Changes in carbon dioxide production and oxygen uptake evaluated using indirect calorimetry in mechanically ventilated patients with sepsis.

BACKGROUND: Several clinical guidelines recommend monitoring blood lactate levels and central venous oxygen saturation for hemodynamic management of patients with sepsis. We hypothesized that carbon dioxide production (VCO2) and oxygen extraction (VO2) evaluated using indirect calorimetry (IC) might provide additional information to understand the dynamic metabolic changes in sepsis. METHODS: Adult patients with sepsis who required mechanical ventilation in the intensive care unit (ICU) of our hospital between September 2019 and March 2020 were prospectively enrolled. Sepsis was diagnosed according to Sepsis-3. Continuous measurement of VCO2 and VO2 using IC for 2 h was conducted within 24 h after tracheal intubation, and the changes in VCO2 and VO2 over 2 h were calculated as the slopes by linear regression analysis. Furthermore, temporal lactate changes were evaluated. The primary outcome was 28-day survival. RESULTS: Thirty-four patients with sepsis were enrolled, 26 of whom survived 76%. Significant differences in the slope of VCO2 (- 1.412 vs. - 0.446) (p = 0.012) and VO2 (- 2.098 vs. - 0.851) (p = 0.023) changes were observed between non-survivors and survivors. Of note, all eight non-survivors and 17 of the 26 survivors showed negative slopes of VCO2 and VO2 changes. For these patients, 17 survivors had a median lactate of - 2.4% changes per hour (%/h), whereas non-survivors had a median lactate of 2.6%/hr (p = 0.023). CONCLUSIONS: The non-survivors in this study showed temporal decreases in both VCO2 and VO2 along with lactate elevation. Monitoring the temporal changes in VCO2 and VO2 along with blood lactate levels may be useful in predicting the prognosis of sepsis.

Recombinant Thrombomodulin on Neutrophil Extracellular Traps in Murine Intestinal Ischemia-Reperfusion.

BACKGROUND: In multiple-organ dysfunction, an injury affecting one organ remotely impacts others, and the injured organs synergistically worsen outcomes. Recently, several mediators, including extracellular histones and neutrophil extracellular traps, were identified as contributors to distant organ damage. This study aimed to elucidate whether these mediators play a crucial role in remote organ damage induced by intestinal ischemia-reperfusion. This study also aimed to evaluate the protective effects of recombinant thrombomodulin, which has been reported to neutralize extracellular histones, on multiple-organ dysfunction after intestinal ischemia-reperfusion. METHODS: Intestinal ischemia was induced in male C57BL/6J mice via clamping of the superior mesenteric artery. Recombinant thrombomodulin (10 mg/kg) was administered intraperitoneally with the initiation of reperfusion. The mice were subjected to a survival analysis, histologic injury scoring, quantitative polymerase chain reaction analysis of tumor necrosis factor-α and keratinocyte-derived chemokine expression, Evans blue dye vascular permeability assay, and enzyme-linked immunosorbent assay analysis of histones in the jejunum, liver, lung, and kidney after 30- or 45-min ischemia. Neutrophil extracellular trap formation was evaluated by immunofluorescence staining. RESULTS: Recombinant thrombomodulin yielded statistically significant improvements in survival after 45-min ischemia (ischemia-reperfusion without vs. with 10 mg/kg recombinant thrombomodulin: 0% vs. 33%, n = 21 per group, P = 0.001). Recombinant thrombomodulin reduced the histologic injury score, expression of tumor necrosis factor-α and keratinocyte-derived chemokine, and extravasation of Evans blue dye, which were augmented by 30-min ischemia-reperfusion, in the liver, but not in the intestine. Accumulated histones and neutrophil extracellular traps were found in the livers and intestines of 30-min ischemia-reperfusion-injured mice. Recombinant thrombomodulin reduced these accumulations only in the liver. CONCLUSIONS: Recombinant thrombomodulin improved the survival of male mice with intestinal ischemia-reperfusion injury. These findings suggest that histone and neutrophil extracellular trap accumulation exacerbate remote liver injury after intestinal ischemia-reperfusion. Recombinant thrombomodulin may suppress these accumulations and attenuate liver injury.

IFN-ß Improves Sepsis-related Alveolar Macrophage Dysfunction and Postseptic Acute Respiratory Distress Syndrome-related Mortality.

IFN-ß is reported to improve survival in patients with acute respiratory distress syndrome (ARDS), possibly by preventing sepsis-induced immunosuppression, but its therapeutic nature in ARDS pathogenesis is poorly understood. We investigated the therapeutic effects of IFN-ß for postseptic ARDS to better understand its pathogenesis in mice. Postseptic ARDS was reproduced in mice by cecal ligation and puncture to induce sepsis, followed 4 days later by intratracheal instillation of Pseudomonas aeruginosa to cause pneumonia with or without subcutaneous administration of IFN-ß 1 day earlier. Sepsis induced prolonged increases in alveolar TNF-α and IL-10 concentrations and innate immune reprogramming; specifically, it reduced alveolar macrophage (AM) phagocytosis and KC (CXCL1) secretion. Ex vivo AM exposure to TNF-α or IL-10 duplicated cytokine release impairment. Compared with sepsis or pneumonia alone, pneumonia after sepsis was associated with blunted alveolar KC responses and reduced neutrophil recruitment into alveoli despite increased neutrophil burden in lungs (i.e., "incomplete alveolar neutrophil recruitment"), reduced bacterial clearance, increased lung injury, and markedly increased mortality. Importantly, IFN-ß reversed the TNF-α/IL-10-mediated impairment of AM cytokine secretion in vitro, restored alveolar innate immune responsiveness in vivo, improved alveolar neutrophil recruitment and bacterial clearance, and consequently reduced the odds ratio for 7-day mortality by 85% (odds ratio, 0.15; 95% confidence interval, 0.03-0.82; P = 0.045). This mouse model of sequential sepsis → pneumonia infection revealed incomplete alveolar neutrophil recruitment as a novel pathogenic mechanism for postseptic ARDS, and systemic IFN-ß improved survival by restoring the impaired function of AMs, mainly by recruiting neutrophils to alveoli.

Early-phase Innate Immune Suppression in Murine Severe Sepsis Is Restored with Systemic Interferon-ß.

BACKGROUND: Sepsis is a leading cause of death in the intensive care unit. Immune modulatory therapy targeting sepsis-associated proinflammatory responses has not shown survival benefit. Here, the authors evaluated innate immunity at the early stage of murine mild or severe peritoneal sepsis induced by cecal ligation and puncture, and the effect of systemic interferon-ß, a potent inflammatory mediator, on severe sepsis as well as its mechanism of action. METHODS: Mild and severe sepsis was induced in C57BL/6 mice by cecal ligation and puncture with 22- and 18-gauge needles for puncture, respectively. Interferon-ß (700 U/g) was subcutaneously administered either before or 12 h after cecal ligation and puncture for the severe sepsis group. RESULTS: Severe sepsis resulted in significantly lower 6-day survival rates than mild sepsis (n = 48, 25% vs. n = 11, 81.8%, P = 0.002), significantly less phagocytic capacity of peritoneal exudate cells, and lower CXC chemokine receptor-2 expression on circulating neutrophils at 24 h after cecal ligation and puncture. Interferon-ß administration 12 h after cecal ligation and puncture associated with significantly improved survival (n = 34, 52.9%, P = 0.017) increased the number and function of peritoneal exudate cells, peritoneal/systemic inflammatory cytokine/chemokine concentrations, and CXC chemokine receptor-2 on neutrophils, compared with the severe sepsis controls. However, those responses were not observed in the prophylactic interferon-ß group (n = 24). Interferon-ß increased lipopolysaccharide-induced interleukin-6 messenger RNA/protein expression of lipopolysaccharide-tolerant murine peritoneal macrophages, which was not observed in nontolerant cells. CONCLUSIONS: In severe sepsis, immune suppression occurs within 24 h and is associated with worse mortality. Interferon-ß given after the onset of peritonitis restores impaired innate immunity in vivo and in vitro.

Switching therapy from intravenous beta blocker to bisoprolol transdermal patch for atrial fibrillation tachycardia.

Beta-blockers are important for severe-status patients with atrial fibrillation-related tachycardia. Beta 1-selective intravenous injection are routinely used, but long-term administration is difficult due to cost-performance- or management-related issues. A bisoprolol patch, a beta-blocker to be percutaneously absorbed, recently became commercially available in Japan. As it may facilitate effective absorption and a mild elevation of the blood concentration, we retrospectively analyzed 16 patients with atrial fibrillation-related tachycardia who were admitted to the Intensive Care Unit of Hitachi General Hospital Emergency and Critical Care Center, and underwent switching therapy from landiolol to a bisoprolol patch. For switching, the bisoprolol patch (4 mg) was attached to each patient. The bisoprolol patch was introduced 88 h after the start of landiolol administration, when the rate was approximately 3 µg/kg/min. Landiolol injection was combined with bisoprolol for 15.4 ± 17.5 h. Switching therapy was successful in all subjects. The introduction of the bisoprolol patch did not induce any significant changes in the blood pressure or heart rate. After the completion of landiolol administration, there were also no significant changes in either parameter. There were no adverse events. In severe-status patients, switching therapy from landiolol injection to the bisoprolol patch can be conducted safely, and might be useful for heart-rate control.

The high-mobility group protein B1-Toll-like receptor 4 pathway contributes to the acute lung injury induced by bilateral nephrectomy.

Acute lung injury and acute kidney injury are severe complications in critically ill patients and synergistically increase mortality in intensive care units. Organ cross-talk between the kidney and the lung has been implicated recently as amplifying injury in each organ. Here we sought to identify a possible mechanism of acute kidney injury-induced acute lung injury using a mouse bilateral nephrectomy model. Toll-like receptor 4 (TLR4)-mutant C3H/HeJ mice were more resistant to lung injury including neutrophil infiltration, increased neutrophil elastase activity, and vascular permeability caused by bilateral nephrectomy compared with TLR4-wild-type C3H/HeN mice 6 h after surgery. High-mobility group protein B1 (HMGB1) is one agonist for TLR4. Its blood concentrations were increased significantly by bilateral nephrectomy. Blockade of HMGB1 by neutralizing antibody reduced neutrophil infiltration in TLR4-wild-type C3H/HeN but not in TLR4-mutant C3H/HeJ mice. However, HMGB1 blockade in a renal ischemia reperfusion model reduced pulmonary neutrophil infiltration independent from TLR4. Thus, an enhanced HMGB1-TLR4 pathway contributes to lung injury induced by bilateral nephrectomy and the other HMGB1-dependent pathway exists in pulmonary neutrophil infiltration caused by renal ischemia reperfusion. Targeting the HMGB1-TLR4 pathway might enable development of a new therapeutic strategy to improve the outcomes of severely ill patients with both acute lung and acute kidney injury.

Mortality prediction by acute kidney injury biomarkers in comparison with serum creatinine.

OBJECTIVES: To investigate the performance of acute kidney injury (AKI) biomarkers for mortality prediction. MATERIALS AND METHODS: Cutoff values of urinary L-type fatty acid-binding protein (L-FABP) and N-acetyl-ß-d-glucosaminidase (NAG) for AKI diagnosis in ICU were determined in the derivation cohort. The performance of these AKI biomarkers for mortality prediction was evaluated in the validation cohort with stratification of serum-creatinine based AKI diagnosis. RESULTS: Mortality in the AKI patients diagnosed by serum creatinine was increased remarkably when urinary L-FABP and NAG were positive. CONCLUSIONS: These AKI biomarkers can specifically detect high-risk patients among creatinine-base diagnosed AKI.

Acute respiratory distress syndrome (ARDS) treated successfully by veno-venous extracorporeal membrane oxygenation (ECMO) in a nearly drowned patient.

This report highlights about one acute respiratory distress syndrome (ARDS) case after near-drowning resuscitated using extracorporeal membrane oxygenation (ECMO). Few cases have been reported about ECMO use for near-drowning and in most of these cases, ECMO was initiated within the first week. However, in our report, we would like to emphasize that seemingly irreversible secondary worsening of ARDS after nearly drowned patient was successfully treated by ECMO use more than 1 week after near-drowning followed by discharge without home oxygen therapy, social support, or any complication. This is probably due to sufficient lung rest for ventilator-associated lung injury during ECMO use. Based on our case's clinical course, intensive care unit physicians must consider ECMO even in the late phase of worsened ARDS after near-drowning.

Endotoxin adsorption by polymyxin B column or intraaortic balloon pumping use for severe septic cardiomyopathy.

Septic patients often have low cardiac output. Some of them present severe cardiac dysfunction such as septic cardiomyopathy. However, no well-known and effective treatment for septic cardiomyopathy exists. The effect of endotoxin adsorption by polymyxin B­immobilized fiber column­direct hemoperfusion (PMX-DHP) and intraaortic balloon pumping (IABP) for septic shock remains uncertain. We experienced 2 very contrastive case reports of severe septic cardiomyopathy. We experienced 2 cases of severe septic cardiomyopathy with refractory shock. Case 1 with colon perforation presented refractory shock 6 hours after PMX-DHP, and IABP immediately improved her hemodynamics. In contrast, IABP had no effect at all in case 2 with viral enteritis, but PMXDHP improved her blood pressure and stroke volume markedly. The probability of impaired coronary microcirculation and relative bradycardia is the least required conditions for IABP use in severe septic cardiomyopathy. Meanwhile, PMX-DHP could be a good option for septic cardiomyopathy because of its fewer complications.

Hyperammonemia in idiopathic epileptic seizure.

OBJECTIVE: It is known that patients with convulsion often present hyperammonemia. The elevation of ammonia levels in convulsion is considered to occur along with extensive muscle contractions, but the details remain unclear. In emergency pathologies, such as cardiopulmonary arrest or hemorrhagic shock without muscle contraction, red blood cells are known to produce ammonia through acidosis, leading to hyperammonemia. A similar effect would be considered to be involved in idiopathic epileptic seizure patients as well. METHODS: We retrospectively analyzed the cases of epileptic seizure that were transported to the emergency medical care center of Ohta Nishinouchi Hospital and diagnosed by neurologist as idiopathic epileptic seizure or epilepsy due to cerebrovascular disorder. Forty-four patients were idiopathic epilepsy, and 8 had epilepsy due to cerebrovascular disorder. Those with hepatic encephalopathy, metabolic disorder, alcohol consumption, tumor, and patients taking oral valproic acid were excluded. RESULTS: High ammonia levels (>35 µmol/L) were observed in 22 cases. Maximum ammonia level was 506 µmol/L. Significant differences were observed in the pH (r = 0.838, P < .0001) and base excess (BE) (r = 0.863, P < .0001), the values suggesting a strong negative correlation between the ammonia level and pH/BE. CONCLUSION: Idiopathic epileptic seizures can present with prominent hyperammonemia with acidosis. Because high ammonia level in epileptic seizure was strongly correlated with pH and BE, we speculate that hyperammonemia is not only because of extensive muscle contractions but is also related to ammonia production in the red blood cells through acidosis like other emergency conditions.

Development of information systems and clinical decision support systems for emergency departments: a long road ahead for Japan.

Emergency care services face common challenges worldwide, including the failure to identify emergency illnesses, deviations from standard treatments, deterioration in the quality of medical care, increased costs from unnecessary testing, and insufficient education and training of emergency personnel. These issues are currently being addressed by implementing emergency department information systems (EDIS) and clinical decision support systems (CDSS). Such systems have been shown to increase the efficiency and safety of emergency medical care. In Japan, however, their development is hindered by a shortage of emergency physicians and insufficient funding. In addition, language barriers make it difficult to introduce EDIS and CDSS in Japan that have been created for an English-speaking market. This perspective addresses the key events that motivated a campaign to prioritise these services in Japan and the need to customise EDIS and CDSS for its population.

Bite wound and mauling of a zookeeper by a gorilla.

The majority of bite wounds that we encounter in the emergency department are caused by dogs, cats and humans, but bite injuries can be caused by a variety of animals. Here, we describe a case of bite wound and trauma caused by a large gorilla (Western lowland gorilla) weighing over 170 kg. Gorilla bites are rare, and the patient had an open fracture of the right distal radioulna in addition to multiple bite wounds. Treatment required careful consideration of gorilla antigenicity and a literature review to guide the selection of appropriate antimicrobial agents. Furthermore, trauma inflicted by large animals tends to require systemic traumatological screening, and patients can develop acute stress disorder because of a fear of being attacked again; therefore, early psychiatric intervention is important.

Subcutaneous injection of organophosphate (Fenitrothion)-Management of preventing the appearance of toxic symptoms: A case report.

There is a risk of unnecessary extensive incision because of swelling after the subcutaneous injection; however, removing completely the injected organophosphate by making a skin incision before the appearance of toxic symptoms could reduce sequelae.

Early diagnosis and antibiotic treatment for fulminant Clostridium difficile infection.

In fulminant Clostridium difficile infection (CDI), early diagnosis is important, and early diagnosis could save fulminant CDI patients that do not qualify for surgery due to severe complicating conditions by conservative antibiotic therapy.

Recombinant thrombomodulin prevents acute lung injury induced by renal ischemia-reperfusion injury.

Acute kidney injury (AKI) complicated by acute lung injury has a detrimental effect on mortality among critically ill patients. Recently, a renal ischemia-reperfusion (IR) model suggested the involvement of histones and neutrophil extracellular traps (NETs) in the development of distant lung injury after renal IR. Given that recombinant thrombomodulin (rTM) has anti-inflammatory roles by binding to circulating histones, we aimed to clarify its effect on distant lung injury induced by AKI in a murine bilateral renal IR model. Both pretreatment and delayed treatment with rTM significantly decreased pulmonary myeloperoxidase activity, but they did not affect renal dysfunction at 24 h after renal IR. Additionally, rTM mitigated the renal IR-augmented expression of proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, and keratinocyte-derived chemokine), and vascular leakage, as well as the degree of lung damage. Intense histone accumulation and active NET formation occurred in both the kidneys and the lungs; however, rTM significantly decreased the histone and NET accumulation only in the lungs. Administration of rTM may have protective impact on the lungs after renal IR by blocking histone and NET accumulation in the lungs, although no protection was observed in the kidneys. Treatment with rTM may be an adjuvant strategy to attenuate distant lung injury complicating AKI.