Optimal target blood pressure in elderly with septic shock (OPTPRESS) trial: study protocol for a randomized controlled trial.

BACKGROUND: Hemodynamic stabilization is a core component in the resuscitation of septic shock. However, the optimal target blood pressure remains debatable. Previous randomized controlled trials suggested that uniformly adopting a target mean arterial pressure (MAP) higher than 65 mmHg for all adult septic shock patients would not be beneficial; however, it has also been proposed that higher target MAP may be beneficial for elderly patients, especially those with arteriosclerosis. METHODS: A multicenter, pragmatic single-blind randomized controlled trial will be conducted to compare target MAP of 80-85 mmHg (high-target) and 65-70 mmHg (control) in the resuscitation of septic shock patients admitted to 28 hospitals in Japan. Patients with septic shock aged ≥65 years are randomly assigned to the high-target or control groups. The target MAP shall be maintained for 72 h after randomization or until vasopressors are no longer needed to improve patients' condition. To minimize the adverse effects related to catecholamines, if norepinephrine dose of ≥ 0.1 µg/kg/min is needed to maintain the target MAP, vasopressin will be initiated. Other therapeutic approaches, including fluid administration, hydrocortisone use, and antibiotic choice, will be determined by the physician in charge based on the latest clinical guidelines. The primary outcome is all-cause mortality at 90 days after randomization. DISCUSSION: The result of this trial will provide great insight on the resuscitation strategy for septic shock in the era of global aged society. Also, it will provide the better understanding on the importance of individualized treatment strategy in hemodynamic management in critically ill patients. TRIAL REGISTRATION: UMIN Clinical Trials Registry; UMIN000041775. Registered 13 September 2020.

Pharmacokinetics and the optimal regimen for levofloxacin in critically ill patients receiving continuous hemodiafiltration.

The aim of this study was to establish the pharmacokinetics of levofloxacin (LVFX) and determine the optimal dose of this drug in critically ill patients receiving continuous hemodiafiltration (CHDF). The results of in vivo and in vitro studies showed the pharmacokinetics of LVFX total clearance (CLtotal) according to the creatinine clearance (CLCre), dialysate flow (QD), and ultrafiltrate flow (QF), to be as follows: CLtotal (l/h) = 0.0836 × CLCre (ml/min) + 0.013 × body weight (kg) + 0.94(QD + QF) (l/h). The optimal dose of LVFX was expressed by the following formula: 50 × CLtotal. These results demonstrate that the usual dose of LVFX (500 mg) was sufficient for the patients evaluated in this study.

Rapid evaluation of fibrinogen levels using the CG02N whole blood coagulation analyzer.

Rapid evaluation of fibrinogen (Fbg) levels is essential for maintaining homeostasis in patients with massive bleeding during severe trauma and major surgery. This study evaluated the accuracy of fibrinogen levels measured by the CG02N whole blood coagulation analyzer (A&T Corporation, Kanagawa, Japan) using heparinized blood drawn for blood gas analysis (whole blood-Fbg). A total of 100 matched pairs of heparinized blood samples and citrated blood samples were simultaneously collected from patients in the intensive care unit. Whole blood-Fbg results were compared with those of citrated plasma (standard-Fbg). The whole blood coagulation analyzer measured fibrinogen levels within 2 minutes. Strong correlations between standard-Fbg and whole blood-Fbg were observed (ρ = 0.91, p < 0.001). Error grid analysis showed that 88% of the values were clinically acceptable, and 12% were in a range with possible effects on clinical decision-making; none were in a clinically dangerous range without appropriate treatment. Using a fibrinogen cutoff value of 1.5 g/L for standard-Fbg, the area under the receiver operating characteristic curve of whole blood-Fbg was 0.980 (95% confidence interval 0.951-1.000, p < 0.001). The whole blood coagulation analyzer can rapidly measure fibrinogen levels in heparinized blood and could be useful in critical care settings where excessive bleeding is a concern.

Fibrinogen level deteriorates before other routine coagulation parameters and massive transfusion in the early phase of severe trauma: a retrospective observational study.

In trauma, hemostatic functions should be maintained appropriately to prevent massive bleeding. This study elucidated the time-dependent changes in platelet count and coagulation variables, and the effects of disseminated intravascular coagulation (DIC) on these changes during the early phase of trauma. Trauma patients with an injury severity score ≥16 were enrolled. The critical levels of platelet count and coagulation variables were defined according to recent trauma guidelines. Massive transfusion was defined as >10 units red cell concentrate. The time from arrival at the emergency department to reaching the critical levels and meeting the criteria for massive transfusion were evaluated. Eighty trauma patients were enrolled; 35 were diagnosed with DIC on arrival. Among all patients, fibrinogen levels reached the critical level earliest among routine coagulation parameters; other routine coagulation parameters deteriorated after the patients met the criteria for massive transfusion. Routine coagulation parameters reached their critical levels earlier in DIC patients than patients without DIC. Massive transfusion was performed more frequently in DIC patients, who met the criteria earlier. During the early phase of trauma, fibrinogen levels deteriorate earlier than other routine coagulation parameters, especially in DIC patients.

Noble-Collip Drum Trauma Induces Disseminated Intravascular Coagulation But Not Acute Coagulopathy of Trauma-Shock.

BACKGROUND: There are two opposing possibilities for the main pathogenesis of trauma-induced coagulopathy: an acute coagulopathy of trauma shock and disseminated intravascular coagulation with the fibrinolytic phenotype. OBJECTIVE: The objective of this study was to clarify the main pathogenesis of trauma-induced coagulopathy using a rat model of Noble-Collip drum trauma. METHODS: Eighteen rats were divided into the control, trauma 0, and trauma 30 groups. The trauma 0 and 30 groups were exposed to Noble-Collip drum trauma. Blood samples were drawn without, immediately after, and 30 min after Noble-Collip drum trauma in the control, trauma 0, and trauma 30 groups, respectively. Coagulation and fibrinolysis markers were measured. Thrombin generation was assessed according to a calibrated automated thrombogram. RESULTS: Spontaneous thrombin bursts resulting from circulating procoagulants were observed in the nonstimulated thrombin generation assay immediately after trauma. Soluble fibrin levels (a marker of thrombin generation in the systemic circulation) were 50-fold greater in the trauma groups than in the control group. The resultant coagulation activation consumed platelets, coagulation factors, and antithrombin. Endogenous thrombin potential and factor II ratio were significantly negatively correlated with antithrombin levels, suggesting insufficient control of thrombin generation by antithrombin. High levels of active tissue-type plasminogen activator induced hyperfibrin(ogen)olysis. Soluble thrombomodulin increased significantly. However, activated protein C levels did not change. CONCLUSIONS: The systemic thrombin generation accelerated by insufficient antithrombin control leads to the consumption of platelets and coagulation factors associated with hyperfibrin(ogen)olysis. These changes are collectively termed disseminated intravascular coagulation with the fibrinolytic phenotype.

Hemostasis during the early stages of trauma: comparison with disseminated intravascular coagulation.

INTRODUCTION: We tested two hypotheses that disseminated intravascular coagulation (DIC) and acute coagulopathy of trauma-shock (ACOTS) in the early phase of trauma are similar disease entities and that the DIC score on admission can be used to predict the prognosis of patients with coagulopathy of trauma. METHODS: We conducted a retrospective study of 562 trauma patients, including 338 patients whose data were obtained immediately after admission to the emergency department. We collected serial data for the platelet counts, global markers of coagulation and fibrinolysis, and antithrombin levels. DIC was diagnosed according to the Japanese Association for Acute Medicine (JAAM) DIC scoring system, and ACOTS was defined as a prothrombin-time ratio of >1.2. RESULTS: The higher levels of fibrin/fibrinogen degradation products (FDP) and D-dimer and greater FDP/D-dimer ratios in the DIC patients suggested DIC with the fibrinolytic phenotype. The DIC patients with the fibrinolytic phenotype exhibited persistently lower platelet counts and fibrinogen levels, increased prothrombin time ratios, higher FDP and D-dimer levels, and lower antithrombin levels compared with the non-DIC patients on arrival to the emergency department and during the early stage of trauma. Almost all ACOTS patients met the criteria for a diagnosis of DIC; therefore, the same changes were observed in the platelet counts, global markers of coagulation and fibrinolysis, and antithrombin levels as noted in the DIC patients. The JAAM DIC score obtained immediately after arrival to the emergency department was an independent predictor of massive transfusion and death due to trauma and correlated with the amount of blood transfused. CONCLUSIONS: Patients who develop DIC with the fibrinolytic phenotype during the early stage of trauma exhibit consumption coagulopathy associated with increased fibrin(ogen)olysis and lower levels of antithrombin. The same is true in patients with ACOTS. The JAAM DIC score can be used to predict the prognosis of patients with coagulopathy of trauma.

Effects of Rikkunshito (traditional Japanese medicine) on enteral feeding and the plasma ghrelin level in critically ill patients: a pilot study.

BACKGROUND: Rikkunshito is a traditional Japanese medicine that has been widely prescribed for patients with various gastrointestinal symptoms. Recently, the prokinetic effects of Rikkunshito in patients with a variety of diseases have attracted attention in Japan. The prokinetic effects of Rikkunshito are believed to result from an increase of active ghrelin, which is most abundant in the stomach and which has a gastrokinetic function. The aim of the present pilot study was to investigate the effects of Rikkunshito on intragastric enteral feeding and plasma ghrelin levels in critically ill patients. METHODS: The study population consisted of critically ill patients who were projected to require intragastric tube feeding for more than 7 days. The patients were prospectively assigned to one of two treatment groups and were randomized to receive either Rikkunshito (2.5 g) or metoclopramide (10 mg) every 8 h. All patients received standard enteral nutrition. Patients in both groups were begun on intragastric tube feeding according to our institution's feeding protocol. RESULTS: All patients were undergoing mechanical ventilation at the time of enrollment. The portions of enteral nutrition provided to the target amount and the quantity of gastric discharge were not statistically significantly different between the two groups. The Rikkunshito group reached 50% of the target amount of enteral feeding significantly earlier than the metoclopramide group, although the proportion of patients in whom enteral feeding was successful did not differ significantly between the two groups. Patients in the Rikkunshito group showed significantly higher plasma levels of active ghrelin compared to those in the metoclopramide group. CONCLUSIONS: The administration of Rikkunshito increased the plasma level of active ghrelin, and induced prokinetic effects that were greater than those observed following treatment with metoclopramide in critically ill patients. TRIAL REGISTRATION: UMIN00000356.

Coagulofibrinolytic changes in patients with disseminated intravascular coagulation associated with post-cardiac arrest syndrome--fibrinolytic shutdown and insufficient activation of fibrinolysis lead to organ dysfunction.

INTRODUCTION: Post-cardiac arrest syndrome (PCAS) is often associated with disseminated intravascular coagulation (DIC), thus leading to the development of multiple organ dysfunction syndrome (MODS). The aim of this study was to examine the pathophysiological relationships between coagulation, fibrinolysis and fibrinolytic shutdown by evaluating the levels of coagulofibrinolytic markers, including soluble fibrin, thrombin-activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator-plasminogen activator inhibitor-1 complex (tPAIC), plasmin-alpha2 plasmin inhibitor complex (PPIC), neutrophil elastase and fibrin degradation product by neutrophil elastase (EXDP). MATERIALS AND METHODS: Fifty-two resuscitated patients were divided into two groups: 22 DIC and 30 non-DIC patients. RESULTS: The levels of soluble fibrin, PPIC, tPAIC, EXDP and neutrophil elastase in the DIC patients with PCAS were significantly higher than those observed in the non-DIC patients. The values of the tPAIC and JAAM DIC scores were found to be independent predictors of increased SOFA scores in the DIC patients. The MODS patients demonstrated significantly higher levels of soluble fibrin and tPAIC; however, the levels of TAFI and EXDP were identical between the patients with and without MODS. In addition, positive correlations were observed between the levels of tPAIC and EXDP in the patients with non-MODS; however, no correlations were observed between these markers in the MODS patients. CONCLUSIONS: Thrombin activation and fibrinolytic shutdown play important roles in the development of organ dysfunction in PCAS patients. Neutrophil elastase-mediated fibrinolysis cannot overcome the fibrinolytic shutdown that occurs in DIC patients with PCAS, thus resulting in the development of MODS.

Normal prothrombinase activity, increased systemic thrombin activity, and lower antithrombin levels in patients with disseminated intravascular coagulation at an early phase of trauma: comparison with acute coagulopathy of trauma-shock.

BACKGROUND: We tested the hypotheses that an increase in systemic thrombin activity occurs in both disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype and in acute coagulopathy of trauma shock (ACoTS), and that the patients diagnosed as having ACoTS overlap or are identical with those diagnosed as having DIC. METHODS: We made a prospective study of 57 trauma patients, including 30 patients with DIC and 27 patients without DIC. Patients with ACoTS, defined as a prothrombin time ratio >1.2, were also investigated. We included 12 healthy volunteers as controls. The levels of soluble fibrin, antithrombin, prothrombinase activity, soluble thrombomodulin, and markers of fibrin(ogen)olysis were measured on days 1 and 3 after the trauma. The systemic inflammatory response syndrome and the Sequential Organ Failure Assessment were scored to evaluate the extent of inflammation and organ dysfunction. RESULTS: Patients with DIC showed more systemic inflammation and greater Sequential Organ Failure Assessment scores and were transfused with more blood products than the patients without DIC. On day 1, normal prothrombinase activity, increased soluble fibrin, lesser levels of antithrombin, and increased soluble thrombomodulin were observed in patients with DIC in comparison with controls and non-DIC patients. These changes were more prominent in patients with DIC who met the overt criteria for DIC established by the International Society on Thrombosis and Haemostasis. Multiple regression analysis showed that antithrombin is an independent predictor of high soluble fibrin in DIC patients. Greater levels of fibrin and fibrinogen degradation products, D-dimer, and the fibrin and fibrinogen degradation products/D-dimer ratio indicated increased fibrin(ogen)olysis in DIC patients. Almost all ACoTS patients overlapped with the DIC patients. The changes in the measured variables in ACoTS patients coincided with those in DIC patients. CONCLUSION: Normal prothrombinase activity and insufficient control of coagulation give rise to systemic increase in thrombin generation and its activity in patients with DIC with the fibrinolytic phenotype at an early phase of trauma. The same is true in patients with ACoTS, and shutoff of thrombin generation was not observed.

Massive amounts of tissue factor induce fibrinogenolysis without tissue hypoperfusion in rats.

Trauma-induced tissue factor (TF) release into the systemic circulation is considered to play an important role in the development of disseminated intravascular coagulation (DIC) immediately after severe trauma. However, the relationship between TF and hyperfibrinolysis, especially fibrinogenolysis, has been unclear. A total of 18 rats were divided into three groups: (a) the control group was infused with normal saline; (b) the low-dose group was infused with 4 U/kg TF; and (c) the high-dose group was infused with 16 U/kg TF. Arterial blood was drawn immediately and 2 and 4 h after the start of TF infusion. At each sampling point, arterial blood gases, platelet counts, and coagulation variables were measured. The fibrinogen degradation products were evaluated by a Western blot analysis. Hypotension, hypoxemia, and lactic acidosis were not observed in any of the three groups. In proportion to the doses of TF, the platelet counts, coagulation, and fibrinolysis variables deteriorated in line with DIC. The α2-plasmin inhibitor levels significantly decreased in the high-dose group compared with the other groups. The amounts of fibrinogen degradation products increased in proportion to the doses of TF. The plasmin-α2-plasmin inhibitor complex level in the high-dose group increased more than that of the other groups. In conclusion, TF can induce DIC associated with fibrinolysis and fibrinogenolysis without tissue hypoperfusion. The decrease in the α2-plasmin inhibitor level and the significant increase in the plasmin level may be the two main factors underlying the pathogenesis of hyperfibrin(ogen)olysis after TF administration.

The role of angiogenic factors and their soluble receptors in acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS) associated with critical illness.

BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by a disruption of the endothelium and alveolar epithelial barriers involving increased microvascular permeability, thus resulting in the set of protein-rich pulmonary edema. Angiogenic factors and their receptors, including vascular endothelial growth factor (VEGF)/VEGF-receptor (VEGFR) and the angiopoietin (Ang)/Tie2 signaling pathways, play pivotal roles in both angiogenesis and microvascular permeability. The aim of the study was to assess the relationship between angiogenic factors, their soluble receptors and ALI/ARDS associated with critically ill patients, including sepsis, severe trauma, and post-cardiac arrest syndrome (PCAS). METHODS: One hundred fifty-nine critically ill patients, including 50 patients with sepsis, 57 patients with severe trauma and 52 resuscitated after out-of-hospital cardiac arrest, were divided into three subgroups: including 25 ALI patients, 101 ARDS patients and 22 non-ALI/ARDS patients. The serum levels of angiogenic factors were measured at the time of admission (day 1), as well as day 3 and day 5 and then were compared among the ALI, ARDS and non-ALI/ARDS groups. Their predictive values for developing ALI/ARDS and 28-day mortality were evaluated. RESULTS: Higher levels of sVEGFR1 and Ang2 were observed in the ALI and ARDS patients than in the non-ALI/ARDS patients during the entire study period. The Ang2/Ang1 ratio in the ARDS group was also significantly higher than that in the non-ALI/ADRS group. The sVEGFR2 levels in the ARDS group on day 1 were significantly lower than those of the non-ALI/ADRS group. In addition, significant positive correlations were seen between the sVEGFR1, Ang2, Ang2/Ang1, and the development of ALI/ARDS in critical illness. There were also significant negative correlations between the minimal value of sVEGFR2, the maximal value of Ang1 and the ALI/ARDS group. In particular, sVEGFR2 and Ang2 were independent predictors of developing ALI/ARDS. Moreover, Ang2 and sVEGFR2 also independently predicted the mortality in ALI/ARDS patients. CONCLUSIONS: Angiogenic factors and their soluble receptors, particularly sVEGFR2 and Ang2, are thus considered to be valuable predictive biomarkers in the development of ALI/ARDS associated with critical illness and mortality in ALI/ARDS patients.

Effectiveness of end-expiratory lung volume measurements during the lung recruitment maneuver for patients with atelectasis.

PURPOSE: The aim of this study was to determine whether the relative change in the end-expiratory lung volume (EELV) obtained by the recruitment maneuver (RM) can serve as an indicator of the change in the P/F ratio. MATERIALS AND METHODS: The effects of the intermittent stepwise increases in the RM (peak inspiratory pressure, 45, 50, and 55 cm H2O) were compared in 21 patients with atelectasis under mechanical ventilation. The EELV, the ratio of arterial oxygen concentration to the fraction of inspired oxygen P/F ratio, and relative change rate (Δ) in these parameters were evaluated after each RM. RESULTS: A greater improvement in the EELV (1157 ± 344 mL vs 1469 ± 396 mL) and P/F ratio (250 ± 99 vs 320 ± 92) was observed after the RM. The ΔEELV was correlated with the ΔP/F ratio (ρ = 0.73, P < .01) and was identified as an accurate predictor of the improvement of the ΔP/F ratio by the receiver operating characteristic curve (the area under the curve, 0.93; P < .01). CONCLUSIONS: These results suggest that the ΔEELV obtained by intermittent stepwise RM can serve as an indicator of the change in the P/F ratio.

Angiogenic factors and their soluble receptors predict organ dysfunction and mortality in post-cardiac arrest syndrome.

INTRODUCTION: Post-cardiac arrest syndrome (PCAS) often leads to multiple organ dysfunction syndrome (MODS) with a poor prognosis. Endothelial and leukocyte activation after whole-body ischemia/reperfusion following resuscitation from cardiac arrest is a critical step in endothelial injury and related organ damage. Angiogenic factors, including vascular endothelial growth factor (VEGF) and angiopoietin (Ang), and their receptors play crucial roles in endothelial growth, survival signals, pathological angiogenesis and microvascular permeability. The aim of this study was to confirm the efficacy of angiogenic factors and their soluble receptors in predicting organ dysfunction and mortality in patients with PCAS. METHODS: A total of 52 resuscitated patients were divided into two subgroups: 23 survivors and 29 non-survivors. The serum levels of VEGF, soluble VEGF receptor (sVEGFR)1, sVEGFR2, Ang1, Ang2 and soluble Tie2 (sTie2) were measured at the time of admission (Day 1) and on Day 3 and Day 5. The ratio of Ang2 to Ang1 (Ang2/Ang1) was also calculated. This study compared the levels of angiogenic factors and their soluble receptors between survivors and non-survivors, and evaluated the predictive value of these factors for organ dysfunction and 28-day mortality. RESULTS: The non-survivors demonstrated more severe degrees of organ dysfunction and a higher prevalence of MODS. Non-survivors showed significant increases in the Ang2 levels and the Ang2/Ang1 ratios compared to survivors. A stepwise logistic regression analysis demonstrated that the Ang2 levels or the Ang2/Ang1 ratios on Day 1 independently predicted the 28-day mortality. The receiver operating characteristic curves of the Ang2 levels, and the Ang2/Ang1 ratios on Day 1 were good predictors of 28-day mortality. The Ang2 levels also independently predicted increases in the Sequential Organ Failure Assessment (SOFA) scores. CONCLUSIONS: We observed a marked imbalance between Ang1 and Ang2 in favor of Ang2 in PCAS patients, and the effect was more prominent in non-survivors. Angiogenic factors and their soluble receptors, particularly Ang2 and Ang2/Ang1, are considered to be valuable predictive biomarkers in the development of organ dysfunction and poor outcomes in PCAS patients.

The response of antithrombin III activity after supplementation decreases in proportion to the severity of sepsis and liver dysfunction.

The decrease in the antithrombin III activity is thought to result from consumption by ongoing coagulation, degradation by neutrophil elastase, capillary leak syndrome, and impaired synthesis. A retrospective data analysis of patients with sepsis was conducted to investigate the response of antithrombin III activity after supplementation in patients with sepsis, and to determine what factors affect the response of antithrombin III activity. The study included 42 patients with sepsis, 75 patients with severe sepsis, and 65 patients with septic shock, who were administered antithrombin III. Antithrombin III activity, platelet counts, coagulation, and fibrinolytic markers were collected before administration and 24 h after the supplementation. In the patients with septic shock, the response of antithrombin III activity after supplementation was 0.37% +/- 1.21%/IU per kg body weight, which was significantly lower in comparison with those in the patients with sepsis (1.81 +/- 1.75; P < 0.001) or severe sepsis (1.36 +/- 1.65; P < 0.001). The patients with liver dysfunction had significantly lower response to antithrombin III activity than that of the patients without liver dysfunction (P < 0.0001). A stepwise multiple linear regression analysis revealed that the severity of sepsis and liver function were independent predictors for the response to antithrombin III activity. These results suggest that the response to antithrombin III supplementation may be affected by both a systemic inflammation and impaired synthesis in patients with sepsis.

Insufficient production of urinary trypsin inhibitor for neutrophil elastase release after cardiac arrest.

To investigate the relationship between the inflammatory responses and postresuscitation syndrome, we prospectively examined the serial changes of neutrophil elastase (NE), urinary trypsin inhibitor (UTI), and TNF-alpha) in successfully resuscitated patients after out-of-hospital cardiac arrest. This study included 36 patients with out-of-hospital cardiac arrests who were admitted to our intensive care unit after return of spontaneous circulation (ROSC). The 11 patients who restored to spontaneous circulation within 30 min after cardiac arrest were defined as the short cardiac arrest group. The 25 patients who restored to spontaneous circulation more than 30 min after cardiac arrest were defined as the long cardiac arrest group. Eight healthy volunteers served as control group. Daily plasma levels of NE, UTI, and TNF-alpha were measured from days 1 to 5 after ROSC. The releases of NE from activated neutrophil just after ROSC in the patients with long cardiac arrest were statistically higher than those of the short cardiac arrest group. There was a significant correlation between the NE levels and the duration of cardiac arrest. A high but insufficient production of UTI for NE release was observed on day 1, especially in the patients with a long duration of cardiac arrest. The cerebral performance category of the short cardiac arrest group was better than that of the long cardiac arrest group. Although high levels of TNF-alpha were sustained in the postresuscitation period, the levels of TNF-alpha were unrelated to the duration of cardiac arrest. In conclusion, a massive release of NE in proportion to the duration of cardiac arrest and an insufficient production of UTI for the NE release may contribute to the pathogenesis of postresuscitation syndrome after out-of-hospital cardiac arrest.