Proposal and Validation of a Clinically Relevant Modification of the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation Diagnostic Criteria for Sepsis.

BACKGROUND: Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) criteria were launched nearly 20 years ago. Following the revised conceptual definition of sepsis and subsequent omission of systemic inflammatory response syndrome (SIRS) score from the latest sepsis diagnostic criteria, we omitted the SIRS score and proposed a modified version of JAAM DIC criteria, the JAAM-2 DIC criteria. OBJECTIVES: To validate and compare performance between new JAAM-2 DIC criteria and conventional JAAM DIC criteria for sepsis. METHODS: We used three datasets containing adult sepsis patients from a multicenter nationwide Japanese cohort study (J-septic DIC, FORECAST, and SPICE-ICU registries). JAAM-2 DIC criteria omitted the SIRS score and set the cutoff value at ≥3 points. Receiver operating characteristic (ROC) analyses were performed between the two DIC criteria to evaluate prognostic value. Associations between in-hospital mortality and anticoagulant therapy according to DIC status were analyzed using propensity score weighting to compare significance of the criteria in determining introduction of anticoagulants against sepsis. RESULTS: Final study cohorts of the datasets included 2,154, 1,065, and 608 sepsis patients, respectively. ROC analysis revealed that curves for both JAAM and JAAM-2 DIC criteria as predictors of in-hospital mortality were almost consistent. Survival curves for the anticoagulant and control groups in the propensity score-weighted prediction model diagnosed using the two criteria were also almost entirely consistent. CONCLUSION: JAAM-2 DIC criteria were equivalent to JAAM DIC criteria regarding prognostic and diagnostic values for initiating anticoagulation. The newly proposed JAAM-2 DIC criteria could be potentially alternative criteria for sepsis management.

A meta-analysis and trial sequential analysis of randomised controlled trials comparing nonoperative and operative management of chest trauma with multiple rib fractures.

BACKGROUND: Operative treatment of traumatic rib fractures for better outcomes remains under debate. Surgical stabilization of rib fractures has dramatically increased in the last decade. This study aimed to perform a systematic review and meta-analysis of randomised controlled trials (RCTs) to assess the effectiveness and safety of operative treatment compared to conservative treatment in adult patients with traumatic multiple rib fractures. METHODS: A systematic literature review was performed according to the preferred reporting items for systematic reviews and meta-analyses guidelines. We searched MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials and used the Cochrane Risk-of-Bias 2 tool to evaluate methodological quality. Relative risks with 95% confidence interval (CI) were calculated for outcomes: all-cause mortality, pneumonia incidence, and number of mechanical ventilation days. Overall certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, with trial sequential analysis performed to establish implications for further research. RESULTS: From 719 records, we included nine RCTs, which recruited 862 patients. Patients were assigned to the operative group (received surgical stabilization of chest wall injury, n = 423) or control group (n = 439). All-cause mortality was not significantly different (RR = 0.53; 95% CI 0.21 to 1.38, P = 0.35, I2 = 11%) between the two groups. However, in the operative group, duration of mechanical ventilation (mean difference -4.62; 95% CI -7.64 to -1.60, P < 0.00001, I2 = 94%) and length of intensive care unit stay (mean difference -3.05; 95% CI -5.87 to -0.22; P < 0.00001, I2 = 96%) were significantly shorter, and pneumonia incidence (RR = 0.57; 95% CI 0.35 to 0.92; P = 0.02, I2 = 57%) was significantly lower. Trial sequential analysis for mortality indicated insufficient sample size for a definitive judgment. GRADE showed this meta-analysis to have very low to low confidence. CONCLUSION: Meta-analysis of large-scale trials showed that surgical stabilization of multiple rib fractures shortened the duration of mechanical ventilation and reduced the incidence of pneumonia but lacked clear evidence for improvement of mortality compared to conservative treatment. Trial sequential analysis suggested the need for more cases, and GRADE highlighted low certainty, emphasizing the necessity for further targeted RCTs, especially in mechanically ventilated patients. SYSTEMATIC REVIEW REGISTRATION: UMIN Clinical Trials Registry UMIN000049365.

Blood Purification in Patients with Sepsis Associated with Acute Kidney Injury: A Narrative Review.

Sepsis leads to organ dysfunction. Acute kidney injury, a common type of organ dysfunction, is associated with a high mortality rate in patients with sepsis. Kidney replacement therapy can correct the metabolic, electrolyte, and fluid imbalances caused by acute kidney injury. While this therapy can improve outcomes, evidence of its beneficial effects is lacking. Herein, we review the indications for blood purification therapy, including kidney replacement therapy, and the current knowledge regarding acute kidney injury in terms of renal and non-renal indications. While renal indications have been well-documented, indications for blood purification therapy in sepsis (non-renal indications) remain controversial. Excessive inflammation is an important factor in the development of sepsis; blood purification therapy has been shown to reduce inflammatory mediators and improve hemodynamic instability. Given the pathophysiology of sepsis, blood purification therapy may decrease mortality rates in these patients. Further trials are needed in order to establish the effectiveness of blood purification therapy for sepsis.

Real-world evidence on disseminated intravascular coagulation from Japan.

Many descriptive epidemiological and comparative studies using big data have been reported recently from outside Japan. Within Japan, diagnosis procedure combination (DPC) data and medical receipt data are being stored in electronic media, and real-world evidence in various fields has started to be reported. We reviewed clinical studies on disseminated intravascular coagulation (DIC) using DPC data obtained from an insurance database with large numbers of cases and a related commercially available dataset including DPC and laboratory data. After DPC was introduced in 2003, 19 studies on DIC using Japanese national DPC data and two studies using the Medical Data Vision database were reported. Epidemiological findings in seven studies showed that the proportion of drugs administered for each underlying disease differed, with antithrombin and recombinant thrombomodulin (rTM) being used more frequently in clinical settings. In 14 comparative studies on anti-DIC agents, antithrombin for severe pneumonia, postoperative intestinal perforation, and severe burn, and rTM for acute cholangitis were associated with improved survival rates. Large-scale observational studies using big data can show results similar to those of randomized control trials if the quality of individual research is high. Real-world data analysis will be increasingly necessary to complement the evidence gap unfilled by randomized control trials.

Diagnostic Pitfalls in Papillary Muscle Rupture-Associated Acute Mitral Regurgitation after Acute Myocardial Infarction.

Papillary muscle rupture (PMR) is a rare and fatal complication of acute myocardial infarction (AMI). We report a case of acute mitral regurgitation (MR) due to PMR with pulmonary edema and cardiogenic shock following AMI with small myocardial necrosis. An 88-year-old woman was brought to our emergency department in acute respiratory distress, shock, and coma. She had no systolic murmur, and transthoracic echocardiography was inconclusive. Coronary angiography showed obstruction of the posterior descending branch of the right coronary artery. Although the infarction was small, the hemodynamics did not improve. Transesophageal echocardiography established papillary muscle rupture with severe mitral regurgitation 5 days after admission. Thereafter, the patient and her family did not consent to heart surgery, and she eventually died of progressive heart failure. Physicians should be aware of papillary muscle rupture with acute mitral regurgitation following AMI in patients with unstable hemodynamics, no systolic murmur, and no abnormalities revealed on transthoracic echocardiography.

Multisystem Inflammatory Syndrome in Children　- A New Syndrome Complicated With Acute Heart Failure Following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a rare syndrome temporally related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MIS-C shares similarities with Kawasaki disease, but left ventricular dysfunction is more common in MIS-C.Methods and Results:This study reports the case of a 16-year-old Japanese male patient with MIS-C. Although the initial presentation was severe with circulatory and respiratory failure, the patient recovered completely. Endomyocardial biopsy showed active myocarditis with fibrosis. Immunoglobulin treatment was useful for recovery. CONCLUSIONS: This is the first reported case of MIS-C in Japan. Cardiologists should be aware of MIS-C, a new disease, occurring during the global SARS-CoV-2 pandemic.

Acidemia subtypes in critically ill patients: An international cohort study.

PURPOSE: To study the prevalence, characteristic, outcome, and acid-base biomarker predictors of outcome for different acidemia subtypes. METHODS: We used national intensive care databases from three countries and classified acidemia subtypes as metabolic (standard base excess [SBE] < -2 mEq/L only), respiratory (PaCO2 > 42 mmHg only), and combined (both SBE < -2 mEq/L and PaCO2 > 42 mmHg) based on blood gas analysis in the first 24 h after ICU admission. To investigate acid-base predictors for hospital mortality, we applied the area under the receiver operating characteristic curve approach. RESULTS: We screened 643,689 ICU patients (2014-2018) and detected acidemia in 57.8%. The most common subtype was metabolic (42.9%), followed by combined (30.3%) and respiratory (25.9%). Combined acidemia had a mortality of 12.7%, compared with 11% for metabolic and 5.5% for respiratory. For combined acidemia, the best predictor of hospital mortality was pH. However, for metabolic or respiratory acidemia, it was SBE or PaCO2, respectively. CONCLUSIONS: In ICU patients with acidemia, mortality differs according to subtype and is highest in the combined subtype. Best acid-base predictors of mortality also differ according to subtype with best performance for pH in combined, SBE in metabolic, and PaCO2 in respiratory acidemia.

Early metabolic acidosis in critically ill patients: a binational multicentre study.

Objective: We aimed to measure the incidence, prevalence, characteristics and outcomes of intensive care unit (ICU) patients with early (first 24 hours) metabolic acidosis (MA) according to two different levels of severity with a focus on recent data. Design: We retrospectively applied two diagnostic criteria to our analysis based on literature for early MA: i) severe MA criteria (pH ≤ 7.20 and Paco2 ≤ 45 mmHg and HCO3- ≤ 20 mmol/L with total Sequential Organ Failure Assessment [SOFA] score ≥ 4 or lactate ≥ 2 mmol/L), and ii) moderate MA criteria (pH < 7.30 and base excess < -4 mmol/L and Paco2 ≤ 45 mmHg). Setting: ICUs in the Australian and New Zealand Intensive Care Society Adult Patient Database program. Participants: Adult patients registered to the database from 2008 to 2018. Main outcome measures: Incidence, prevalence, and hospital mortality of patients with MA by the two criteria. Results: We screened 1 076 087 patients. Given the Australian and New Zealand population during the study period, we estimated the incidence of severe MA at 39.5 per million per year versus 349.2-411.5 per million per year for moderate MA. In the most recent 2 years, we observed early severe MA in 1.5% (1350/87 110) of patients compared with 8.4% (20 679/244 740) for moderate MA. Overall, hospital mortality for patients with early severe MA was 48.3% (652/1350) compared with 21.5% (4444/20 679) for moderate MA. Conclusions: Early severe MA is uncommon in Australian and New Zealand ICUs and carries a very high mortality. Moderate MA is over seven-fold more common and still carries a high mortality.

Nafamostat Mesylate Improved Survival Outcomes of Sepsis Patients Who Underwent Blood Purification: A Nationwide Registry Study in Japan.

Nafamostat mesylate (NM) is a synthetic serine protease inhibitor that can be used as an anticoagulant during blood purification in critically ill patients, as well as a treatment for disseminated intravascular coagulation. Although NM has been reported to reduce the risk of bleeding during blood purification, its effect on survival outcomes of patients who received blood purification treatments is unclear. We hypothesized that administration of NM during blood purification can reduce mortality in patients with sepsis. A post hoc analysis was conducted on a nationwide retrospective registry that included data from 3195 sepsis patients registered at 42 intensive care units throughout Japan. We evaluated the effect of NM on hospital mortality and bleeding complications using propensity score matching in 1216 sepsis patients who underwent blood purification in the intensive care unit (ICU). Two-hundred-and-sixty-eight pairs of propensity score-matched patients who received NM and conventional therapy were compared. Hospital and ICU mortality rates in the NM group were significantly lower than those in the conventional therapy group. However, rates of bleeding complications did not differ significantly between the two groups. These data suggest that administration of NM improved the survival outcomes of sepsis patients who underwent blood purification in the ICU.

Beneficial effect modification on survival outcome of sepsis between ART-123 and polymyxin B­immobilised haemoperfusion: a nationwide Japanese registry study.

BACKGROUND: Although recently published randomised controlled trials did not confirm significant positive effect of ART-123 or polymyxin B­immobilised haemoperfusion (PMX-HP) on survival outcome, previous studies using a dataset of 3195 patients with sepsis registered at 42 intensive care units throughout Japan revealed significantly reduced mortality following these treatments. A study has suggested the efficacy of combination therapy with ART-123 and PMX-HP; however, it did not evaluate the effect modification between them. We hypothesised that coadministration of ART-123 and PMX-HP has a significant positive effect modification on survival outcome. The purpose of this study was to evaluate the effect modification between ART-123 and PMX-HP treatment on the survival outcome of sepsis using post hoc analysis of the dataset of the Japan Septic Disseminated Intravascular Coagulation registry. RESULTS: Of the 3195 patients recorded in the registry, 2350 were analysed. The product term between ART-123 and PMX-HP was analysed by the Cox regression model to evaluate significance. The primary outcome of this study was hospital mortality. Although the administration of ART-123 was independently positively associated with survival outcome (adjusted hazard ratio [HR]: 0.834, 95% confidence interval [CI] 0.695-0.999; P = 0.049) in the model prior to the introduction of the product term, a significant effect modification on survival outcome was observed between the administration of ART-123 and PMX-HP treatment (adjusted HR: 0.667, 95% CI 0.462-0.961; P = 0.030). CONCLUSIONS: The main effect of the administration of ART-123 may be beneficial for survival outcome in patients with sepsis. In addition, a significant beneficial effect modification on survival outcome was observed between the administration of ART-123 and PMX-HP treatment.

A comprehensive protocol for ventilator weaning and extubation: a prospective observational study.

BACKGROUND: Ventilator weaning protocols have been shown to reduce the duration of mechanical ventilation (MV), intensive care unit length of stay, and resource use. However, weaning protocols have not significantly affected mortality or reintubation rates. The extubation process is a critical component of respiratory care in patients who receive MV. Post-extubation respiratory failure (PERF) is a common event associated with significant morbidity and mortality. We hypothesized that a comprehensive protocol for ventilator weaning and extubation would be effective for preventing PERF and reintubation and reducing mortality in critically ill patients. METHODS: A ventilator weaning and extubation protocol was developed. The protocol consisted of checklists across four evaluations: spontaneous breathing trial, extubation, prophylactic non-invasive positive pressure ventilation (NPPV), and evaluation after extubation. Observational data were collected after implementing the protocol in patients admitted to the Advanced Emergency and Critical Care Center of Shinshu University Hospital. Not only outcomes of patients but also influences of each component of the protocol on the clinical decision-making process were investigated. Further, a comparison between PERF and non-PERF patients was performed. RESULTS: A total of 464 consecutive patients received MV for more than 48 h, and 248 (77 women; mean age, 65 ± 17 years) were deemed eligible. The overall PERF and reintubation rates were 9.7% and 5.2%, respectively. Overall, 54.1% of patients with PERF received reintubation. Hospital stay and mortality were not significantly different between PERF and non-PERF patients (p = 0.16 and 0.057, respectively). As a result, the 28-day and hospital mortality were 1.2% and 6.9%, respectively. CONCLUSIONS: We found that the rates of PERF, reintubation, and hospital mortality were lower than those in previous reports even with nearly the same degree of severity at extubation. The comprehensive protocol for ventilator weaning and extubation may prevent PERF and reintubation and reduce mortality in critically ill patients.

Usefulness of Measuring Changes in SOFA Score for the Prediction of 28-Day Mortality in Patients With Sepsis-Associated Disseminated Intravascular Coagulation.

The primary end point for sepsis trial is 28-day mortality. However, additional methods for determining the efficacy may have benefits. The purpose of this study was to search a useful indicator of anticoagulant therapy in patients with sepsis with disseminated intravascular coagulation (DIC). Data from 323 patients with sepsis with coagulopathy treated with antithrombin supplementation were analyzed. The changes in the Sequential Organ Failure Assessment (Δ SOFA) score, the overt-DIC (Δ overt-DIC) score, and the Japanese Society for Acute Medicine DIC (Δ JAAM DIC) score from baseline to day 7 were retrospectively analyzed in relation to the 28-day mortality. Significant correlations were found between the 28-day mortality and Δ SOFA, Δ overt-DIC score, and Δ JAAM DIC score. The accuracy of the prediction was higher for Δ SOFA (80.5%) than for Δ overt-DIC (66.7%, P < .001). The areas under the curve for mortality calculated using a receiver operating characteristic curve analysis were 0.812 for Δ SOFA, 0.655 for Δ overt-DIC, and 0.693 for Δ JAAM DIC. The mortality rate was significantly lower among cases with an improved SOFA score compared to those without an improvement. The Δ SOFA had the strongest association with the 28-day mortality in patients with sepsis and DIC.

Early Changes in the Sequential Organ Failure Assessment Score Among Patients With Sepsis-Induced Disseminated Intravascular Coagulation.

It is unclear whether initial infection control or anticoagulant therapy exerts a greater effect on early changes in the Sequential Organ Failure Assessment (SOFA) score among patients with sepsis-induced disseminated intravascular coagulation (DIC). This retrospective propensity score cohort study aimed to evaluate whether adequacy of infection control or anticoagulation therapy had a greater effect on early changes in the SOFA scores among 52 patients with sepsis-induced DIC. Inadequate initial infection control was associated with a lower 28-day survival rate among patients with sepsis-induced DIC (odds ratio [OR]: 0.116, 95% confidence interval [CI]: 0.022-0.601; P = .010); however, the adequacy was not associated with an early improvement in the SOFA score. However, despite adjusting for inadequate initial infection control, administration of recombinant human soluble thrombomodulin was associated with an early improvement in the SOFA score (OR: 5.058, 95% CI: 1.047-24.450; P = .044). Therefore, early changes in the SOFA score within 48 hours after the DIC diagnosis were more strongly affected by the administration of recombinant human soluble thrombomodulin than the adequacy of initial infection control.

Impact of a negative D-dimer result on the initial assessment of acute aortic dissection.

BACKGROUND: D-dimer shows high sensitivity but low specificity for the diagnosis of acute aortic dissection (AAD). Previous reports indicated that negative D-dimer patients have shorter dissection length. However, whether patients with negative D-dimer results have a good prognosis is unknown. This study aimed to elucidate the clinical characteristics and implications of a negative D-dimer result on AAD diagnosis. METHODS: The study group comprised 126 patients (71 males, 55 females; mean age, 69 ±â€¯11 years) with AAD admitted to our hospital between April 2009 and March 2015. Blood samples on presentation were used for D-dimer measurement. Clinical characteristics and outcomes were assessed. RESULTS: Nine (7.1%) and 117 (92.9%) exhibited negative and positive D-dimer results, respectively. The negative group showed a significantly lower extension score and a higher platelet count than the positive group. Multivariate analysis demonstrated that platelet count (odds ratio, 1.31 (1.09-1.58), p = 0.003) and extension score (odds ratio, 0.56 (0.33-0.96), p = 0.03) were significantly related to a negative result. Notably, 44% of patients in the negative group had type A dissection and 33% underwent an emergency operation due to cardiac tamponade. CONCLUSION: We found that high platelet count and low extension score were independent factors related to a negative D-dimer result. Even if the length of the dissection is short, an emergency operation is necessary in some patients with a negative D-dimer result. Physicians should recognize that a negative D-dimer result alone cannot exclude patients with fatal AAD conditions.

Importance of respiratory rate for the prediction of clinical deterioration after emergency department discharge: a single-center, case-control study.

Aim: The purpose of the present study was to investigate the predictors of clinical deterioration soon after emergency department (ED) discharge. Methods: We undertook a case-control study using the ED database of the Nagano Municipal Hospital (Nagano, Japan) from January 2012 to December 2013. We selected adult patients with medical conditions who revisited the ED with deterioration within 2 days of ED discharge (deterioration group). The deterioration group was compared with a control group. Results: During the study period, 15,724 adult medical patients were discharged from the ED. Of these, 170 patients revisited the ED because of clinical deterioration within 2 days. Among the initial vital signs, respiratory rate was less frequently recorded than other vital signs (P < 0.001 versus all other vital signs in each group). The frequency of recording each vital sign did not differ significantly between the groups. Overall, patients in the deterioration group had significantly higher respiratory rates than those in the control group (21 ± 5/min versus 18 ± 5/min, respectively; P = 0.002). A binary logistic regression analysis revealed that respiratory rate was an independent risk factor for clinical deterioration (unadjusted odds ratio, 1.15; 95% confidence interval, 1.04-1.26; adjusted odds ratio, 1.15; 95% confidence interval, 1.01-1.29). Conclusions: An increased respiratory rate is a predictor of early clinical deterioration after ED discharge. Vital signs, especially respiratory rate, should be carefully evaluated when making decisions about patient disposition in the ED.

Influence of body position during Heimlich maneuver to relieve supralaryngeal obstruction: a manikin study.

To study the most effective body position for Heimlich maneuver. Methods: A choking simulation manikin was connected to a laryngeal model of a child or an adult, and a differential pressure transducer recorded the airway pressure and waveform during the maneuver. A konjac jelly was placed on the larynx to mimic complete supralaryngeal obstruction. The maneuver (five successive compressions) was carried out six times each in standing, prone, and supine positions. For cases of children, we added a supine position with a pillow under the back. Results: In the adult model, airway obstruction was more frequently relieved in the supine and prone positions than in the standing position (P < 0.001). In the child model, airway obstruction was more frequently relieved in the supine position, with a pillow, and in the prone position, than in the standing position (P < 0.001). Without relief, successive Heimlich maneuvers made the airway pressure increasingly negative (adult, from -21.9 ± 6.5 cmH2O to -31.5 ± 9.1 cmH2O in the standing position [P < 0.001]; child, from -15.0 ± 9.5 cmH2O to -30.0 ± 9.2 cmH2O in the standing position [P < 0.001] and from -35.0 ± 17.4 cmH2O to -47.3 ± 25.1 cmH2O in the supine position without a pillow [P = 0.002]). Conclusions: The Heimlich maneuver was more effective in the supine and prone positions. In children, the prone position may be most effective. Successive Heimlich maneuvers may be harmful when the airway is not relieved after the first compression.

Diffuse Alveolar Hemorrhage Associated with Edoxaban Therapy.

Introduction. The main adverse effect of anticoagulant therapy is bleeding, and major bleeding, including intracranial, gastrointestinal, and retroperitoneal bleeding, has been reported as an adverse effect of edoxaban, a direct oral anticoagulant (DOAC). Bleeding during systemic anticoagulation with edoxaban presents a therapeutic conundrum, because there is currently no safe or efficacious reversal agent to stop major bleeding. Case Report. A 51-year-old woman had multiple traumatic injuries, including lower limb fractures. On day 8, she developed deep venous thrombosis, and edoxaban was administered orally. On day 38, she developed fungemia, which was treated with an antifungal drug. On day 43, she presented with dyspnea. Chest computed tomography scan showed bilateral diffuse ground-glass opacities in the whole lung fields. The results of the subsequent workup (i.e., serum levels of the antineutrophil cytoplasmic antibody, antinuclear antibody, and antiglomerular basement membrane antibody) and microbiological study were unremarkable. Based on these findings, her condition was diagnosed as diffuse alveolar hemorrhage (DAH) associated with edoxaban therapy. The lung opacities disappeared spontaneously after edoxaban therapy was discontinued. Conclusion. DAH is a dangerous complication associated with edoxaban therapy. DOACs, including edoxaban, should be prescribed with caution, especially for patients in a critical condition.

Crossed Cerebellar Diaschisis in Status Epilepticus.

Crossed cerebellar diaschisis (CCD) is an interesting phenomenon which classically refers to the depressed blood flow and metabolism affecting one cerebellar hemisphere after a contralateral hemispheric infarction. However, CCD can also be caused by a prolonged seizure. We herein report a case of CCD due to status epilepticus in a patient who showed unique magnetic resonance imaging findings.