Comparison of Nutrition Indices for Prognostic Utility in Patients with Sepsis: A Real-World Observational Study.

BACKGROUND: Nutritional status of critically ill patients is an important factor affecting complications and mortality. This study aimed to investigate the impact of three nutritional indices, the Geriatric Nutritional Risk Index (GNRI), Prognostic Nutritional Index (PNI), and Controlling Nutritional Status (CONUT), on mortality in patients with sepsis in Japan. METHODS: This retrospective observational study used the Medical Data Vision database containing data from 42 acute-care hospitals in Japan. We extracted data on baseline characteristics on admission. GNRI, PNI, and CONUT scores on admission were also calculated. To evaluate the significance of these three nutritional indices on mortality, we used logistic regression to fit restricted cubic spline models and constructed Kaplan-Meier survival curves. RESULTS: We identified 32,159 patients with sepsis according to the inclusion criteria. Of them, 1804 patients were treated in intensive care units, and 3461 patients were non-survivors. When the GNRI dropped below 100, the risk of mortality rose sharply, as did that when the PNI dropped below about 40. An increased CONUT score was associated with increased mortality in an apparent linear manner. CONCLUSION: In sepsis management, GNRI and PNI values may potentially be helpful in identifying patients with a high risk of death.

Ischemia prediction score (IsPS) in patients with strangulated small bowel obstruction: a retrospective cohort study.

BACKGROUNDS: Intestinal ischemia of strangulated small bowel obstruction (SSBO) requires prompt identification and early intervention. This study aimed to evaluate the risk factors and develop a prediction model of intestinal ischemia requiring bowel resection in SSBO. METHODS: This was a single-center, retrospective cohort study of consecutive patients underwent emergency surgery for SSBO from April 2007 to December 2021. Univariate analysis was performed to identify the risk factors for bowel resection in these patients. Two clinical scores (with contrasted computed tomography [CT] and without contrasted CT) were developed to predict intestinal ischemia. The scores were validated in an independent cohort. RESULTS: A total of 127 patients were included, 100 in the development cohort (DC) and 27 in the validation cohort (VC). Univariate analysis showed that high white blood cell count (WBC), low base excess (BE), ascites and reduced bowel enhancement were significantly associated with bowel resection. The ischemia prediction score (IsPS) comprised 1 point each for WBC ≥ 10,000/L, BE ≤ -1.0 mmol/L, ascites, and 2 points for reduced bowel enhancement. The simple IsPS (s-IsPS, without contrasted CT) of 2 or more had a sensitivity of 69.4%, specificity of 65.4%. The modified IsPS (m-IsPS, with contrasted CT) of 3 or more had a sensitivity of 86.7%, specificity of 76.0%. AUC of s-IsPS was 0.716 in DC and 0.812 in VC, and AUC of m-IsPS was 0.838 and 0.814. CONCLUSION: IsPS predicted possibility of ischemic intestinal resection with high accuracy and can help in the early identification of intestinal ischemia in SSBO.

[A Case of Long-Term Survival with Tumor Resection and DOX plus DTIC Therapy for Desmoid Tumor after FAP Surgery].

The patient is a 22-year-old, female. She had a family history of familial adenomatous polyposis(FAP)and a prophylactic total colorectal resection was performed for FAP at age of 18. She presented with fever and abdominal distention and palpated a mass with tenderness in the right lower abdomen. Contrast-enhanced CT scan of the abdomen showed a heterogeneous contrast effect around the tumor margins. With the diagnosis of intra-abdominal desmoid tumor, a partial duodenal resection, small bowel mass resection, and right fallopian tube resection were performed along with the tumor, and an artificial anus was created with the jejunum. Contrast-enhanced CT scan of the abdomen 16 months after resection of desmoid tumor showed a 6.5 cm long desmoid tumor recurrence in the mesentery. She received 5 courses of doxorubicin (DOX)plus dacarbazine(DTIC)therapy followed by continued NSAIDs. Seven years after the operation, she has been able to maintain the shrinkage of the recurrent tumor and is still on medication. Long-term surveillance is necessary because of the possibility of the appearance of other associated lesions in the future.

[A Case of Right Hemicolectomy for Inflammatory Myofibroblastic Tumor Arising in the Right Transverse Colon].

The patient was a 21-year-old male. He presented with right lower abdominal pain and showed tenderness in the same area. An abdominal contrast-enhanced CT examination revealed a 45 mm tumor that continuously stained in the right transverse colon. The patient presented with tenderness and rebound tenderness. Due to a suspected submucosal tumor, laparotomy was performed and an elastic hard tumor of 5 cm in size was found on the serous membrane side of the right transverse colon. As malignancy could not be ruled out, a right hemicolectomy with lymph node dissection was performed. The pathological diagnosis was an inflammatory myofibroblastic tumor(IMT), characterized by the proliferation of spindle- shaped spindle-shaped fibroblast-like cells with inflammatory cell infiltration. As of 9 years post-surgery, there has been no recurrence. However, long-term surveillance is necessary.

[A Case of Surgery for Skin Metastasis of Papillary Thyroid Carcinoma in a Very Elderly Patient to Improve the Quality of Life].

The patient was a 100-year-old woman who underwent right lobe thyroidectomy for papillary thyroid cancer in another hospital around 1990. She developed local recurrence in 2010 and underwent anterior tracheal local recurrence resection in May 2017. Subsequently, metastases were confirmed in the lateral cervical lymph nodes, but the patient only received TSH suppression because of her advanced age. Multiple pulmonary metastases developed in November 2020 and supraclavicular lymph node metastases in July 2021, but the patient was under the care of a visiting physician on best supportive care. The patient was referred to our hospital in January 2022 due to the appearance of a cutaneous mass in the sternal incision area, which gradually increased in size. A well-mobile, well-defined, spherical mass was found in the sternotomy area. The maximum diameter was 19 mm. The cytological findings were consistent with cutaneous metastasis of papillary thyroid carcinoma. As the patient was elderly and had multiple pulmonary metastases, she was temporarily observed. However, by June 2022, the mass had increased from 19 mm to 33 mm with cutaneous discoloration. There was no tendency for multiple pulmonary metastases to grow during this period. The decision was made to operate in order to prevent a decline in quality of life due to self-destruction of the cutaneous metastasis. The tumor was removed under general anesthesia, including the cutaneous discoloration, and reconstructed with a rhomboid skin flap. Post-operatively, there was no local recurrence or significant increase in pulmonary metastases. It is suggested that resection of cutaneous metastasis of malignant tumors may be effective in preserving quality of life even in a 100-year-old elderly patient like the present case and should be considered as an indication.

[Long-Term Survival of a Patient with Advanced Antral Gastric Cancer Successfully Treated with Multidisciplinary Therapy].

We report the case of long-term survival of a patient with advanced antral gastric cancer with multiple paraaortic lymph nodes metastasis who was successfully treated with multidisciplinary therapy. A 70-year-old female was admitted to our hospital complaining of vomiting. Upper gastrointestinal endoscopy revealed a Type 3 tumor in the gastric antrum. Computed tomography(CT)showed a marked decrease in the size of the primary gastric tumor and lymph nodes after 9 courses of mFOLFOX6 therapy. Subsequently, 7 courses of paclitaxel plus ramucirumab(PTX plus Rmab)therapy and 10 courses of nivolumab therapy were administered. After nivolumab therapy, marked shrinkage of the lymph nodes was observed on CT. Distal gastrectomy with D2(+ #16a2+b1)lymph node dissection was performed. The pathological finding was ypT0N1M0 with a Grade 3 effect of the chemotherapy. After 6 months of adjuvant chemotherapy with S-1, CT revealed supraclavicular lymph node metastases. After 4 courses of nivolumab therapy, CT showed a marked increase in the size of the lymph node. Consequently, the regimen was changed to irinotecan. After 16 courses of irinotecan therapy, CT showed a marked shrinkage in the size of the lymph node. The patient is currently alive with no signs of recurrence for 5 years, ie, since the initiation of the multidisciplinary therapy.

[An Experience of Multidisciplinary Treatment for Advanced Esophageal Cancer with Tumor Perforation during Preoperative Chemotherapy].

Perforation of esophageal cancer is one of the fatal oncologic emergencies, and a prompt and accurate treatment strategy is required. Here, we report a case of advanced esophageal cancer that had perforated during preoperative chemotherapy and was successfully resected with multidisciplinary treatment. The prognosis of perforated esophageal cancer can be expected to improve by multidisciplinary treatment appropriately combining initial treatment for infection control and subsequent cancer treatment.

Robotic complete mesocolic excision of right-sided colon cancer with bulky lymph node metastases using the da Vinci® Si™ system: A case report.

Reports on robotic surgery in the treatment of right-sided colorectal cancer most commonly use the da Vinci® Xi™ system; however, with the increasing popularity of robotic surgery for the treatment of colon cancer, it is likely to be performed using the da Vinci Si™ and X™ systems. The present study reported the case of a 63-year-old woman who underwent complete mesocolic excision (CME) with the da Vinci Si system involving a rotation technique for ascending colon cancer with bulky lymph node metastasis to the anterior pancreas. Robot-assisted right hemicolectomy was planned for this patient with T4aN2bM0, stage IIIc cancer. A lap protector and EZ access (Hakko Co. Ltd.) were fixed in the umbilical incision, and the da Vinci camera port was placed just off-center at the EZ access to allow the camera port to be repositioned by rotating it. The medial approach was used. The bulky metastatic lymph nodes at the head of the pancreas were dissected after ligating the right colic artery and vein. During CME, rotation of the EZ access was used to avoid interference between the robotic arms. The right colon was released from the retroperitoneum and resected. A functional end-to-end anastomosis was created, and right colectomy was successfully completed. The total operation time was 271 min and the console time with the da Vinci Si system was 140 min. The patient was discharged on postoperative day 8 without complications. In conclusion, robotic right colectomy was successfully performed and rotation of the EZ access facilitated robotic surgery using the da Vinci Si system.

Non-linear and Interaction Analyses of Biomarkers for Organ Dysfunctions as Predictive Markers for Sepsis: A Nationwide Retrospective Study.

The Sequential Organ Failure Assessment (SOFA) score is predominantly used to assess the severity of organ dysfunction in sepsis. However, differences in prognostic value between SOFA subscores have not been sufficiently evaluated. This retrospective observational study used a large-scale database containing about 30 million patients. Among them, we included 38,869 adult patients with sepsis from 2006 to 2019. The cardiovascular and neurological subscores were calculated by a modified method. Associations between the biomarkers of the SOFA components and mortality were examined using restricted cubic spline analyses, which showed that an increase in the total modified SOFA score was linearly associated with increased mortality. However, the prognostic association of subscores varied widely: platelet count showed a J-shaped association, creatinine showed an inverted J-shaped association, and bilirubin showed only a weak association. We also evaluated interaction effects on mortality between an increase of one subscore and another. The joint odds ratios on mortality of two modified SOFA subscores were synergistically increased compared to the sum of the single odds ratios, especially in cardiovascular-neurological, coagulation-hepatic, and renal-hepatic combinations. In conclusion, total modified SOFA score was associated with increased mortality despite the varied prognostic associations of the subscores, possibly because interactions between subscores synergistically enhanced prognostic accuracy.

[A Case of Malignant Rectal B Cell Lymphoma That Was Difficult to Differentiate from Rectal Neuroendocrine Tumor].

A 74-year-old woman with a chief complaint of hematochezia was admitted to our hospital. Colonoscopy revealed a 2 cm submucosal tumor with an erosion in the Rb of the rectum. Biopsy showed various inflammatory cell clusters, but no malignant findings. Thoracoabdominal CT and abdominal MRI showed no abnormal findings other than that of rectal wall thickening. Somatostatin receptor scintigraphy performed on suspected rectal NET showed no abnormal accumulation. A total of 3 biopsies were performed, but a definitive diagnosis was not confirmed, and transanal rectal mucosal resection was performed for diagnostic purposes. Immunohistochemistry showed CD20(+)and bcl-2(+), and the lesion was diagnosed as malignant rectal B cell lymphoma. For 1 year postoperatively, the patient showed no recurrence. For this case, biopsy often failed to confirm a definitive diagnosis on rectal submucosal tumors. If the tumor is >1 cm in diameter in a rectal NET, a rectal resection with lymph node dissection is required, and anal function may be impaired. Local tumor excision for diagnosis and treatment may be worthwhile in rectal submucosal tumors if pre-resection diagnosis with biopsy is difficult.

[A Case of Nivolumab Responding to Multiple Lymph Node Metastases during Multidisciplinary Treatment for Esophageal Cancer].

In nivolumab therapy for unresectable advanced esophageal cancer, there are a few cases that show a complete response, and long-term survival can be expected in such cases. Here, we report a case in which nivolumab had a complete response to multiple lymph node metastases during multidisciplinary treatment for esophageal cancer and survived for a relatively long period despite being elderly. Examination of complete response cases provides us with significant insights in considering the unexplained biomarkers of immune checkpoint inhibitors and treatment discontinuation during complete response.

Effect of tranexamic acid on thrombotic events and seizures in bleeding patients: a systematic review and meta-analysis.

BACKGROUND: Tranexamic acid (TXA) reduces surgical bleeding and reduces death from bleeding after trauma and childbirth. However, its effects on thrombotic events and seizures are less clear. We conducted a systematic review and meta-analysis to examine the safety of TXA in bleeding patients. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled trials from inception until June 1, 2020. We included randomized trials comparing intravenous tranexamic acid and placebo or no intervention in bleeding patients. The primary outcomes were thrombotic events, venous thromboembolism, acute coronary syndrome, stroke and seizures. A meta-analysis was performed using a random effects model and meta-regression analysis was performed to evaluate how effects vary by dose. We assessed the certainty of evidence using the grading of recommendations, assessment, development and evaluations (GRADE) approach. RESULTS: A total of 234 studies with 102,681 patients were included in the meta-analysis. In bleeding patients, there was no evidence that TXA increased the risk of thrombotic events (RR = 1.00 [95% CI 0.93-1.08]), seizures (1.18 [0.91-1.53]), venous thromboembolism (1.04 [0.92-1.17]), acute coronary syndrome (0.88 [0.78-1.00]) or stroke (1.12 [0.98-1.27]). In a dose-by-dose sensitivity analysis, seizures were increased in patients receiving more than 2 g/day of TXA (3.05 [1.01-9.20]). Meta-regression showed an increased risk of seizures with increased dose of TXA (p = 0.011). CONCLUSION: Tranexamic acid did not appear to increase the risk of thrombotic events in bleeding patients. However, because there may be dose-dependent increase in the risk of seizures, very high doses should be avoided.

Effect of Earlier Door-to-CT and Door-to-Bleeding Control in Severe Blunt Trauma: A Retrospective Cohort Study.

Blunt trauma is a potentially life-threatening injury that requires prompt diagnostic examination and therapeutic intervention. Nevertheless, how impactful a rapid response time is on mortality or functional outcomes has not been well-investigated. This study aimed to evaluate effects of earlier door-to-computed tomography time (D2CT) and door-to-bleeding control time (D2BC) on clinical outcomes in severe blunt trauma. This was a single-center, retrospective cohort study of patients with severe blunt trauma (Injury Severity Score > 16). To assess the effect of earlier D2CT and D2BC on clinical outcomes, we conducted multivariable regression analyses with a consideration for nonlinear associations. Among 671 patients with severe blunt trauma who underwent CT scanning, 163 patients received an emergency bleeding control procedure. The median D2CT and D2BC were 19 min and 57 min, respectively. In a Cox proportional hazard regression model, earlier D2CT was not associated with improved 28-day mortality (p = 0.30), but it was significantly associated with decreased mortality from exsanguination (p = 0.003). Earlier D2BC was significantly associated with improved 28-day mortality (p = 0.026). In conclusion, earlier time to a hemostatic procedure was independently associated with decreased mortality. Meanwhile, time benefits of earlier CT examination were not observed for overall survival but were observed for decreased mortality from exsanguination.

Optimal target blood pressure in critically ill adult patients with vasodilatory shock: a protocol for a systematic review and meta-analysis.

INTRODUCTION: The optimal target of mean arterial pressure (MAP) for better outcomes in patients with vasodilatory shock remains a matter of debate. Although catecholamines are generally used to maintain target blood pressure in hypotensive patients with vasodilatory shock, the adverse effects of catecholamines must also be considered. We will perform a systematic review and meta-analysis of randomised controlled trials (RCTs) to assess the certainty of evidence determining the optimal target of MAP control for patients with vasodilatory shock in critically ill settings. METHODS AND ANALYSIS: This study protocol was registered in the University Hospital Medical Information Network Clinical Trials Registry. We will include only RCTs that evaluated the two different comparators for target MAP to be maintained for clinical outcomes of all-cause mortality: organ dysfunction and adverse events in critically ill adult patients with vasodilatory shock. We will search the electronic bibliographic databases of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials in November 2020. Two reviewers will independently screen titles and abstracts, perform full article reviews and extract study data. We will report study characteristics and assess methodological quality using the Cochrane Risk-of-Bias 2 tool. If pooling is appropriate, we will calculate relative risks with 95% CIs for all outcome measures. Clinical and methodological subgroup and sensitivity analyses will be performed to explore heterogeneity. Overall certainty of evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION: This study will not involve primary data collection, and formal ethics approval will therefore not be required. We aim to publish this systematic review in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000042624.

Comparative Analysis of Three Machine-Learning Techniques and Conventional Techniques for Predicting Sepsis-Induced Coagulopathy Progression.

Sepsis-induced coagulopathy has poor prognosis; however, there is no established tool for predicting it. We aimed to create predictive models for coagulopathy progression using machine-learning techniques to evaluate predictive accuracies of machine-learning and conventional techniques. A post-hoc subgroup analysis was conducted based on the Japan Septic Disseminated Intravascular Coagulation retrospective study. We used the International Society on Thrombosis and Haemostasis disseminated intravascular coagulation (DIC) score to calculate the ΔDIC score as ((DIC score on Day 3) - (DIC score on Day 1)). The primary outcome was to determine whether the predictive accuracy of ΔDIC was more than 0. The secondary outcome was the actual predictive accuracy of ΔDIC (predicted ΔDIC-real ΔDIC). We used the machine-learning methods, such as random forests (RF), support vector machines (SVM), and neural networks (NN); their predictive accuracies were compared with those of conventional methods. In total, 1017 patients were included. Regarding DIC progression, predictive accuracy of the multiple linear regression, RF, SVM, and NN models was 63.7%, 67.0%, 64.4%, and 59.8%, respectively. The difference between predicted ΔDIC and real ΔDIC was 2.05, 1.54, 2.24, and 1.77 for the multiple linear regression, RF, SVM, and NN models, respectively. RF had the highest predictive accuracy.

Safety of tranexamic acid in thrombotic adverse events and seizure in patients with haemorrhage: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine that inhibits fibrinolysis by blocking lysine-binding sites on plasminogen, which contribute to reduced bleeding, the need for transfusion and mortality. Although there is reliable evidence of the efficacy of TXA, its effects on other important outcomes, adverse events, including thrombotic events and seizure, remain uncertain. METHODS AND ANALYSIS: We will conduct a systematic review and meta-analysis of randomised controlled trials with the objective of evaluating the incidence of thrombotic adverse events and seizure and how the effect of TXA varies by dose and underlying disease. We will include patients with bleeding in any underlying disease. We will search MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials for randomised controlled trials. The planned date of our systematic search is 1 June 2020. We will follow the recommendations of the Cochrane Collaboration and the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. Subgroup and sensitivity analyses will be performed to explore residual heterogeneity and inconsistency. Meta-regression analysis will be carried out to investigate the association between the incidence of adverse events and the TXA dose. The risk of systematic errors (bias) and random errors will be assessed and the overall quality of evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION: This study will not involve primary data collection, and formal ethics approval will therefore not be required. We aim to publish this systematic review in a peer-review journal. TRIAL REGISTRATION NUMBER: UMIN000039611.

Clinical Significance of MicroRNAs in Patients with Sepsis: Protocol for a Systematic Review and Meta-Analysis.

Sepsis is a dysregulated immune response that leads to organ dysfunction and has high mortality rates despite recent therapeutic advancements. Accurate diagnosis and risk stratification are important for effective sepsis treatment; however, no decisive diagnostic or prognostic biomarkers are currently available. To understand whether microRNA (miRNA) might be useful biomarkers of sepsis, we aim to assess the diagnostic and prognostic accuracy of three miRNAs (122, 150, and 223) in sepsis patients via a meta-analysis of relevant published data. We will search electronic bibliographic databases (MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials) for pertinent retrospective and prospective studies in October 2019. Two reviewers will evaluate the collected titles, abstracts, and full articles, and extract the data. We will assess the included studies using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. If feasible, we will use bivariate random effects and hierarchical summary receiver operating characteristic (ROC) models to estimate summary ROCs, pooled sensitivity and specificity values, and the corresponding 95% confidence intervals. We will evaluate heterogeneity via clinical and methodological subgroup and sensitivity analyses. This systematic review will clarify the diagnostic and prognostic accuracy of select miRNAs in sepsis. It may also identify knowledge gaps in sepsis' diagnosis and prognosis.

A Systematic Summary of Systematic Reviews on Anticoagulant Therapy in Sepsis.

Many systematic reviews have been published regarding anticoagulant therapy in sepsis, among which there is substantial heterogeneity. This study aimed to provide an overview of existing systematic reviews of randomized controlled trials by using a comprehensive search method. We searched MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews. Of 895 records screened, 19 systematic reviews were included. The target agent was as follows: antithrombin (n = 4), recombinant thrombomodulin (n = 3), heparin (n = 3), recombinant activated protein C (n = 8), and all anticoagulants (n = 1). Antithrombin did not improve mortality in critically ill patients but indicated a beneficial effect in sepsis-induced disseminated intravascular coagulation (DIC), although the certainty of evidence was judged as low. Recombinant thrombomodulin was associated with a trend in reduced mortality in sepsis with coagulopathy with no increased risk of bleeding, although the difference was not statistically significant and the required information size for any declarative judgement insufficient. Although three systematic reviews showed potential survival benefits of unfractionated heparin and low-molecular-weight heparin in patients with sepsis, trials with low risk of bias were lacking, and the overall impact remains unclear. None of the meta-analyses of recombinant activated protein C showed beneficial effects in sepsis. In summary, a beneficial effect was not observed in overall sepsis in poorly characterized patient groups but was observed in sepsis-induced DIC or sepsis with coagulopathy in more specific patient groups. This umbrella review of anticoagulant therapy suggests that characteristics of the target populations resulted in heterogeneity among the systematic reviews.

Optimal Timing and Early Intervention With Anticoagulant Therapy for Sepsis-Induced Disseminated Intravascular Coagulation.

Optimizing diagnostic criteria to detect specific patients likely to benefit from anticoagulants is warranted. A cutoff of 5 points for the International Society on Thrombosis and Haemostasis overt disseminated intravascular coagulation (DIC) scoring system was determined in the original article, but its validity was not evaluated. This study aimed to explore the optimal cutoff points of DIC scoring systems and evaluate the effectiveness of early intervention with anticoagulants. We used a nationwide retrospective registry of consecutive adult patients with sepsis in Japan to develop simulated survival data, assuming anticoagulants were conducted strictly according to each cutoff point. Estimated treatment effects of anticoagulants for in-hospital mortality and risk of bleeding were calculated by logistic regression analysis with inverse probability of treatment weighting using propensity scoring. Of 2663 patients with sepsis, 1247 patients received anticoagulants and 1416 none. The simulation model showed no increase in estimated mortality between 0 and 3 cutoff points, whereas at ≥4 cutoff points, mortality increased linearly. The estimated bleeding tended to decrease in accordance with the increase in cutoff points. The optimal cutoff for determining anticoagulant therapy may be 3 points to minimize nonsurvival with acceptable bleeding complications. The findings of the present study suggested a beneficial association of early intervention with anticoagulant therapy and mortality in the patients with sepsis-induced DIC. Present cutoff points of DIC scoring systems may be suboptimal for determining the start of anticoagulant therapy and delay its initiation.

Recombinant Human Soluble Thrombomodulin in Sepsis-Induced Coagulopathy: An Updated Systematic Review and Meta-Analysis.

BACKGROUND: Clinical effectiveness of recombinant human soluble thrombomodulin (rhTM) in sepsis or sepsis-induced coagulopathy remains a matter of dispute. Recently, the Sepsis Coagulopathy Asahi Recombinant LE Thrombomodulin (SCARLET) trial, the latest multinational multi-centre phase III randomized controlled trial, was completed. OBJECTIVE: This article assesses the benefits and harms of rhTM therapy in sepsis-induced coagulopathy by updating our previous systematic review. METHODS: We performed a systematic review and meta-analysis of rhTM therapy for sepsis-induced coagulopathy in randomized controlled trials. All-cause 28-day mortality as efficacy and serious bleeding complications as the adverse effect were measured as primary outcomes. We assessed the certainty of a body of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: We analysed five trials enrolling 1,762 patients. Approximately 13% reduction in the risk of mortality was observed in the rhTM group, but the difference was not significant (relative risk, 0.87; 95% confidence interval, 0.74-1.03; p = 0.10; I 2 = 0%). Risk of serious bleeding complications did not increase with rhTM administration. We judged the certainty of evidence as moderate for mortality and low for serious bleeding. Trial sequential analysis indicated that only 42.0% of the required information size is actually available at this stage to reject or accept low risk-of-bias trials examining the anticipated effect for all-cause mortality. CONCLUSION: Even in this updated review including the latest SCARLET trial, we currently cannot make any declarative judgments about the beneficial effects of rhTM in sepsis-induced coagulopathy, although some favourable effects were suggested.