Early restricted oxygen therapy after resuscitation from cardiac arrest (ER-OXYTRAC): protocol for a stepped-wedge cluster randomised controlled trial.

INTRODUCTION: Cardiac arrest is a critical condition, and patients often experience postcardiac arrest syndrome (PCAS) even after the return of spontaneous circulation (ROSC). Administering a restricted amount of oxygen in the early phase after ROSC has been suggested as a potential therapy for PCAS; however, the optimal target for arterial partial pressure of oxygen or peripheral oxygen saturation (SpO2) to safely and effectively reduce oxygen remains unclear. Therefore, we aimed to validate the efficacy of restricted oxygen treatment with 94%-95% of the target SpO2 during the initial 12 hours after ROSC for patients with PCAS. METHODS AND ANALYSIS: ER-OXYTRAC (early restricted oxygen therapy after resuscitation from cardiac arrest) is a nationwide, multicentre, pragmatic, single-blind, stepped-wedge cluster randomised controlled trial targeting cases of non-traumatic cardiac arrest. This study includes adult patients with out-of-hospital or in-hospital cardiac arrest who achieved ROSC in 39 tertiary centres across Japan, with a target sample size of 1000. Patients whose circulation has returned before hospital arrival and those with cardiac arrest due to intracranial disease or intoxication are excluded. Study participants are assigned to either the restricted oxygen (titration of a fraction of inspired oxygen with 94%-95% of the target SpO2) or the control (98%-100% of the target SpO2) group based on cluster randomisation per institution. The trial intervention continues until 12 hours after ROSC. Other treatments for PCAS, including oxygen administration later than 12 hours, can be determined by the treating physicians. The primary outcome is favourable neurological function, defined as cerebral performance category 1-2 at 90 days after ROSC, to be compared using an intention-to-treat analysis. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board at Keio University School of Medicine (approval number: 20211106). Written informed consent will be obtained from all participants or their legal representatives. Results will be disseminated via publications and presentations. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry (UMIN000046914).

Optimal tentative abdominal closure for open abdomen: a multicenter retrospective observational study (OPTITAC study).

BACKGROUND: Primary fascia closure is often difficult following an open abdomen (OA). While negative-pressure wound therapy (NPWT) is recommended to enhance successful primary fascia closure, the optimal methods and degree of negative pressure remain unclear. This study aimed to elucidate optimal methods of NPWT as a tentative abdominal closure for OA to achieve primary abdominal fascia closure. MATERIALS AND METHODS: A multicenter, retrospective, cohort study of adults who survived OA greater than 48 h was conducted in 12 institutions between 2010 and 2022. The achievement of primary fascia closure and incidence of enteroatmospheric fistula were examined based on methods (homemade, superficial NPWT kit, or open-abdomen kit) or degrees of negative pressure (<50, 50-100, or >100 mmHg). A generalized estimating equation was used to adjust for age, BMI, comorbidities, etiology for laparotomy requiring OA, vital signs, transfusion, severity of critical illness, and institutional characteristics. RESULTS: Of the 279 included patients, 252 achieved primary fascia closure. A higher degree of negative pressure (>100 mmHg) was associated with fewer primary fascia closures than less than 50 mmHg [OR, 0.18 (95% CI: 0.50-0.69), P =0.012] and with more frequent enteroatmospheric fistula [OR, 13.83 (95% CI: 2.30-82.93)]. The methods of NPWT were not associated with successful primary fascia closure. However, the use of the open-abdomen kit was related to a lower incidence of enteroatmospheric fistula [OR, 0.02 (95% CI: 0.00-0.50)]. CONCLUSION: High negative pressure (>100 mmHg) should be avoided in NPWT during tentative abdominal closure for OA.

Risk prediction of biomarkers for early multiple organ dysfunction in critically ill patients.

BACKGROUND: Shock and organ damage occur in critically ill patients in the emergency department because of biological responses to invasion, and cytokines play an important role in their development. It is important to predict early multiple organ dysfunction (MOD) because it is useful in predicting patient outcomes and selecting treatment strategies. This study examined the accuracy of biomarkers, including interleukin (IL)-6, in predicting early MOD in critically ill patients compared with that of quick sequential organ failure assessment (qSOFA). METHODS: This was a multicenter observational sub-study. Five universities from 2016 to 2018. Data of adult patients with systemic inflammatory response syndrome who presented to the emergency department or were admitted to the intensive care unit were prospectively evaluated. qSOFA score and each biomarker (IL-6, IL-8, IL-10, tumor necrosis factor-α, C-reactive protein, and procalcitonin [PCT]) level were assessed on Days 0, 1, and 2. The primary outcome was set as MOD on Day 2, and the area under the curve (AUC) was analyzed to evaluate qSOFA scores and biomarker levels. RESULTS: Of 199 patients, 38 were excluded and 161 were included. Patients with MOD on Day 2 had significantly higher qSOFA, SOFA, and Acute Physiology and Chronic Health Evaluation II scores and a trend toward worse prognosis, including mortality. The AUC for qSOFA score (Day 0) that predicted MOD (Day 2) was 0.728 (95% confidence interval [CI]: 0.651-0.794). IL-6 (Day 1) showed the highest AUC among all biomarkers (0.790 [95% CI: 0.711-852]). The combination of qSOFA (Day 0) and IL-6 (Day 1) showed improved prediction accuracy (0.842 [95% CI: 0.771-0.893]). The combination model using qSOFA (Day 1) and IL-6 (Day 1) also showed a higher AUC (0.868 [95% CI: 0.799-0.915]). The combination model of IL-8 and PCT also showed a significant improvement in AUC. CONCLUSIONS: The addition of IL-6, IL-8 and PCT to qSOFA scores improved the accuracy of early MOD prediction.

Accuracy for Mortality Prediction With Additive Biomarkers Including Interleukin-6 in Critically Ill Patients: A Multicenter Prospective Observational Study.

OBJECTIVES: Several inflammation markers have been reported to be associated with unfavorable clinical outcomes in critically ill patients. We aimed to elucidate whether serum interleukin-6 concentration considered with Sequential Organ Failure Assessment score can better predict mortality in critically ill patients. DESIGN: A prospective observational study. SETTING: Five university hospitals in 2016-2018. PATIENTS: Critically ill adult patients who met greater than or equal to two systemic inflammatory response syndrome criteria at admission were included, and those who died or were discharged within 48 hours were excluded. INTERVENTIONS: Inflammatory biomarkers including interleukin (interleukin)-6, -8, and -10; tumor necrosis factor-α; C-reactive protein; and procalcitonin were blindly measured daily for 3 days. Area under the receiver operating characteristic curve for Sequential Organ Failure Assessment score at day 2 according to 28-day mortality was calculated as baseline. Combination models of Sequential Organ Failure Assessment score and additional biomarkers were developed using logistic regression, and area under the receiver operating characteristic curve calculated in each model was compared with the baseline. MEASUREMENTS AND MAIN RESULTS: Among 161 patients included in the study, 18 (11.2%) did not survive at day 28. Univariate analysis for each biomarker identified that the interleukin-6 (days 1-3), interleukin-8 (days 0-3), and interleukin-10 (days 1-3) were higher in nonsurvivors than in survivors. Analyses of 28-day mortality prediction by a single biomarker showed interleukin-6, -8, and -10 at days 1-3 had a significant discrimination power, and the interleukin-6 at day 3 had the highest area under the receiver operating characteristic curve (0.766 [0.656-0.876]). The baseline area under the receiver operating characteristic curve for Sequential Organ Failure Assessment score predicting 28-day mortality was 0.776 (0.672-0.880). The combination model using additional interleukin-6 at day 3 had higher area under the receiver operating characteristic curve than baseline (area under the receiver operating characteristic curve = 0.844, area under the receiver operating characteristic curve improvement = 0.068 [0.002-0.133]), whereas other biomarkers did not improve accuracy in predicting 28-day mortality. CONCLUSIONS: Accuracy for 28-day mortality prediction was improved by adding serum interleukin-6 concentration to Sequential Organ Failure Assessment score.

Blood Interleukin-6 Levels Predict Multiple Organ Dysfunction in Critically Ill Patients.

BACKGROUND: Predicting multiple organ dysfunction (MOD) in the late phase of critical illnesses is essential. Cytokines are considered biomarkers that can predict clinical outcomes; however, their predictive value for late-phase MOD is unknown. This study aimed to identify the biomarker with the highest predictive value for late-phase MOD. METHODS: This observational study prospectively evaluated data on adult patients with systemic inflammatory response syndrome, those who presented to the emergency department or were admitted to intensive care units in five tertiary hospitals (n = 174). Seven blood biomarkers levels (interleukin-6 [IL-6], IL-8, IL-10, tumor-necrosis factor-α, white blood cells, C-reactive protein, and procalcitonin) were measured at three timepoints (days 0, 1, and 2). The area under the receiver operating characteristic curve (AUC) was analyzed to evaluate predictive values for MOD (primary outcome, MOD on day 7 [late-phase]; secondary outcome, MOD on day 3 [early-phase]). RESULTS: Of the measured 7 biomarkers, blood IL-6 levels on day 2 had the highest predictive value for MOD on day 7 using single timepoint data (AUC 0.825, 95% confidence interval [CI] 0.754-0.879). Using three timepoint biomarkers, blood IL-6 levels had the highest predictive value of MOD on day 7 (AUC 0.838, 95% CI 0.768-0.890). Blood IL-6 levels using three timepoint biomarkers had also the highest predictive value for MOD on day 3 (AUC 0.836, 95% CI 0.766-0.888). CONCLUSION: Of the measured biomarkers, blood IL-6 levels had the highest predictive value for MOD on days 3 and 7. Blood IL-6 levels predict early- and late-phase MOD in critically ill patients.

Modified abbreviated burn severity index as a predictor of in-hospital mortality in patients with inhalation injury: development and validation using independent cohorts.

PURPOSE: The ability to accurately evaluate the severity of inhalation injury can help to optimize patient care. However, there is no accepted severity grading system, especially for inhalation injury. METHODS: We screened a multicenter burn registry and included adult patients who required oxygen treatment or mechanical ventilation. After the patient data were divided into development and validation cohorts, missing values were replaced with multiple imputation. Twelve potential predictors were analyzed using multivariate logistic regression to identify prognostic variables for in-hospital mortality and scores were assigned to each predictor based on odds ratios to develop the Modified Abbreviated Burn Severity Index, mABSI. The mABSI was validated using c-statistics and calibration curves. RESULTS: We randomly assigned 1377 and 919 patients to the development and validation cohorts, respectively. Age, self-inflicted injury, cutaneous burn area, and mechanical ventilation requirement were identified as independent predictors, and the mABSI (1-17 scale) was, thus, developed. The mABSI has a high discriminatory power (c-statistic = 0.94; 95% CI 0.92-0.97), and both estimated and observed in-hospital mortalities increased from 1% at score ≤ 5 to almost 100% at score ≥ 14 with linear calibration plots. CONCLUSIONS: We developed and validated the mABSI which accurately predicts in-hospital mortality.

Hydrogen gas inhalation alleviates oxidative stress in patients with post-cardiac arrest syndrome.

Oxidative stress plays a key role in the pathophysiology of post-cardiac arrest syndrome. Molecular hydrogen reduces oxidative stress and exerts anti-inflammatory effects in an animal model of cardiac arrest. However, its effect on human post-cardiac arrest syndrome is unclear. We consecutively enrolled five comatose post-cardiac arrest patients (three males; mean age, 65 ± 15 years; four cardiogenic, one septic cardiac arrest) and evaluated temporal changes in oxidative stress markers and cytokines with inhaled hydrogen. All patients were treated with target temperature management. Hydrogen gas inhalation (2% hydrogen with titrated oxygen) was initiated upon admission for 18 h. Blood hydrogen concentrations, plasma and urine oxidative stress markers (derivatives of reactive oxygen metabolites, biological antioxidant potential, 8-hydroxy-2'-deoxyguanosine, N ɛ-hexanoyl-lysine, lipid hydroperoxide), and cytokines (interleukin-6 and tumor necrosis factor-α) were measured before and 3, 9, 18, and 24 h after hydrogen gas inhalation. Arterial hydrogen concentration was measurable and it was equilibrated with inhaled hydrogen. Oxidative stress was reduced and cytokine levels were unchanged in cardiogenic patients, whereas oxidative stress was unchanged and cytokine levels were diminished in the septic patient. The effect of inhaled hydrogen on oxidative stress and cytokines in comatose post-cardiac arrest patients remains indefinite because of methodological weaknesses.

Self-inflicted Burn Injury Is Independently Associated With Increased Mortality in a More Economically Developed Country: A Propensity Score Matching Analysis.

Self-inflicted burn accounts for considerable morbidity and mortality in more economically developed countries, and there is a substantial debate regarding the pathophysiological relevance between self-inflicted burns and unfavorable outcomes. To validate whether self-inflicted injury is an independent predictor of high mortality regardless of the severity of burn, they conducted a retrospective observational study using the Japan Trauma Data Bank, a nationwide database including over 200 major tertiary care centers. Among 2006 patients with burn who had arrived at collaborating centers between 2004 and 2016, they included patients aged ≥15 years, those who did not present with cardiopulmonary arrest upon arrival, and those who had ≥10 percent total body surface area burns. Patients with missing survival data or unknown mechanism of injury were excluded. In total, 1094 patients were eligible, of whom 222 (20.3 percent) had self-inflicted burns. The patients were divided into the self-inflicted and non-self-inflicted groups, and propensity score was calculated using the demographic information of the patients, injury variables, time from injury to hospital arrival, and other survival predictors. Via a propensity score matching, 98 pairs were selected, and the self-inflicted group had a higher mortality than the non-self-inflicted group (43.9 vs 28.6 percent, hazard ratio = 1.77; 95% confidence interval = 1.10-2.86; P = .02). Inverse probability weighting and multivariate logistic regression were performed as sensitivity analyses, and results validated that self-inflicted burn was independently associated with increased in-hospital mortality. Therefore, patients with self-inflicted burns should receive judicious management, regardless of burn injury severity.

Effect of Retroperitoneal Pelvic Packing on Pelvic Cavity Pressure: A Cadaveric Study.

Limited clinical evidence demonstrates the effectiveness of direct retroperitoneal pelvic packing for hemorrhage control in pelvic fractures due to the difficulty in measuring pressure on the pelvic walls within the pelvic cavity after retroperitoneal pelvic packing. Using a cadaver model, the authors aimed to assess whether retroperitoneal pelvic packing generates pressure that exceeds the venous return and arterial pressure in the pelvis. The pressure on the pelvic wall was measured in 5 fresh Japanese cadavers. Sensors were placed at 4 points on the pelvic wall, and the pressure at each point was measured after the insertion of each of 3 sponges, per the procedure originally described for direct retroperitoneal pelvic packing. In each specimen, the average pressure across all 4 points on the pelvic wall increased with the addition of each sponge, reaching 12.3±4.5 mm Hg when all 3 sponges were inserted. Furthermore, the pressure at the pelvic floor and posterior pelvic brim increased significantly, whereas the pressure at the anterior and middle pelvic brim increased nonsignificantly. The results of this study suggest that retroperitoneal pelvic packing provides pressure on the pelvic wall that exceeds the venous pressure and is thus effective for the control of venous hemorrhage in pelvic fractures. Currently, the recommended procedure combines external fixation for venous bleeding, transcatheter arterial embolization, and pelvic packing; however, the authors' results suggest that pelvic packing alone may be effective for controlling venous hemorrhage in pelvic fracture. [Orthopedics. 2017; 40(6);e947-e951.].

Hyperfibrinolysis in severe isolated traumatic brain injury may occur without tissue hypoperfusion: a retrospective observational multicentre study.

BACKGROUND: Hyperfibrinolysis is a critical complication in severe trauma. Hyperfibrinolysis is traditionally diagnosed via elevated D-dimer or fibrin/fibrinogen degradation product levels, and recently, using thromboelastometry. Although hyperfibrinolysis is observed in patients with severe isolated traumatic brain injury (TBI) on arrival at the emergency department (ED), it is unclear which factors induce hyperfibrinolysis. The present study aimed to investigate the factors associated with hyperfibrinolysis in patients with isolated severe TBI. METHODS: We conducted a multicentre retrospective review of data for adult trauma patients with an injury severity score ≥ 16, and selected patients with isolated TBI (TBI group) and extra-cranial trauma (non-TBI group). The TBI group included patients with an abbreviated injury score (AIS) for the head ≥ 4 and an extra-cranial AIS < 2. The non-TBI group included patients with an extra-cranial AIS ≥ 3 and head AIS < 2. Hyperfibrinolysis was defined as a D-dimer level ≥ 38 mg/L on arrival at the ED. We evaluated the relationships between hyperfibrinolysis and injury severity/tissue injury/tissue perfusion in TBI patients by comparing them with non-TBI patients. RESULTS: We enrolled 111 patients in the TBI group and 126 in the non-TBI group. In both groups, patients with hyperfibrinolysis had more severe injuries and received transfusion more frequently than patients without hyperfibrinolysis. Tissue injury, evaluated on the basis of lactate dehydrogenase and creatine kinase levels, was associated with hyperfibrinolysis in both groups. Among patients with TBI, the mortality rate was higher in those with hyperfibrinolysis than in those without hyperfibrinolysis. Tissue hypoperfusion, evaluated on the basis of lactate level, was associated with hyperfibrinolysis in only the non-TBI group. Although the increase in lactate level was correlated with the deterioration of coagulofibrinolytic variables (prolonged prothrombin time and activated partial thromboplastin time, decreased fibrinogen levels, and increased D-dimer levels) in the non-TBI group, no such correlation was observed in the TBI group. CONCLUSIONS: Hyperfibrinolysis is associated with tissue injury and trauma severity in TBI and non-TBI patients. However, tissue hypoperfusion is associated with hyperfibrinolysis in non-TBI patients, but not in TBI patients. Tissue hypoperfusion may not be a prerequisite for the occurrence of hyperfibrinolysis in patients with isolated TBI.

Fibrinogen level on admission is a predictor for massive transfusion in patients with severe blunt trauma: Analyses of a retrospective multicentre observational study.

INTRODUCTION: In the early phase of trauma, fibrinogen (Fbg) plays an important role in clot formation. However, to the best of our knowledge, few studies have analysed methods of predicting the need for massive transfusion (MT) based on Fbg levels using multiple logistic regression. Therefore, the present study aimed to evaluate whether Fbg levels on admission can be used to predict the need for MT in patients with trauma. METHODS: We conducted a retrospective multicentre observational study. Patients with blunt trauma with ISS ≥16 who were admitted to 15 tertiary emergency and critical care centres in Japan participating in the J-OCTET were enrolled in the present study. MT was defined as the transfusion of packed red blood cells (PRBC) ≥10 units or death caused by bleeding within 24h after admission. Patients were divided into non-MT and MT groups. Multiple logistic-regression analysis was used to assess the predictive value of the variables age, sex, vital signs, Glasgow Coma Scale (GCS) score, and Fbg levels for MT. We also evaluated the discrimination threshold of MT prediction via receiver operating characteristic curve (ROC) analysis for each variable. RESULTS: Higher heart rate (HR; per 10 beats per minutes [bpm]), systolic blood pressure (SBP; per 10mm Hg), GCS, and Fbg levels (per 10mg/dL) were independent predictors of MT (odds ratio [OR] 1.480, 95% confidence interval [CI] 1.326-1.668; OR 0.851, 95% CI 0.789-0.914; OR 0.907, 95% CI 0.855-0.962; and OR 0.931, 95% CI 0.898-0.963, respectively). The optimal cut-off values for HR, SBP, GCS, and Fbg levels were ≥100 bpm (sensitivity 62.4%, specificity 79.8%), ≤120mm Hg (sensitivity 61.5%, specificity 70.5%), ≤12 points (sensitivity 63.3%, specificity 63.6%), and ≤190mg/dL (sensitivity 55.1%, specificity 78.6%), respectively. CONCLUSIONS: Our findings suggest that vital signs, GCS, and decreased Fbg levels can be regarded as predictors of MT. Therefore, future studies should consider Fbg levels when devising models for the prediction of MT.

Feasibility and Safety of Hydrogen Gas Inhalation for Post-Cardiac Arrest Syndrome　- First-in-Human Pilot Study.

BACKGROUND: Hydrogen gas inhalation (HI) ameliorates cerebral and cardiac dysfunction in animal models of post-cardiac arrest syndrome (PCAS). HI for human patients with PCAS has never been studied. METHODS AND RESULTS: Between January 2014 and January 2015, 21 of 107 patients with out-of-hospital cardiac arrest achieved spontaneous return of circulation. After excluding 16 patients with specific criteria, 5 patients underwent HI together with target temperature management (TTM). No undesirable effects attributable to HI were observed and 4 patients survived 90 days with a favorable neurological outcome. CONCLUSIONS: HI in combination with TTM is a feasible therapy for patients with PCAS. (Circ J 2016; 80: 1870-1873).

Development of Novel Criteria of the "Lethal Triad" as an Indicator of Decision Making in Current Trauma Care: A Retrospective Multicenter Observational Study in Japan.

OBJECTIVES: To evaluate the utility of the conventional lethal triad in current trauma care practice and to develop novel criteria as indicators of treatment strategy. DESIGN: Retrospective observational study. SETTINGS: Fifteen acute critical care medical centers in Japan. PATIENTS: In total, 796 consecutive trauma patients who were admitted to emergency departments with an injury severity score of greater than or equal to 16 from January 2012 to December 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All data were retrospectively collected, including laboratory data on arrival. Sensitivities to predict trauma death within 28 days of prothrombin time international normalized ratio greater than 1.50, pH less than 7.2, and body temperature less than 35°C were 15.7%, 17.5%, and 15.9%, respectively, and corresponding specificities of these were 96.4%, 96.6%, and 93.6%, respectively. The best predictors associated with hemostatic disorder and acidosis were fibrin/fibrinogen degradation product and base excess (the cutoff values were 88.8 µg/mL and -3.05 mmol/L). The optimal cutoff value of hypothermia was 36.0°C. The impact of the fibrin/fibrinogen degradation product and base excess abnormality on the outcome were approximately three- and two-folds compared with those of hypothermia. Using these variables, if the patient had a hemostatic disorder alone or a combined disorder with acidosis and hypothermia, the sensitivity and specificity were 80.7% and 66.8%. CONCLUSIONS: Because of the low sensitivity and high specificity, conventional criteria were unsuitable as prognostic indicators. Our revised criteria are assumed to be useful for predicting trauma death and have the potential to be the objective indicators for activating the damage control strategy in early trauma care.

HIGH D-DIMER LEVELS PREDICT A POOR OUTCOME IN PATIENTS WITH SEVERE TRAUMA, EVEN WITH HIGH FIBRINOGEN LEVELS ON ARRIVAL: A MULTICENTER RETROSPECTIVE STUDY.

Elevated D-dimer level in trauma patients is associated with tissue damage severity and is an indicator of hyperfibrinolysis during the early phase of trauma. To investigate the interacting effects of fibrinogen and D-dimer levels on arrival at the emergency department for massive transfusion and mortality in severe trauma patients in a multicenter retrospective study. This study included 519 adult trauma patients with an injury severity score ≥16. Patients with ≥10 units of red cell concentrate transfusion and/or death during the first 24 h were classified as having a poor outcome. Receiver operating characteristic curve analysis for predicting poor outcome showed the optimal cut-off fibrinogen and D-dimer values to be 190 mg/dL and 38 mg/L, respectively. On the basis of these values, patients were divided into four groups: low D-dimer (<38 mg/L)/high fibrinogen (>190 mg/dL), low D-dimer (<38 mg/L)/low fibrinogen (≤190 mg/dL), high D-dimer (≥38 mg/L)/high fibrinogen (>190 mg/dL), and high D-dimer (≥38 mg/L)/low fibrinogen (≤190 mg/dL). The survival rate was lower in the high D-dimer/low fibrinogen group than in the other groups. Moreover, the survival rate was lower in the high D-dimer/high fibrinogen group than in the low D-dimer/high fibrinogen and low D-dimer/low fibrinogen groups. High D-dimer level on arrival is a strong predictor of early death or requirement for massive transfusion in severe trauma patients, even with high fibrinogen levels.