原 嘉孝

OBJECTIVES: Damage associated molecular patterns (DAMPs) levels are associated with sepsis severity and prognosis. Histone and high mobility group box 1 (HMGB1) levels are also potential indicators of prognosis. We investigated the relationship between serum histone H3 and HMGB1 levels and the illness severity score and prognosis in postoperative patients. METHODS: Postoperative serum histone H3 and HMGB1 levels in 39 intensive care unit (ICU) patients treated at our institution were measured. The correlation between peak histone H3 and HMGB1 levels in each patient and clinical data (age, sex, surgical time, length of ICU stay, and survival after ICU discharge), which also included the patients' illness severity score, was examined. RESULTS: Histone H3 but not HMGB1 levels were positively correlated with surgical time, the Sequential Organ Failure Assessment score, the Japanese Association for Acute Medicine acute phase disseminated intravascular coagulation diagnosis score, and the length of ICU stay. Both histone H3 and HMGB1 levels were negatively correlated with age. However, survival post-ICU discharge was not correlated with histone H3 or HMGB1 levels. CONCLUSIONS: Histone H3 levels are correlated with severity scores and the length of ICU stay. Serum histone H3 and HMGB1 levels are elevated postoperatively. These DAMPs, however, are not prognostic indicators in postoperative ICU patients.

Blood purification is performed to control cytokines in critically ill patients. The relationship between the clearance (CL) and the membrane area during adsorption is not clear. We hypothesized that the CL increases with the hydrophobic area when hydrophobic binding contributes to cytokine adsorption. We investigated the relationship between the hemofilter membrane area and the CL of the high mobility group box 1 protein (HMGB-1) and interleukin-6 (IL-6). We performed experimental hemofiltration in vitro using polymethyl methacrylate membranes CH-1.8W (1.8 m2) and CH-1.0N (1.0 m2), as well as polysulfone membrane NV-18X (1.8 m2). After adding 100 mg of HMGB1 or 10 μg of IL-6 into the test solution, experimental hemofiltration was conducted for 360 min in a closed-loop circulation system, and the same amount of HMGB1 and IL-6 was added after 180 min. With CH-1.8W and CH-1.0N, both HMGB-1 and IL-6 showed a rapid concentration decrease of more than 70% at 180 min and 360 min after the re-addition. At 15 min, the CL of HMGB-1 was CH-1.8W: 28.4 and CH-1.0N: 19.8, and that of IL-6 was CH-1.8W: 41.1 and CH-1.0N: 25.4. CH-1.8W and CH-1.0N removed HMGB1 and IL-6 by adsorption and CH-1.8W was superior in CL, which increased with a greater membrane area.

Infection during extracorporeal membrane oxygenation (ECMO) is a common complication that leads to increased mortality. Thus, antimicrobial prophylaxis during ECMO is often performed to prevent of nosocomial infections. However, the current status of antimicrobial prophylaxis during ECMO in Japan is unclear. Therefore, we conducted a national survey of members of the Japanese Society of Intensive Care Medicine (JSICM) to clarify the current status of antimicrobial prophylaxis during ECMO in intensive care units. An 11-question survey was devised to assess antimicrobial prophylaxis and surveillance practices during ECMO. A total of 253 hospitals responded. Of these, 235 hospitals were the JSICM-certified hospitals, and the response rate was 64%. A total of 96 hospitals (39%) administered antimicrobial prophylaxis during ECMO, and 17% of hospitals had a standardized protocol for antimicrobial prophylaxis during ECMO. Of these 96 hospitals, 79% used single agents. First-generation cephalosporins were the most commonly used (54%), followed by penicillins or penicillin-derived combinations (24%), second-generation cephalosporins (7%), and anti-methicillin-resistant Staphylococcus aureus agents (6%). In conclusion, our survey revealed 39% of hospitals administered antimicrobial prophylaxis during ECMO in Japan. First-generation cephalosporins were the agents most commonly used.

Myoglobin, which can cause acute kidney injury, has a relatively high molecular weight and is poorly cleared by diffusion. We compared and examined myoglobin clearance by changing the blood purification membrane and modality in patients with a myoglobin blood concentration ≥ 1000 ng/ml. We retrospectively analyzed three patient groups based on the following three types of continuous hemofiltration (CHF): AN69ST membrane, polymethylmethacrylate (PMMA) membrane, and high-flow hemodiafiltration (HDF) with increased dialysate flow rate using the PMMA membrane. There was no significant difference in clearance in CHF between AN69ST and PMMA membranes. However, the high-flow HDF group showed the highest myoglobin clearance (p = 0.003). In the PMMA membrane, changing the treatment modality to high-flow HDF increased clearance above the theoretical value, possibly due to internal filtration. To remove myoglobin by kidney replacement therapy from patients with hypermyoglobinemia, a modality such as high-flow HDF would be desirable.

OBJECTIVES: Hyperchloremia is a potential risk factor for acute kidney injury (AKI) in critically ill patients. However, the relationship between hyperchloremia and postoperative AKI in adult patients undergoing cardiovascular surgery with cardiopulmonary bypass (CPB) remains unclear. The authors aimed to determine whether postoperative hyperchloremia was associated with postoperative AKI in these populations. OBJECTIVES: Retrospective, single-center study. SETTING: Tertiary care hospital. PARTICIPANTS: Adult patients who underwent cardiovascular surgery with CPB. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients with and without postoperative hyperchloremia were matched (1:1). The primary outcome was the rate of postoperative AKI diagnosed using the Kidney Disease: Improving Global Outcomes consensus criteria. Postoperative hyperchloremia was defined as postoperative serum chloride levels of >110 mmol/L during the first 48 hours. An increase in serum chloride levels (Δ[Cl-]) was defined as the difference between the preoperative and maximum postoperative serum chloride levels during the first 48 hours ([Cl-]max). Propensity-score matching and univariate and multivariate logistic regression analyses were employed. A total of 323 patients were included. Propensity-score matching selected 55 pairs for the final comparison. The incidence of postoperative AKI did not differ between the two groups (47% v 46%, p = 1.0). In the multivariate logistic regression analysis, Δ[Cl-] was associated independently with the development of postoperative AKI (odds ratio, 1.13; 95% confidence interval, 1.06-1.21; p < 0.001). CONCLUSIONS: Exposure to postoperative hyperchloremia was not associated with postoperative AKI in adult patients undergoing cardiovascular surgery with CPB. However, an increase in the serum chloride level might be associated with postoperative AKI.

Spontaneous abdominal wall hematomas are relatively rare and mainly attributed to anticoagulation and severe cough. Despite the high incidence of anticoagulation-related bleeding complications, there are no reports of spontaneous abdominal wall hematomas during extracorporeal membrane oxygenation (ECMO). We report a case of a spontaneous rectus sheath hematoma caused by alternation of the lateral semi-prone position during ECMO in a 76-year-old female patient with severe acute respiratory distress syndrome. Unfractionated heparin 12,000-14,000 units/day was administered for anticoagulation during ECMO. From Day 6 of ECMO, the patient who was under deep sedation was alternately placed in the left and right lateral semi-prone positions every 4 h, for approximately 20 h per day. On Day 12 of ECMO, the patient developed hypotension with anemia and a palpable mass in the right lower abdomen. Abdominal ultrasonographic imaging revealed a huge echo-free space centered in the right lower abdomen. Emergency contrast-enhanced computed tomography (CT) scanning showed extravasation from the superior and inferior epigastric arteries as well as a rectus sheath hematoma. Despite no apparent contrast leakage, an inferior epigastric artery embolization was undertaken because the patient was on ECMO. On Day 13 after ECMO initiation, ECMO and anticoagulation were discontinued. On CT scanning a week later, the hematoma had reduced. In conclusion, spontaneous abdominal wall hematoma is a rare and important complication that might occur during ECMO. Thus, careful physical examination should be routinely conducted when the patient is semi-prone during ECMO.

The Coronavirus disease 2019 (COVID-19) has spread worldwide since early 2020, and there are still no signs of resolution. The Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J-SSCG) 2020 Special Committee created the Japanese Rapid/Living recommendations on drug management for COVID-19 using the experience of creating the J-SSCGs. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence and strength of the recommendations. The first edition of this guideline was released on September 9, 2020, and this document is the revised edition (ver. 3.1) (released on March 30, 2021). Clinical questions (CQs) were set for the following seven drugs: favipiravir (CQ1), remdesivir (CQ-2), hydroxychloroquine (CQ-3), corticosteroids (CQ-4), tocilizumab (CQ-5), ciclesonide (CQ-6), and anticoagulants (CQ-7). Favipiravir is recommended for patients with mild COVID-19 not requiring supplemental oxygen (GRADE 2C); remdesivir for moderate COVID-19 patients requiring supplemental oxygen/hospitalization (GRADE 2B); hydroxychloroquine is not recommended for all COVID-19 patients (GRADE 1B); corticosteroids are recommended for moderate COVID-19 patients requiring supplemental oxygen/hospitalization (GRADE 1B) and severe COVID-19 patients requiring ventilator management/intensive care (GRADE 1A); however, their administration is not recommended for mild COVID-19 patients not requiring supplemental oxygen (GRADE 1B); tocilizumab is recommended for moderate COVID-19 patients requiring supplemental oxygen/hospitalization (GRADE 2B); and anticoagulant therapy for moderate COVID-19 patients requiring supplemental oxygen/hospitalization and severe COVID-19 patients requiring ventilator management/intensive care (GRADE 2C). We hope that these clinical practice guidelines will aid medical professionals involved in the care of COVID-19 patients.

ABO blood groups have been implicated as potential risk factors for various diseases. However, no study has investigated the association between sepsis mortality and ABO blood types. We aimed to evaluate the impact of these blood types on mortality in patients with sepsis and septic shock. This retrospective observational study was conducted at two general hospitals in Japan. Patients diagnosed with sepsis or septic shock were included and divided into four groups based on blood type (O, A, B, and AB). The association between type O vs. other types and 28- and 90-day mortalities was evaluated using multivariate logistic regression analysis adjusted for age, sex, and Sequential (Sepsis-related) Organ Failure Assessment score. This study included 415 patients, of whom 131 (31.6%), 171 (41.2%), 81 (19.5%), and 32 (7.7%) had type O, A, B, and AB, respectively. Blood type O was not associated with 28-day (odds ratio: 1.7 p = 0.08) or 90-day mortality (odds ratio: 1.53, p = 0.091). However, type O was significantly associated with higher 90-day mortality (odds ratio: 3.26, p = 0.009) in patients with septic shock. The role of ABO blood type in risk stratification for septic shock and the mechanisms that potentially affect the prognosis of sepsis patients need further investigation.

Patients who undergo renal replacement therapy often exhibit a high plasma linezolid concentration. Linezolid is metabolized via oxidation. Nafamostat mesilate has antioxidant effects and is frequently used as an anticoagulant during renal replacement therapy. We aimed to investigate the effect of nafamostat mesilate on plasma linezolid concentration. We examined whether the co-administration of linezolid and nafamostat had any effect on plasma linezolid concentration. Mice were randomly allocated to two groups (n = 18/group): linezolid (100 mg kg-1 , subcutaneous injection) + nafamostat (30 mg kg-1 , intraperitoneal injection) and linezolid + saline. At 5 hours, the linezolid concentration was significantly higher in the linezolid + nafamostat co-administration group than that in the linezolid + saline group (20.6 ± 9.8 vs 3.6 ± 1.2 μg/mL, respectively P < .001). The antioxidant effects of nafamostat may inhibit linezolid metabolism, resulting in the adverse event of high linezolid concentration if both are administered concurrently during renal replacement therapy.

We aimed to evaluate whether cardiac output assessed by transpulmonary thermodilution during blood purification is affected by the difference between the blood return temperature and core temperature. We applied different blood return temperatures using a thermostat bath during blood purification in four pigs. After the blood return temperature stabilized and blood purification process stopped, the cardiac output assessed by transpulmonary thermodilution was measured. The thermostat bath was set at 35°C, 40°C, 45°C, and 50°C, with the order changed at random; four measurements were made at each temperature. Cardiac function was evaluated by echocardiography when ice-cold saline was administered in a pig. A decrease in the blood return temperature resulted in decreased cardiac output assessed by transpulmonary thermodilution, whereas an increase resulted in increased cardiac output assessed by transpulmonary thermodilution. Echocardiography revealed that the change in the blood return temperature did not affect the left ventricular ejection fraction.

© 2018 Elsevier Ltd Introduction: The benefits and harm caused by anticoagulant treatments for sepsis induced disseminated intravascular coagulation (DIC) remain unclear. Therefore, we performed a network meta-analysis to assess the effect of available anticoagulant treatments on patient mortality, DIC resolution and the incidence of bleeding complication in patients with septic DIC. Materials and methods: We considered all studies from four recent systematic reviews and searched the PubMed, MEDLINE, and Cochrane databases for other studies that investigated anticoagulant treatment for septic DIC using antithrombin, thrombomodulin, heparin, or protease inhibitors in adult critically ill patients. These four anticoagulants and placebo were compared. The primary outcome in this study was patient mortality, and the secondary outcomes were the DIC resolution rate and incidence of bleeding complications. Results: The network meta-analysis included 1340 patients from nine studies. There were no significant differences in the risks of mortality and bleeding complications among all direct comparisons and the network meta-analysis. Using a placebo was associated with a significantly lower rate of DIC resolution, compared to antithrombin in the direct comparison (odds ratio [OR]: 0.20, 95% credible interval [95% CrI]: 0.046–0.81) and in the network meta-analysis (OR: 0.20, 95% CrI: 0.043–0.84). Conclusions: Our study revealed no significant differences in the risks for mortality and bleeding complications when a placebo and all four anticoagulants were compared in septic DIC patients. The results also indicated that antithrombin was associated with a five-fold higher likelihood of DIC resolution, compared to placebo.

【はじめに】AN69ST膜ヘモフィルターを用いた持続血液濾過(AN-CHF)では、しばしば静脈チャンバーで凝血することが報告されている。nafamostat mesilate(NM)の吸着の可能性があるとの私見もあるが、証明されていない。当ICUでは、フィルター前からのみNM投与を行っていたが、フィルター前後に分配して投与する方法を導入した。【方法】AN-CHFを施行した敗血症症例を抽出し、フィルター前のみ(A法:30mg/hr)と前後に分配した(AV法:前25mg/hr、後5mg/hr)投与法について後向きに比較・検討した。1本のフィルターで22時間以上CHFを行った場合を「目標達成」と定義した。【結果】ライフタイム(A法23.5時間 vs AV法23.2時間、p=0.60)、目標達成率(85.1% vs 78.9%、p=0.34)において有意差を認めなかった。目標達成に寄与する因子としてsequential organ failure assessmentスコア(オッズ比:0.997、p=0.0002)、AV法(オッズ比:0.216、p=0.011)があげられた。【結語】AN-CHFにおいてフィルター前25mg/hr、後5mg/hrにNM投与を分配する抗凝固療法は、有効でない可能性が示された。(著者抄録)

腸管出血性大腸菌（enterohemorrhagic Escherichia coli, EHEC）感染による溶血性尿毒症症候群（hemolytic uremic syndrome, HUS）に対する血漿交換療法（plasma exchange, PE）の有用性は不明である。一方，中枢神経症状発症時期と腎機能障害の関係を示した報告はほとんどない。今回，当院ICUに入室しPEを施行したEHEC感染によるHUSの小児2例，PEを施行しなかったEHECによるHUSの小児1例の経過について腎機能の推移を含め報告する。対象は当院ICUへ入室したEHECによるHUS患児3例。入室時に全例で無尿を認め，持続的血液透析濾過（continuous hemodiafiltration, CHDF）を開始。中枢神経系（central nervous system, CNS）障害を認めた2例に対し，消化器症状発症からそれぞれ9，10日目にPEを3日間施行。2例とも退室時にCNS障害を認めず，CHDF期間はそれぞれ9，13日間であった。CNS障害を認めなかったPE非施行例のCHDF期間は36日間であった。

Polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) therapy is widely used for the treatment of severe sepsis and septic shock, and is generally performed for 2 h. Although previous studies demonstrated the efficacy of PMX-DHP therapy, it currently remains unclear whether its optimal duration is 2 h. This retrospective study analyzed 37 patients with septic shock who showed a poor clinical response to 2 h of PMX-DHP, and underwent a longer duration of this therapy. The mean duration of PMX-DHP therapy was 15.8 +/- 7.9 h, and none of the patients developed adverse events, which enabled the therapy to be performed safely. The pressure catecholamine index [CAIP = catecholamine index/mean arterial pressure; catecholamine index = dopamine + dobutamine + (adrenaline + noradrenaline) x 100 mu g/kg per min], as an indicator of hemodynamics, improved significantly in the survival group in the period between the start and 24 h after the end of PMX-DHP therapy (P &lt; 0.01), and between 2 h after the start of and the end of this therapy (P &lt; 0.05). In addition, the P/F ratio improved significantly in the group of surviving patients with acute respiratory distress syndrome (ARDS) in the period between the start and 24 h after the end of PMX-DHP therapy (P &lt; 0.01), and between 2 h after the start of and the end of this therapy (P &lt; 0.01). These results suggest that a longer duration of PMX-DHP therapy can be expected to improve the hemodynamics and pulmonary oxygenation capacity of patients with severe sepsis/septic shock. Strict prospective studies are needed in the future.