (PMNL) play important roles in both host defenses and systemic inflammatory responses after insults. The objectives of this study are to examine the serial changes in PMNL priming and apoptosis in severely injured patients and to evaluate the impact of second hits on primed PMNL function and systemic vascular endothelial damage. METHODS Twenty-four severely injured patients (mean Injury Severity Score, 31.1 +/- 9.7) were included. Infections were seen as second hits after trauma in seven patients. Oxidative activity, phagocytosis, and apoptosis of PMNL from serial blood samples were measured by flow cytometry. Oxidative activity with no stimulus and with formylmethionyl-leucyl-phenylalanine (FMLP) were analyzed as the priming index and FMLP response, respectively. Interleukin (IL)-6, IL-10, PMNL elastase, and thrombomodulin concentrations in blood were also measured before and after the second hit. RESULTS The PMNL priming index was elevated from days 2 to 13, especially days 2 to 5 after injury. FMLP response was enhanced from days 2 to 21 after injury. Apoptosis of PMNL was inhibited for as long as 3 weeks after injury. Infections as second hits after trauma enhanced both the priming index and the FMLP response within 24 hours after diagnosis of infection and increased serum IL-6 concentrations. However, serum thrombomodulin levels were not affected by second hits. All patients with second hits survived. CONCLUSION Severe trauma stimulated acute-phase priming in PMNL and inhibited apoptosis. Infections after trauma induced second-hit priming in PMNL, but the unchanged serum levels of thrombomodulin suggest that priming per se may not cause systemic vascular endothelial damage.

Morbidity and mortality of hospitalized patients after the 1995 Hanshin-Awaji earthquake

The objective of this study was to provide an overview of the morbidity and mortality of hospitalized patients during the Hanshin-Awaji earthquake. Medical records of 6,107 patients admitted to 95 hospitals (48 affected hospitals within the disaster area and 47 back-up hospitals in the surrounding area) during the initial 15 days after the earthquake were analyzed retrospectively. Patient census data, diagnoses, dispositions, and prognoses were considered. A total of 2,718 patients with earthquake-related injuries were admitted to the 95 hospitals included in our survey, including 372 patients with crush syndrome and 2,346 with other injuries. There were 3,389 patients admitted with illnesses. Seventy-five percent of the injured were hospitalized during the first 3 days. In contrast, the number of patients with illnesses continued to increase over the entire 15-day period after the earthquake. The mortality rates were 13.4% (50/372), 5.5% (128/2,346), and 10.3% (349/3,389) associated with crush syndrome, other injuries, and illness, respectively. The overall mortality rate was 8.6% (527/6,107 patients). Morbidity as well as mortality rates increased with age in patients with both injuries and illnesses. In the initial 15-day period, there was an unprecedented number of patients suffering from trauma, and they converged upon the affected hospitals. Subsequently an increased incidence of illness was observed. This survey underscores the need for adequate disaster response in such an urban situation.

Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study

IntroductionCross-talk between the coagulation system and inflammatory reactions during sepsis causes organ damage followed by multiple organ dysfunction syndrome or even death. Therefore, anticoagulant therapies have been expected to be beneficial in the treatment of severe sepsis. Recombinant human soluble thrombomodulin (rhTM) binds to thrombin to inactivate coagulation, and the thrombin-rhTM complex activates protein C to produce activated protein C. The purpose of this study was to examine the efficacy of rhTM for treating patients with sepsis-induced disseminated intravascular coagulation (DIC).MethodsThis study comprised 65 patients with sepsis-induced DIC who required ventilatory management. All patients fulfilled the criteria of severe sepsis and the International Society on Thrombosis and Haemostasis criteria for overt DIC. The initial 45 patients were treated without rhTM (control group), and the following 20 consecutive patients were treated with rhTM (0.06 mg/kg/day) for six days (rhTM group). The primary outcome measure was 28-day mortality. Stepwise multivariate Cox regression analysis was used to assess which independent variables were associated with mortality. Comparisons of Sequential Organ Failure Assessment (SOFA) score on sequential days between the two groups were analyzed by repeated measures analysis of variance.ResultsCox regression analysis showed 28-day mortality to be significantly lower in the rhTM group than in the control group (adjusted hazard ratio, 0.303; 95% confidence interval, 0.106 to 0.871; P = 0.027). SOFA score in the rhTM group decreased significantly in comparison with that in the control group (P = 0.028). In the post hoc test, SOFA score decreased rapidly in the rhTM group compared with that in the control group on day 1 (P < 0.05).ConclusionsWe found that rhTM administration may improve organ dysfunction in patients with sepsis-induced DIC. Further clinical investigations are necessary to evaluate the effect of rhTM on the pathophysiology of sepsis-induced DIC.

Analysis of 2,702 Traumatized Patients in the 1995 Hanshin-awaji Earthquake

BACKGROUND This study was undertaken to define the factors that affected the final outcome of trauma patients in the Hanshin-Awaji earthquake. METHODS Medical records of patients admitted to 95 hospitals within or surrounding the affected area during the first 15 days after the quake were reviewed. RESULTS There were 2,702 traumatized patients. One-third of the patients were transported to hospitals in the surrounding area and had a mortality rate of 3%. The remainder, who were treated in the affected hospitals, showed a significantly higher mortality rate (8%; p < 0.05). Intensive care was provided for 513 patients, most of whom suffered from crush syndrome or from injuries to vital organs; these patients had a high mortality rate. Patients with other types of injuries had a lower mortality rate. CONCLUSION Crush syndrome and injuries to vital organs were potentially life-threatening. We believe that early transportation of such patients to undamaged hospitals with the ability to provide intensive care would have improved the survival rate.

Impact of transport to critical care medical centers on outcomes after out-of-hospital cardiac arrest ,

BACKGROUND Post-resuscitation care has emerged as an important predictor of survival from out-of-hospital cardiac arrest (OHCA). In Japan, selected hospitals are certified as Critical Care Medical Centers (CCMCs) based on their ability and expertise. HYPOTHESIS Outcome after OHCA is better in patients transported to a CCMC compared a non-critical care hospital (NCCH). MATERIALS AND METHODS Adults with OHCA of presumed cardiac etiology, treated by emergency medical services systems, and transported in Osaka from January 1, 2005 to December 31, 2007 were registered using a prospective Utstein style population cohort database. Primary outcome measure was 1 month neurologically favorable survival (CPC< or =2). Outcomes of patients transported to CCMC were compared with patients transported to NCCH using multiple logistic regressions and stratified on the basis of stratified field ROSC. RESULTS 10,383 cases were transported. Of these, 2881 were transported to CCMC and 7502 to NCCH. Neurologically favorable 1-month survival was greater in the CCMC group [6.7% versus 2.8%, P<0.001]. Among patients who were transported to hospital without field ROSC, neurologically favorable outcome was greater in the CCMC group than the NCCH group [1.7% versus 0.5%; adjusted odds ratio (OR), 3.39; 95% confidence interval (CI), 2.17-5.29; P<0.001]. In the presence of field ROSC, survival was similar between the groups [43% versus 41%; adjusted OR, 1.09; 95% CI, 0.82-1.45; P=0.554]. CONCLUSIONS Survival after OHCA of presumed cardiac etiology transported to CCMCs was better than those transported to NCCHs. For OHCA patients without field ROSC, transport to a CCMC was an independent predictor for a good neurological outcome.

Overview of evacuation and transport of patients following the 1995 Hanshin-Awaji earthquake.

We investigated how patients were evacuated and transported from affected hospitals in the disaster area to backup hospitals following the 1995 catastrophic Hanshin-Awaji earthquake. A retrospective review was conducted of medical records of 6107 patients hospitalized during the first 15 days after the earthquake, collected from 48 affected hospitals in the disaster area and 47 backup hospitals in the surrounding area. Of the 6107 patients, a total of 2290 (38%) were transferred to backup hospitals, consisting of 187 patients (50%) with crush syndrome, 702 (26%) with other traumas, and 1401 (41%) with illness. Of those 2290 patients, 1741 (76%) were transferred from affected hospitals to backup hospitals, while 549 patients (24%) were evacuated directly to backup hospitals. The peak in transport came during the first 4 days. The family car was the most frequently used means of transport; ambulance was used in only 26% of cases, and helicopters were used minimally. There was no notable difference in the percentage of intensive care patients and nonintensive care patients transferred to backup hospitals. The mortality rate for patients with trauma and crush syndrome was significantly higher in the affected hospitals. These results suggest that the existing emergency medical service system was not adequate for this urban earthquake. From our vantage point, we are keenly aware of the need for improved communications between hospitals, a well equipped patient transport system, and a well coordinated disaster response mechanism.

Recombinant human soluble thrombomodulin improves mortality and respiratory dysfunction in patients with severe sepsis.

BACKGROUND: Respiratory dysfunction associated with severe sepsis is a serious condition leading to poor prognosis. Activation of coagulation is a consequence of and contributor to ongoing lung injury in severe sepsis. The purpose of this study was to examine the efficacy of recombinant human soluble thrombomodulin (rhTM), a novel anticoagulant agent, for treating patients with sepsis-induced disseminated intravascular coagulation (DIC) in terms of mortality and respiratory dysfunction. METHODS: This study comprised 86 consecutive patients with sepsis-induced DIC who required ventilator management. The initial 45 patients were treated without rhTM (control group), and the following 41 patients were given rhTM (0.06 mg/kg/d) for 6 days (rhTM group). Patients were followed up for 90 days after study entry. Sequential Organ Failure Assessment (SOFA) score and lung injury score were recorded until 7 days after entry. RESULTS: The baseline characteristic of severity of illness was significantly higher in the rhTM group than in the control group. Nevertheless, 90-day mortality rate in the rhTM group was significantly lower than that in the control group (37% vs. 58%, p = 0.038). There was a significant difference in the serial change of SOFA score from baseline to day 7 between the two groups (p = 0.009). Both the respiratory component of the SOFA score and the lung injury score in the rhTM group were significantly lower compared with the control group (p = 0.034 and p < 0.001, respectively). CONCLUSIONS: rhTM may have a significant beneficial effect on mortality and respiratory dysfunction in patients with sepsis-induced DIC. LEVEL OF EVIDENCE: III, therapeutic study.

Enhanced expression of heat shock proteins in activated polymorphonuclear leukocytes in patients with sepsis.

BACKGROUND Heat shock proteins (HSPs) in cells, as molecular chaperons, have been reported to regulate cell functions. The objective of this study was to investigate the HSP expression in polymorphonuclear leukocytes (PMNLs) from severe septic patients and the relation between the expression of HSPs and PMNL function. METHODS In blood samples from 21 patients with sepsis and serum C-reactive protein levels more than 10 mg/dL, we used flow cytometry to measure expressions of HSP27, HSP60, HSP70, and HSP90; oxidative activity; and levels of apoptosis in PMNLs during sepsis. In in vitro studies, we used cells from 14 healthy volunteers to examine the relation between the expression of HSP70 and PMNL function. Quercetin (30 microM), a suppressor of HSP, and sodium arsenite (100 microM), an inducer of HSP, were used to regulate the expression of HSP70 in PMNLs, and oxidative activity and apoptosis in these cells were measured. RESULTS In patients with sepsis, the expressions of HSP27, HSP60, HSP70, and HSP90 and oxidative activity in PMNLs were significantly increased. Apoptosis of these PMNLs was markedly inhibited. In the in vitro studies, administration of sodium arsenite enhanced the expression of HSP70, significantly increased oxidative activity, and inhibited apoptosis. Administration of quercetin before sodium arsenite prevented the expression of HSP70, the increase in oxidative activity, and the inhibition of apoptosis. CONCLUSION Sepsis causes the enhanced expression of HSPs in activated PMNLs. In PMNLs with enhanced expression of HSP70, oxidative activity is increased and apoptosis is inhibited. The enhanced expression of HSPs may play a role in regulating PMNL function in patients with sepsis.