Comparison between midazolam and propofol in acute phase for ventilated patients with sepsis: a post-hoc analysis of the DESIRE trial.

Aim: There are few assessments of sedatives during the acute phase under sedation protocols for patients with sepsis. We aimed to compare the influence of different sedation strategies using midazolam and propofol under light sedation on clinical outcomes of ventilated patients with sepsis. Methods: This study was a post-hoc analysis of data from the dexmedetomidine for sepsis in the ICU Randomized Evaluation (DESIRE) trial. Patients were divided into propofol and midazolam groups based on continuously used drug, and sedation control between groups compared on day three. We assessed the incidence of delirium, length of ICU stay, number of ventilator-free days within the first 28 days, and mortality after 28 days. Results: The midazolam and propofol groups consisted of 51 and 66 patients, respectively. Both groups had similar characteristics, except for age and emergency surgery. The number of well-controlled sedation patients in the propofol group on day three was significantly higher than that in the midazolam group (odds ratio [OR] 3.9, 95% CI [1.30, 11.7]). The incidence of daily coma and delirium within the initial week was different between groups and increased with midazolam administration (P = 0.0138). The number of Confusion Assessment Method for ICU-positive patients was significantly higher in the midazolam group than in the propofol group (OR 5.71, 95% CI [2.30, 14.2]). Conclusion: In patients with sepsis required mechanical ventilation, sedation with midazolam based on a light sedation protocol may be associated with inappropriate sedation during the acute phase, with increased coma and delirium as compared to propofol.

Association of trauma severity with antibody seroconversion in heparin-induced thrombocytopenia: A multicenter, prospective, observational study.

BACKGROUND: Heparin administration can induce the production of anti-platelet factor 4 (PF4)/heparin antibodies with platelet-activating properties, causing heparin-induced thrombocytopenia (HIT). Previous studies have suggested that trauma severity influences HIT immune responses, but their relationship has not been fully explained. This study aimed to clarify this association by multicenter prospective observational study. METHODS: Trauma patients who met the criteria of age 18 years or older and Injury Severity Scores (ISSs) of ≥9 from March 2018 to February 2019 were included. Patients who did not receive any heparin and those who received it as flushes or for treatment were also included. Patients were divided into three groups based on trauma severity (to mild [ISS 9-15], moderate [ISS 16-24], and severe injury groups [ISS ≥25]) and were compared by the seroconversion time and rate, as well as the disappearance rate of antibodies on day 30. RESULTS: A total of 184 patients were included: 55, 62, and 67 patients were classified into the mild, moderate, and severe injury groups, respectively. Overall, the seroconversion rates of anti-PF4/heparin immunoglobulin G (IgG) and HIT antibodies by washed platelet activation assay were 26.6% and 16.3%, respectively. There was a significant difference in the seroconversion rates of anti-PF4/heparin IgG ( p = 0.016) and HIT antibodies ( p = 0.046) among the groups. Seroconversion rates in both assays increased with increasing trauma severity. The time required to achieve seroconversion was similar (between 5 and 10 days of trauma onset) regardless of heparin administration. Anti-PF4/heparin IgG and HIT antibodies were no longer detected on day 30 in 28.6% and 60.9% of seroconverted patients, respectively. CONCLUSION: Development of HIT antibodies was observed commonly in severely injured trauma patients. Heparin-induced thrombocytopenia antibody development may be related to trauma severity, with a high disappearance frequency on day 30. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Effect of age on dexmedetomidine treatment for ventilated patients with sepsis: a post-hoc analysis of the DESIRE trial.

AIM: There are no definitive data to determine whether age influences the effects of dexmedetomidine (DEX) treatment. Thus, we investigated whether older age was associated with more favorable sedative action by DEX in sepsis patients who required mechanical ventilation. METHODS: This study involved a post-hoc analysis of data from the Dexmedetomidine for Sepsis in the ICU Randomized Evaluation (DESIRE) trial. The patients were categorized based on median age into elderly and younger groups. The two groups were then compared during the first 7 days after ventilation based on proportion of patients with well-controlled sedation (Richmond Agitation-Sedation Scale score between -3 and +1), days free from delirium (based on the Confusion Assessment Method for ICU), and days free from coma (Richmond Agitation-Sedation Scale score between -4 and -5). RESULTS: One hundred and one patients were assigned to the elderly group and 100 patients were assigned to the younger group. In the elderly group, 50 patients received DEX treatment and 51 patients received non-DEX treatment, with the DEX arm having significantly better-controlled sedation (range, 14-52% versus 16-27%; P = 0.01). In the younger group, 50 patients received DEX treatment and 50 patients received non-DEX treatment, with no significant difference in the proportions of well-controlled sedation (range, 20-64% versus 24-60%; P = 0.73). There were no significant differences in the numbers of days free from delirium or coma between the groups. CONCLUSION: In elderly sepsis patients who require ventilation, dexmedetomidine could be more effective than other sedative agents for achieving proper sedation.

Retropharyngeal hematoma in a patient with chronic alcoholism.

Retropharyngeal hematoma is a potentially life-threatening condition because it can easily lead to airway obstruction. Most of the previously reported cases of retropharyngeal hematoma are caused by predisposing factors such as head and neck trauma, the use of anticoagulants, or the presence of underlying bleeding diathesis. Herein, we report a case of retropharyngeal hematoma in a patient with chronic alcoholism, where we could not confirm any predisposing factors at the time of examination. A 61-year-old man with chronic alcoholism presented to our emergency department with convulsive seizures. He was diagnosed with alcohol withdrawal and transferred to a secondary hospital after the seizure resolved. However, a few hours later, he returned to our department with a persistent cough and complained of pain and swelling in the neck. One hour later, he suddenly developed dyspnea; therefore, emergency intubation was performed. Although initially computed tomography (CT) showed normal findings, contrast-enhanced CT revealed a retropharyngeal hematoma. He was managed conservatively and transferred to a specialty hospital for intensive care. Chronic alcoholism may be a predisposing factor for retropharyngeal hematoma due to the high incidence of head trauma, neck hyperextension by convulsion, and hemostatic disorders. However, taking an accurate patient history is sometimes difficult because of the effects of intoxication or alcohol withdrawal. If a patient with chronic alcoholism presents with symptoms of airway compression, then a retropharyngeal hematoma should be suspected, and emergency intubation should be considered.

Association of Body Weight Change and Fluid Balance With Extubation Failure in Intensive Care Unit Patients: A Single-Center Observational Study.

PURPOSE: To elucidate whether fluid balance and body weight change are associated with failed planned extubation. MATERIALS AND METHODS: Patients who received invasive mechanical ventilation for over 24 hours were enrolled and divided into extubation success and extubation failure groups. Fluid balance and body weight fluctuation within 24 and 48 hours before extubation and from admission to planned extubation were calculated. The primary outcome was extubation failure (ie, all-cause reintubation within 72 hours). The association of extubation failure with fluid balance and body weight change was assessed via logistic regression analysis. RESULTS: Extubation failure occurred in 12(7.4%)/161 patients. The extubation success group had a significantly lower fluid balance within 24 hours before extubation than did the extubation failure group (-276 mL [-1111 to 456] vs 1217 mL [503 to 1875], P = .002). However, fluid balance within 48 hours before extubation, cumulative fluid balance, and body weight change were not significantly different between the 2 groups. The sensitivity and specificity of water balance +1000 mL within 24 hours before extubation for the extubation failure group were 0.54 and 0.84, respectively, based on the receiver operating characteristic curve. Logistic regression analysis showed that fluid balance within 24 hours before extubation was associated with extubation failure (odds ratio: 22.9, 95% confidence interval: 4.1-128.4). CONCLUSIONS: A larger fluid balance within 24 hours before extubation is associated with extubation failure. Thus, fluid balance may be a good indicator of extubation outcome.

Mortality Effects of Prolonged Hemoperfusion Therapy Using a Polymyxin B-Immobilized Fiber Column for Patients with Septic Shock: A Sub-Analysis of the DESIRE Trial.

BACKGROUND/AIMS: The optimal duration of hemoperfusion therapy with a polymyxin B-immobilized fiber column has not yet been verified. METHODS: This analysis examined whether hemoperfusion therapy with a polymyxin B-immobilized fiber column lasting longer than 2 h (prolonged polymyxin) improved outcomes for patients with septic shock compared to 2-h polymyxin therapy (sub-analysis of data from the DESIRE trial). RESULTS: The 2-h and prolonged polymyxin groups contained 22 and 14 patients, respectively. Both groups had similar characteristics. The polymyxin duration per session in the prolonged polymyxin group was significantly longer (median, 5.5 h) than in the 2-h polymyxin group (p < 0.01). The 28-day mortality rate was significantly higher in the 2-h polymyxin group (7, 31.8%) than in the prolonged polymyxin group (0, 0%; p = 0.019). CONCLUSION: Prolonged polymyxin therapy might be associated with better clinical outcomes than 2-h polymyxin therapy in patients with septic shock. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=491744.

The impact of organ dysfunctions on mortality in patients with severe sepsis: A multicenter prospective observational study.

PURPOSE: Disseminated intravascular coagulations (DIC), acute respiratory distress syndrome (ARDS), and acute kidney injury (AKI) are major organ dysfunctions that occur in patients with sepsis. This study aimed to elucidate the impact of these organ dysfunctions on mortality in patients with severe sepsis. MATERIAL AND METHODS: A prospective observational study was performed in 10 ICUs to obtain data from patients with severe sepsis. Multivariate analyses to examine in-hospital mortality were performed. RESULTS: Data of 573 patients were analyzed. In-hospital mortality rate was 19.4% (111/573). The incidences of DIC, ARDS, and AKI were 58.4%, 18.7%, and 41.7%, while the associated mortality rates were 28.9%, 36.4%, and 31.8%, respectively. In multiple regression model, DIC (odds ratio 2.71, 95% confidence interval [CI] 1.45-5.27) and AKI stage 3 (odds ratio 1.98, 95% CI 1.07-3.63) were significantly associated with higher in-hospital all-cause mortality. DIC (hazard ratio 2.58, 95% CI 1.53-4.55) and AKI stage 3 (hazard ratio 1.73, 95% CI 1.07-2.80) were also significantly associated with longer survival durations. However, severe ARDS was not associated with these outcomes. CONCLUSIONS: DIC and AKI are frequent complications in patients with severe sepsis. In this study, DIC, and AKI stage 3 were independent risk factors of in-hospital mortality.

High-mobility group box 1 is associated with neurological outcome in patients with post-cardiac arrest syndrome after out-of-hospital cardiac arrest.

BACKGROUND: Alarmins, including high-mobility group box 1 (HMGB-1), can be released from damaged tissues and activated cells as inflammatory mediators. We aimed to evaluate HMGB-1 and mitochondrial DNA dynamics and estimate the prognostic value for neurological outcome in patients with post-cardiac arrest syndrome after out-of-hospital cardiac arrest. METHODS: We evaluated the dynamics of HMGB-1, mitochondrial DNA, and other variables in patients with return of spontaneous circulation after out-of-hospital cardiac arrest. Patients were divided into two groups according to the cerebral performance category at 30 days: the favourable outcome group (cerebral performance categories 1 and 2) and unfavourable group (≥3). RESULTS: Twenty-one patients were included, and 11 demonstrated favourable outcomes. HMGB-1 levels and mitochondrial DNA on day 1 were significantly higher than on days 2, 3, 5, and 7. Plasma levels of HMGB-1 on day 1 correlated with prognostic parameters (estimated interval to return of spontaneous circulation, lactate, and NH3), tissue damage, systemic inflammation, and disease severity. HMGB-1 on day 1 in the unfavourable group was significantly higher than in the favourable group (median [interquartile range] 15.5 [6.65-18.7], 39.4 [17-69.5], P = 0.009). These findings were not observed regarding mitochondrial DNA. Regarding HMGB-1 prediction accuracy for a good neurological outcome, the area under the receiver operating characteristic curve was 0.864 (95 % confidence interval 0.702, 1.000). CONCLUSIONS: HMGB-1 may be involved in acute-phase post-cardiac arrest syndrome pathophysiology, and an increase in plasma levels may be associated with a poor neurological outcome. The study was registered with the University Hospital Medical Information Network Clinical Trials Registry ID: UMIN000006714.

Lactate, a useful marker for disease mortality and severity but an unreliable marker of tissue hypoxia/hypoperfusion in critically ill patients.

Early aggressive hemodynamic resuscitation using elevated plasma lactate as a marker is an essential component of managing critically ill patients. Therefore, measurement of blood lactate is recommended to stratify patients based on the need for fluid resuscitation and the risks of multiple organ dysfunction syndrome and death. Hyperlactatemia is common among critically ill patients, and lactate levels and their trend may be reliable markers of illness severity and mortality. Although hyperlactatemia has been widely recognized as a marker of tissue hypoxia/hypoperfusion, it can also result from increased or accelerated aerobic glycolysis during the stress response. Additionally, lactate may represent an important energy source for patients in critical condition. Despite its inherent complexity, the current simplified view of hyperlactatemia is that it reflects the presence of global tissue hypoxia/hypoperfusion with anaerobic glycolysis. This review of hyperlactatemia in critically ill patients focuses on its pathophysiological aspects and recent clinical approaches. Hyperlactatemia in critically ill patients must be considered to be related to tissue hypoxia/hypoperfusion. Therefore, appropriate hemodynamic resuscitation is required to correct the pathological condition immediately. However, hyperlactatemia can also result from aerobic glycolysis, unrelated to tissue dysoxia, which is unlikely to respond to increases in systemic oxygen delivery. Because hyperlactatemia may be simultaneously related to, and unrelated to, tissue hypoxia, physicians should recognize that resuscitation to normalize plasma lactate levels could be over-resuscitation and may worsen the physiological status. Lactate is a reliable indicator of sepsis severity and a marker of resuscitation; however, it is an unreliable marker of tissue hypoxia/hypoperfusion.

WRKY Transcription Factors Phosphorylated by MAPK Regulate a Plant Immune NADPH Oxidase in Nicotiana benthamiana.

Pathogen attack sequentially confers pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) after sensing of pathogen patterns and effectors by plant immune receptors, respectively. Reactive oxygen species (ROS) play pivotal roles in PTI and ETI as signaling molecules. Nicotiana benthamiana RBOHB, an NADPH oxidase, is responsible for both the transient PTI ROS burst and the robust ETI ROS burst. Here, we show that RBOHB transactivation mediated by MAPK contributes to R3a/AVR3a-triggered ETI (AVR3a-ETI) ROS burst. RBOHB is markedly induced during the ETI and INF1-triggered PTI (INF1-PTI), but not flg22-tiggered PTI (flg22-PTI). We found that the RBOHB promoter contains a functional W-box in the R3a/AVR3a and INF1 signal-responsive cis-element. Ectopic expression of four phospho-mimicking mutants of WRKY transcription factors, which are MAPK substrates, induced RBOHB, and yeast one-hybrid analysis indicated that these mutants bind to the cis-element. Chromatin immunoprecipitation assays indicated direct binding of the WRKY to the cis-element in plants. Silencing of multiple WRKY genes compromised the upregulation of RBOHB, resulting in impairment of AVR3a-ETI and INF1-PTI ROS bursts, but not the flg22-PTI ROS burst. These results suggest that the MAPK-WRKY pathway is required for AVR3a-ETI and INF1-PTI ROS bursts by activation of RBOHB.

Body temperature abnormalities in non-neurological critically ill patients: a review of the literature.

Body temperature abnormalities, which occur because of several infectious and non-infectious etiologies, are among the most commonly noted symptoms of critically ill patients. These abnormalities frequently trigger changes in patient management. The purpose of this article was to review the contemporary literature investigating the definition and occurrence of body temperature abnormalities in addition to their impact on illness severity and mortality in critically ill non-neurological patients, particularly in patients with severe sepsis. Reports on the influence of fever on outcomes are inconclusive, and the presence of fever per se may not contribute to increased mortality in critically ill patients. In patients with severe sepsis, the impacts of elevated body temperature and hypothermia on mortality and the severity of physiologic decline are different. Hypothermia is significantly associated with an increased risk of mortality. In contrast, elevated body temperature may not be associated with increased disease severity or risk of mortality. In patients with severe sepsis, the effect of fever and fever control on outcomes requires further research.

Burn-associated delayed dilated cardiomyopathy evaluated by cardiac PET and SPECT: Report of a case.

Dilated cardiomyopathy is a delayed-onset and rarely reported cardiac complication of burn injury although the mechanism remains unclear. We thus report a case of dilated cardiomyopathy following severe burn injury, in which technetium 99m sestamibi single-photon emission computed tomography (SPECT), iodine-123 beta-methyl-iodophenylpentadecanoic acid SPECT and 18F-fluorodeoxyglucose positron emission tomography (PET) were performed to evaluate the pathophysiologic condition in combination with cardiac catheterization and myocardial biopsy. The cardiac PET and SPECT images showed reduced myocardial blood flow, decreased fatty acid metabolism, and increased glucose utilization in the left ventricular lateral wall in spite of normal coronary angiography, no significant cardiac fibrosis, and inflammatory cell infiltration, which suggests that myocardial ischemia due to microcirculatory disturbance in hypermetabolic state associated with burn injury might be a causative mechanism of dilated cardiomyopathy in this case. A beta blocker, bisoprolol, was successfully introduced in this patient in combination with oral inotropic agents, pimobendan and digitalis after the prolonged use of intravenous dobutamine infusion, which might have been beneficial for this patient with burn-associated dilated cardiomyopathy not only to reduce regional myocardial ischemia but also to attenuate hypermetabolic state after severe burn injury. .

Plasma mitochondrial DNA levels in patients with trauma and severe sepsis: time course and the association with clinical status.

PURPOSE: This study aimed to investigate the serial changes in plasma levels of mitochondrial DNA (mtDNA) in patients with trauma and severe sepsis and the mechanism of increase in mtDNA levels and the association between the levels and severity. MATERIALS AND METHODS: We conducted a prospective observational study of patients with trauma having injuries with an Abbreviated Injury Scale score of 3 or higher (n = 37) and patients with severe sepsis (n = 23). The mtDNA concentrations in clarified plasma were measured using real-time quantitative polymerase chain reaction. RESULTS: Concentrations of mtDNA peaked on the day of admission (day 1) in patients with trauma, whereas they increased on day 1 and remained constant until day 5 in patients with sepsis. The mtDNA levels on day 1 correlated with the maximal levels of creatinine phosphokinase in patients with trauma (R(2) = 0.463, P < .05) but not in patients with sepsis (R(2) = 0.028, P = .43). The mtDNA levels on day 1 were significantly higher in nonsurvivors compared with survivors of trauma (P < .05) but not sepsis. CONCLUSIONS: The levels of mtDNA were elevated during traumatic injury and severe sepsis, although time course and prognostic significance differed between the groups, suggesting that the mechanisms of mtDNA release into plasma differ.