Osamu Kemmotsu

Acute brain swelling after out-of-hospital cardiac arrest: pathogenesis and outcome.

ObjectivesFirst, to examine factors that may be related to brain swelling, which was identified by the absence or compression of the lateral and third ventricles and perimesencephalic cisterns on brain computed tomography (CT) scans in the early postresuscitation period in patients who suffered an out-of-hospital cardiac arrest. Second, to characterize the neurologic outcome in those patients in whom cardiac arrest was followed by brain swelling. DesignProspective and retrospective analyses. SettingsGeneral ICU, tertiary care hospital. PatientsFifty-three patients (35 male, 18 female) who had an out-of-hospital cardiac arrest and who also had a brain CT examination on the third day after resuscitation. The 53 patients were divided into two groups: group A (25 patients) experienced brain swelling on postresuscitation day 3; group B (28 patients) did not experience noticeable brain swelling. InterventionsNone Measurements and Main ResultsThere was a significant difference between the two groups in the etiology of the cardiac arrest. Twenty-three of 25 patients in group A had cardiac arrest due to respiratory distress, whereas this finding was true in only five patients in group B. In laboratory data, arterial pH was significantly lower in group A than in group B (6.93 vs. 7.09), as was base deficit (-21.0 mmol/L in group A vs. −13.7 mmol/L in group B). Neurologic outcome was evaluated 1 wk after resuscitation. There were significantly more patients in group A who were not awake and who were diagnosed as braing dead. ConclusionsThe cause of brain swelling may be related to the development of the metabolis acidosis (possibly lactic acidosis) due to hypoxie before the resuscitation period. Brain swelling may be one of the indicators that predicts a poes neurologic outcome in the patients who suffes an out-of-hospital cardiac arrest. (Crit Care Med 1993; 21:104–110)

Activation of the extrinsic coagulation pathway in patients with severe sepsis and septic shock

OBJECTIVES To obtain systematic information on the extrinsic coagulation pathway, as well as to investigate the time course of the coagulation abnormalities in sepsis. DESIGN Prospective observational study. SETTING General intensive care unit. PATIENTS Nineteen patients with the diagnosis of severe sepsis or septic shock and nine control patients. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Tissue factor antigen concentration (tissue factor antigen), prothrombin fragment F1+2, thrombin antithrombin III complex, fibrinopeptide A, D-dimer, and antithrombin III concentrations were measured on the day of diagnosis of severe sepsis and septic shock, and on days 1, 2, 3, and 4 after diagnosis. The concentrations of tissue factor antigen, prothrombin fragment F1+2, fibrinopeptide A, and D-dimer were significantly increased in patients with severe sepsis and septic shock compared with control subjects. However, the concentrations of thrombin antithrombin III complex showed no statistical differences between the septic patients and the control subjects. Significantly, low antithrombin III concentrations were observed in the septic patient groups compared with control subjects. With the exception of D-dimer, the concentrations of the hemostatic markers were similar between severe sepsis and septic shock patients. Significant correlations were noted between tissue factor antigen and the disseminated intravascular coagulation score (r2=.236, p< .0001) and the number of dysfunctioning organs (r2=.229, p=.035). CONCLUSIONS We systematically elucidated coagulation disorders in newly defined sepsis. The extrinsic coagulation pathway is activated in patients with severe sepsis and septic shock. In these patients, enhanced thrombin generation and activation, and fibrin formation were demonstrated when compared with the control subjects. Furthermore, the thrombin generated appears not to be fully neutralized by antithrombin III.

Diminished function and expression of the cardiac Na+-Ca2+ exchanger in diabetic rats: implication in Ca2+ overload

1 The present work was carried out in order to determine whether a decrease in cardiac Na+‐Ca2+ exchanger (NCX) activity observed in diabetes is caused by a reduction in NCX protein and mRNA levels and to elucidate the significance of this decrease in alterations in [Ca2+]i homeostasis in diabetic cardiomyocytes. 2 The NCX current was significantly reduced in ventricular myocytes freshly isolated from streptozotocin‐induced diabetic rat hearts, and its current density was about 55 % of age‐matched controls. 3 Diabetes resulted in a 30 % decrease in cardiac protein and mRNA levels of NCX1, a NCX isoform which is expressed at high levels in the heart. 4 The reduced NCX current and the decreased protein and mRNA levels of NCX1 in diabetes were prevented by insulin therapy. 5 Although both diastolic and peak systolic [Ca2+]i were not different between the two groups of myocytes, increasing external Ca2+ concentration to high levels greatly elevated diastolic [Ca2+]i in diabetic myocytes. Inhibition of NCX by reduction in extracellular Na+ by 50 % could produce a marked rise in diastolic [Ca2+]i in control myocytes in response to high Ca2+, as seen in diabetic myocytes. However, cyclopiazonic acid, an inhibitor of sarcoplasmic reticulum Ca2+ pump ATPase, did not modify the high Ca2+‐induced changes in diastolic [Ca2+]i in either control or diabetic myocytes. 6 Only in papillary muscles from diabetic rats did the addition of high Ca2+ cause a marked rise in resting tension signifying a partial contracture that was possibly due to an increase in diastolic [Ca2+]i. 7 In conclusion, the diminished NCX function in diabetic myocytes shown in this study results in part from the decreased levels of cardiac NCX protein and mRNA. We suggest that this impaired NCX function may play an important role in alterations in Ca2+ handling when [Ca2+]i rises to pathological levels.

Disseminated intravascular coagulation and sustained systemic inflammatory response syndrome predict organ dysfunctions after trauma: application of clinical decision analysis.

OBJECTIVE To determine the accuracy of disseminated intravascular coagulation (DIC) and sustained systemic inflammatory response syndrome (SIRS) in predicting posttrauma multiple organ dysfunction syndrome (MODS) and to find a simple laboratory test for detecting MODS. SUMMARY AND BACKGROUND DATA In trauma patients, the duration of SIRS is the main determinant for MODS and outcome. METHODS One hundred thirty-six patients with trauma were classified into subgroups according to the duration of SIRS: patients without SIRS (n = 27), patients with SIRS for <2 days (n = 52), and patients with SIRS for > or =3 days (n = 57). Platelets and five coagulation and fibrinolytic laboratory tests for diagnosing DIC were measured on the day of admission and on days 1 through 4 after admission. Simultaneously, the DIC score was determined. The diagnostic accuracy of DIC and sustained SIRS for the prediction of MODS was determined using likelihood ratios. A receiver operating characteristic curve of platelet counts for predicting MODS was also constructed. RESULTS Platelet counts showed significant differences among the three groups. The incidence of DIC, acute respiratory distress syndrome, and MODS was significantly higher in patients with SIRS for > or =3 days compared with those in the other groups, and they had a poor outcome. Likelihood ratios of DIC and SIRS for > or =3 days for predicting posttrauma MODS were 11.6 and 6.25, respectively. Platelet counts (80 x 10(9)/l) on day 1 had a sensitivity of 83.3% and a specificity of 100% for predicting MODS. CONCLUSIONS Disseminated intravascular coagulation and sustained SIRS are strong determinants for posttrauma MODS. This retrospective analysis supports the possibility that platelet counts can be used as a simple laboratory test for predicting MODS. This hypothesis requires proof using a prospective clinical survey.

Tissue factor production not balanced by tissue factor pathway inhibitor in sepsis promotes poor prognosis.

ObjectiveTo determine the precise relationship among tissue factor, tissue factor pathway inhibitor (TFPI), and neutrophil elastase in sepsis, as well as to test the hypothesis that low TFPI concentrations are not sufficient to prevent tissue factor-dependent intravascular coagulation, leading to multiple organ dysfunction syndrome and death. DesignProspective, cohort study. SettingGeneral intensive care unit of tertiary care emergency department. PatientsThirty-one consecutive patients with sepsis, classified as 15 survivors and 16 nonsurvivors. Ten normal, healthy volunteers served as controls. InterventionsNone. Measurements and Main ResultsTissue factor antigen concentration (tissue factor), TFPI, neutrophil elastase, and global variables of coagulation and fibrinolysis were measured on the day of diagnosis of sepsis, severe sepsis, and septic shock and days on 1–4 after diagnosis. The number of systemic inflammatory response syndrome criteria that patients met and the disseminated intravascular coagulation score were determined simultaneously. The results of these measurements were compared between the survivors and the nonsurvivors. In the nonsurvivors, significantly higher concentrations of tissue factor and neutrophil elastase were found compared with the survivors and control subjects. However, the TFPI values showed no difference between the two groups. No correlation was found between the peak concentrations of tissue factor and TFPI. Disseminated intravascular coagulation scores and numbers of the SIRS criteria met by the survivors significantly decreased from day 0 to day 4, but those of the nonsurvivors did not improve during the study period. The nonsurvivors showed thrombocytopenia and higher numbers of dysfunctioning organs than did the survivors. ConclusionsWe systematically elucidated the relationship between tissue factor and TFPI in patients with sepsis, severe sepsis, and septic shock. Activation of tissue factor-dependent coagulation pathway not adequately balanced by TFPI has important roles in sustaining DIC and systemic inflammatory response syndrome, and it contributes to multiple organ dysfunction syndrome and death. High concentrations of neutrophil elastase released from activated neutrophils may explain, in part, the imbalance of tissue factor and TFPI in sepsis.

Out-of-hospital cardiac arrest increases soluble vascular endothelial adhesion molecules and neutrophil elastase associated with endothelial injury

Objectives: To investigate the inflammatory responses in patients with out-of-hospital cardiac arrest, we examined the changes in markers of endothelial activation, neutrophil activation, and endothelial injury.¶Design: Prospective, cohort study.¶Setting: General intensive care unit of a tertiary care center.¶Patients and participants: Forty-four out-of-hospital cardiac arrest patients were classified into two groups, those who achieved return of spontaneous circulation (ROSC) (n = 23) and those without ROSC (n = 21). Eight normal healthy volunteers served as control subjects.¶Measurements and results: Serial levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin) as markers of endothelial activation, neutrophil elastase as a marker of neutrophil activation, and soluble thrombomodulin as a marker of endothelial injury were measured during and after cardiopulmonary resuscitation (CPR). In patients with ROSC, cardiac arrest and CPR led to increases in the levels of three vascular endothelial adhesion molecules, neutrophil elastase, and soluble thrombomodulin that peaked 6 h or 24 h after arrival at the emergency department. In patients without ROSC, only neutrophil elastase showed moderate elevation during CPR. We could not find significant differences in all measured parameters between the two groups.¶Conclusions: As evidence of inflammatory responses in whole-body ischemia and reperfusion, our study demonstrates neutrophil-endothelium interaction with signs of endothelial injury in patients with out-of-hospital cardiac arrest. These inflammatory changes may have an important role in post-resuscitation syndrome after human cardiac arrest.

Blood pressure measurement by arterial tonometry in controlled hypotension

A newly developed arterial tonometer enabled us to measure the blood pressure waveforms in addition to determining systolic and diastolic pressures noninvasively and continuously. Twenty-eight adult patients undergoing orthopedic surgery under controlled hypotension were studied. Systolic blood pressure was reduced to two-thirds of baseline values with an infusion of nitroglycerin during nitrous oxide/enflurane anesthesia. Intraarterial blood pressures were simultaneously measured in either the right or the left radial artery with a cannula and a Gould P23XL calibrated transducer; tonometric monitoring was performed on the contralateral radial artery using a Colin CBM-3000 instrument. The outputs of the two blood pressure measurement instruments were recorded for later data analysis. The shape of the tonometric pressure waveform was nearly identical to the waveform recorded intraarterially even during controlled hypotension. Regression analyses of 2039 paired tonometric and intraarterial blood pressure values during the hypotensive period showed good correlations (r = 0.78 for systolic, r = 0.81 for mean, and r = 0.70 for diastolic pressures). The accuracy of systolic, mean, and diastolic readings was from 4 to 7 mm Hg with negligible bias and did not differ significantly among six systolic, four mean, and four diastolic pressure groups. Our results indicate that arterial tonometry can provide accurate, reliable, and real-time monitoring of blood pressure even during controlled hypotension.

Inotropic effects of isoflurane on mechanics of contraction in isolated cat papillary muscles from normal and failing hearts.

The inotropic effect of isoflurane (Forane) was studied in papillary muscles from cats with normal hearts (NH) and those with experimentally produced congestive heart failure (CHF). Mean maximal velocity of shortening (Vmax) and mean maximal developed force (Fm) of CHF muscles were lower than in the normal heart. Isoflurane at the concentration equivalent to MAC in man reduced Vmax an average of 36 per cent in NH and 51 per cent in CHF muscles. Average percentage decreases in Fm were 40 in NH and 52 in CHF muscles. When changes in myocardial contractility of CHF muscles exposed to isoflurane at MAC were compared with the NH control values, reductions of Vmax and Fm were 75 and 74 per cent, respectively. The combined negative inotropic effects of isoflurane and CHF were more pronounced than that of isoflurane alone on the normal heart.

Systemic activation of tissue-factor dependent coagulation pathway in evolving acute respiratory distress syndrome in patients with trauma and sepsis.

BACKGROUND Extravascular coagulation and fibrin deposition coupled with perturbations of intravascular coagulation occurs in association with acute respiratory distress syndrome (ARDS). To evaluate the pathogenetic role of an extrinsic coagulation pathway in the intravascular coagulation of ARDS patients and to explore the time course of the changes of tissue factor levels, platelet counts, and disseminated intravascular coagulation (DIC), we performed a prospective cohort study. METHODS The study subjects consisted of 113 patients: 27 patients with ARDS, 31 patients at risk for but not developing the syndrome, and 55 patients without ARDS. According to the underlying disease, the patients were further subdivided into two groups: patients with trauma (n = 76) and patients with sepsis (n = 37). Ten normal healthy volunteers served as control subjects. Plasma tissue factor antigen (tissue factor) levels and platelet counts were measured on the day of admission and on days 1 through 4 after admission. Simultaneously, the DIC scores were determined. RESULTS The values of tissue factor in the patients with ARDS were significantly more elevated than those measured in the other two groups (p < 0.001) and control subjects (p < 0.001) on the day of admission. The values continued to be markedly high up to day 4 of admission. On the day of admission, the platelet counts in the ARDS patients showed significantly lower values (p < 0.05) than those in the other two groups. The incidence of DIC and the DIC scores in ARDS patients were significantly higher than those in the other two groups. The tissue factor levels (r(s) = 0.428, p < 0.0001) and DIC scores (r(s) = 0.357, p < 0.0002) correlated significantly with Lung Injury Score. When the patients were subdivided into two subgroups, i.e., trauma and sepsis, some differences of the tissue factor levels were noted between the two groups. CONCLUSION We demonstrated that tissue-factor dependent coagulation pathway of plasma is extensively activated in patients with ARDS, followed by intravascular coagulation and platelet consumption. We further provide precise information on the time course of tissue factor levels and DIC in patients with ARDS and those at risk for developing this syndrome.

Coagulofibrinolytic changes after isolated head injury are not different from those in trauma patients without head injury.

BACKGROUND To test the hypothesis that tissue factor release, thrombin activation, fibrin formation, and fibrinolysis after an isolated head injury are equal to those in patients without head injury, as well as to investigate the precise time course of the coagulation and fibrinolytic abnormalities after head injury, we performed prospective and retrospective studies. METHODS AND RESULTS In the prospective study, 5 patients with isolated head injury and 11 trauma patients without head injury took part in this study. Tissue factor antigen concentration, prothrombin fragment F1+2, thrombin antithrombin complex, fibrinopeptide A, and fibrin degradation products (D-dimer) were measured on the day of admission, and days 1, 2, 3, and 4 after admission. The levels of all five hemostatic molecular markers were markedly elevated on the day of admission, and then gradually decreased to day 4. The levels and the time course of these hemostatic markers in patients with isolated head injury were not different from those in the control patients. The same incidence of disseminated intravascular coagulation between the two groups was also observed. In the retrospective study, the records of fibrinopeptide Bbeta15-42, plasmin antiplasmin complex, plasminogen activator inhibitor-1 antigen concentration (PAI-1 antigen), and PAI-1 activity in 76 trauma patients were reviewed. On the basis of the exclusion criteria, 9 patients with isolated head injury and 30 control patients were selected for the study group. Fibrinopeptide Bbeta15-42 and plasmin antiplasmin complex markedly elevated on the day of admission, then decreased on day 1, and tended to increase to day 5. Markedly elevated PAI-1 antigen and PAI-1 activity on the day of admission significantly decreased on day 1 and recovered to the normal values on day 5. The changes of these molecular markers in patients with isolated head injury were equal to those in the control patients. CONCLUSION We systematically elucidated the time course of coagulation and fibrinolysis after isolated head injury. We further demonstrated that changes in coagulofibrinolytic and antifibrinolytic systems in patients with isolated head injury are not different from those in patients without head injury.