Practical approach to thrombocytopenia in patients with sepsis: a narrative review.

Thrombocytopenia frequently occurs in patients with sepsis. Disseminated intravascular coagulation (DIC) may be a possible cause of thrombocytopenia owing to its high prevalence and association with poor outcomes; however, it is important to keep the presence of other diseases in mind in sepsis practice. Thrombotic microangiopathy (TMA), which is characterized by thrombotic thrombocytopenic purpura, Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (HUS), and complement-mediated HUS, is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ damage. TMA has become widely recognized in recent years because of the development of specific treatments. Previous studies have reported a remarkably lower prevalence of TMA than DIC; however, its epidemiology is not well defined, and there may be cases in which TMA is not correctly diagnosed, resulting in poor outcomes. Therefore, it is important to differentiate DIC from TMA. Nevertheless, differentiating between DIC and TMA remains a challenge as indicated by previous reports that most patients with TMA can be diagnosed as DIC using the universal coagulation scoring system. Several algorithms to differentiate sepsis-related DIC from TMA have been suggested, contributing to improving the care of septic patients with thrombocytopenia; however, it may be difficult to apply these algorithms to patients with coexisting DIC and TMA, which has recently been reported. This review describes the disease characteristics, including epidemiology, pathophysiology, and treatment, of DIC, TMA, and other diseases with thrombocytopenia and proposes a novel practical approach flow, which is characterized by the initiation of the diagnosis of TMA in parallel with the diagnosis of DIC. This practical flow also refers to the longitudinal diagnosis and treatment flow with TMA in mind and real clinical timeframes. In conclusion, we aim to widely disseminate the results of this review that emphasize the importance of incorporating consideration of TMA in the management of septic DIC. We anticipate that this practical new approach for the diagnostic and treatment flow will lead to the appropriate diagnosis and treatment of complex cases, improve patient outcomes, and generate new epidemiological evidence regarding TMA.

Risk factors for QT prolongation associated with acute psychotropic drug overdose.

BACKGROUND: Antipsychotic/Antidepressant use is a risk factor for QT interval (QT) prolongation and sudden cardiac death. However, it is unclear which drugs are risk factors for QT prolongation and torsades de pointes in cases of psychotropic drug overdose. METHODS: After correction of QT data by Bazett formula (QTc), QTc was classified into 3 categories (QTc<440 milliseconds, 440 milliseconds≤QTc<500 milliseconds, and QTc≥500 milliseconds), and the blood concentration of each drug was classified as not detected, therapeutic range, or toxic range. The association of the blood concentration of each drug with QTc was analyzed using the ordinal logistic regression model. Drugs that induced QT-heart rate pairs higher than the at-risk line of Isbister's QT-heart rate nomogram (QT nomogram) were further analyzed using the binomial logistic regression model. RESULTS: A total of 649 patients were enrolled in the study. The independent risk factors for QTc prolongation were therapeutic and toxic range of phenotiazine antipsychotic drug (therapeutic range: odds ratio [OR], 1.56 [P=.039]; toxic range: OR, 3.85 [P<.001]), and toxic range of cyclic antidepressants (OR, 2.39; P=.018). In addition, toxic range of phenotiazine antipsychotic drug (OR, 3.87; P=.012) and tricyclic antidepressants (OR, 4.94; P<.001) were risk factors for QT higher than the at-risk line of the QT nomogram. CONCLUSIONS: The possibility of QT prolongation and torsades de pointes due to overdose of phenotiazine antipsychotic drug or tricyclic antidepressants requires particular consideration.

Risk factors for ground-level falls differ by sex.

BACKGROUND: The populations of many developed countries have been aging in recent years, resulting in increasing numbers of elderly-related injuries. Conventionally regarded as minor, injuries from ground-level falls are now associated with a higher risk of death for elderly people. METHODS: The subjects of this study were 15662 adult patients with injuries from ground-level falls who were registered in the Japan Trauma Data Bank between 2007 and 2013. Logistic regression analysis was used to evaluate the effects of age, sex, Injury Severity Score, and Revised Trauma Score (RTS) on inhospital mortality. Patients aged 60 years or older were further categorized into 4 subgroups by age and sex, and the effect of the presence of injuries of Abbreviated Injury Scale greater than or equal to 3 in each region on inhospital mortality was analyzed. RESULTS: Logistic regression analysis for inhospital mortality showed significant interactions between sex and age and between sex and RTS, and subgroup analysis by sex was, therefore, performed. The odds ratio (95% confidence interval) for inhospital mortality compared with patients older than 60 years was 2.75 (1.90-3.96) for men aged 60 to 79 years and 5.44 (3.77-7.85) for men 80 years or older and 1.46 (0.83-2.58) for women aged 60 to 79 years and 2.32 (1.35-4.01) for women 80 years or older. The odds ratios (95% confidence interval) for RTS less than 7.840 was 6.89 (5.56-8.55) for men and 9.97 (7.59-13.10) for women. CONCLUSIONS: The effects of age and RTS on inhospital mortality of patients after ground-level falls differed by sex.

Rapid simultaneous determination of eperisone, tolperisone, and tizanidine in human serum by using a MonoSpin® C18 extraction column and liquid chromatography/tandem mass spectrometry.

A method was developed for rapid toxicological analysis of eperisone, tolperisone, and tizanidine in human serum using a MonoSpin® C18 extraction column and LC/MS/MS. The method was validated for LOD, linearity, precision, and extraction recovery. This method was rapid with an LOD of 0.5 ng/mL, linearity range 1-500.0 ng/mL (r2 = 0.999), and RSD value below 14.6%. Extraction recovery from the sample was greater than 98.6, 98.8, and 88.5% for eperisone, tolperisone, and tizanidine, respectively. Results showed that combination of the MonoSpin C18 extraction column and LC/MS/MS is a simple and rapid method for the analysis of these three analytes, and a method is described for simultaneous quantitative determination of the analytes in human serum by LC/MSIMS. This method was used to determine the serum levels of eperisone in a patient with eperisone poisoning, and could be successfully applied for screening analyses in clinical cases other than poisoning.

Reduction of immunocompetent T cells followed by prolonged lymphopenia in severe sepsis in the elderly.

OBJECTIVE: To investigate the immunological changes caused by severe sepsis in elderly patients. DESIGN: One-year, prospective observational study. SETTING: Emergency department and intensive care unit of a single university hospital. PATIENTS: Seventy-three patients with severe sepsis and 72 healthy donors. MEASUREMENTS AND MAIN RESULTS: In elderly septic patients (aged 65 yr and over), 3-month survival was significantly reduced compared with that for adult patients (18-64 yr) (60% vs. 89%, p < 0.01). We found that lymphopenia was prolonged for at least 21 days in elderly nonsurvivors of sepsis, while the number of lymphocytes recovered in both adult and elderly survivors of sepsis. In order to examine the immunological status of septic patients, blood samples were collected within 48 hrs of diagnosis of severe sepsis, and peripheral blood mononuclear cells were purified for flow cytometric analysis. T cell levels were significantly reduced in both adult and elderly septic patients, compared with those in healthy donors (56% and 57% reduction, respectively). Interestingly, the immunocompetent CD28+ subset of CD4+ T cells decreased, whereas the immunosuppressive PD-1+ T cells and the percentage of regulatory T cells (CD4+ T cells that are both Foxp3+ and CD25+) increased in elderly patients, especially nonsurvivors, presumably reflecting the initial signs of immunosuppression. CONCLUSION: Reduction of immunocompetent T cells followed by prolonged lymphopenia may be associated with poor prognosis in elderly septic patients.

Early restricted oxygen therapy after resuscitation from cardiac arrest (ER-OXYTRAC): protocol for a stepped-wedge cluster randomised controlled trial.

INTRODUCTION: Cardiac arrest is a critical condition, and patients often experience postcardiac arrest syndrome (PCAS) even after the return of spontaneous circulation (ROSC). Administering a restricted amount of oxygen in the early phase after ROSC has been suggested as a potential therapy for PCAS; however, the optimal target for arterial partial pressure of oxygen or peripheral oxygen saturation (SpO2) to safely and effectively reduce oxygen remains unclear. Therefore, we aimed to validate the efficacy of restricted oxygen treatment with 94%-95% of the target SpO2 during the initial 12 hours after ROSC for patients with PCAS. METHODS AND ANALYSIS: ER-OXYTRAC (early restricted oxygen therapy after resuscitation from cardiac arrest) is a nationwide, multicentre, pragmatic, single-blind, stepped-wedge cluster randomised controlled trial targeting cases of non-traumatic cardiac arrest. This study includes adult patients with out-of-hospital or in-hospital cardiac arrest who achieved ROSC in 39 tertiary centres across Japan, with a target sample size of 1000. Patients whose circulation has returned before hospital arrival and those with cardiac arrest due to intracranial disease or intoxication are excluded. Study participants are assigned to either the restricted oxygen (titration of a fraction of inspired oxygen with 94%-95% of the target SpO2) or the control (98%-100% of the target SpO2) group based on cluster randomisation per institution. The trial intervention continues until 12 hours after ROSC. Other treatments for PCAS, including oxygen administration later than 12 hours, can be determined by the treating physicians. The primary outcome is favourable neurological function, defined as cerebral performance category 1-2 at 90 days after ROSC, to be compared using an intention-to-treat analysis. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board at Keio University School of Medicine (approval number: 20211106). Written informed consent will be obtained from all participants or their legal representatives. Results will be disseminated via publications and presentations. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry (UMIN000046914).

Timing of Intravenous Epinephrine Administration During Out-of-Hospital Cardiac Arrest.

BACKGROUND: Current guidelines for cardiopulmonary resuscitation recommend that standard dose of epinephrine be administered every 3 to 5 min during cardiac arrest. However, there is controversy about the association between timing of epinephrine administration and outcomes after out-of-hospital cardiac arrest (OHCA). This study aimed to determine whether the timing of intravenous epinephrine administration is associated with outcomes after OHCA. METHODS: We analyzed Japanese government-led nationwide population-based registry data for OHCA. Adult OHCA patients who received intravenous epinephrine by emergency medical service personnel in the prehospital setting from 2011 to 2017 were included. Multivariable logistic regression models were used to assess the associations between time to first epinephrine administration and outcomes after OHCA. Subsequently, associations between early (≤20 min) versus delayed (>20 min) epinephrine administration and outcomes after OHCA were examined using propensity score-matched analyses. The primary outcome was 1-month neurologically favorable survival. RESULTS: A total of 119,946 patients (mean [SD] age, 75.2 [14.8] years; 61.4% male) were included. The median time to epinephrine was 23 min (interquartile range, 19-29). Longer time to epinephrine was significantly associated with a decreased chance of 1-month neurologically favorable survival (multivariable adjusted OR per minute delay, 0.91 [95% CI, 0.90-0.92]). In the propensity score-matched cohort, when compared with early (≤20 min) epinephrine, delayed (>20 min) epinephrine was associated with a decreased chance of 1-month neurologically favorable survival (959/42,804 [2.2%] vs. 330/42,804 [0.8%]; RR, 0.34; 95% CI, 0.30-0.39; NNT, 69). CONCLUSIONS: Delay in epinephrine administration was associated with a decreased chance of 1-month neurologically favorable survival among patients with OHCA.

Association between time to advanced airway management and neurologically favourable survival during out-of-hospital cardiac arrest.

BACKGROUND: Advanced airway management (AAM) is commonly performed as part of advanced life support. However, there is controversy about the association between the timing of AAM and outcomes after out-of-hospital cardiac arrest (OHCA). This study aimed to determine whether time to AAM is associated with outcomes after OHCA. METHODS: This was a nationwide population-based observational study using the Japanese government-led registry of OHCA. Adults who experienced OHCA and received AAM by EMS personnel in the prehospital setting from 2014 to 2017 were included. Multivariable logistic regression models were used to assess the associations between time to AAM (defined as time in minutes from emergency call to the first successful AAM) and outcomes after OHCA. Then, associations between early (≤ 20 min) vs. delayed (> 20 min) AAM and outcomes after OHCA were examined using propensity score-matched analyses. The primary outcome was one-month neurologically favourable survival. RESULTS: A total of 164,223 patients (median [IQR] age, 80 [69-86] years; 57.7% male) were included. The median time to AAM was 17 min (IQR, 14-22). Longer time to AAM was significantly associated with a decreased chance of one-month neurologically favourable survival (multivariable adjusted OR per minute delay, 0.90 [95% CI, 0.90-0.91]). In the propensity score-matched cohort, compared with early AAM, delayed AAM was associated with a decreased chance of one-month neurologically favourable survival (516 of 50,997 [1.0%] vs. 226 of 50,997 [0.4%]; RR, 0.44; 95% CI, 0.37-0.51; NNT, 176). CONCLUSIONS: Delay in AAM was associated with a decreased chance of one-month neurologically favourable survival among patients with OHCA.

Type of advanced airway and survival after pediatric out-of-hospital cardiac arrest.

BACKGROUND: There is a knowledge gap about advanced airway management (AAM) after pediatric out-of-hospital cardiac arrest (OHCA) in the prehospital setting. We assessed which AAM strategy would be associated with an increased chance of survival after pediatric OHCA. METHODS: A nationwide population-based observational study was conducted using the Japanese government-led registry data of OHCA. Pediatric OHCA patients (aged 1-17 years) who received prehospital AAM via endotracheal intubation (ETI) or supraglottic airway (SGA) insertion by emergency medical service (EMS) personnel from 2011 to 2017 were included. Patients who received ETI were compared with those who received SGA insertion. The primary outcome was one-month survival after OHCA. RESULTS: A total of 967 patients (mean [SD] age, 12.2 [5.1] years; 66.6% male) were included; 113 received ETI, and 854 received SGA insertion. Among the total cohort, 118 (12.2%) survived one month after OHCA. In the propensity score-matched cohort, no difference was observed in one-month survival between the ETI and SGA insertion groups: 13 of 113 patients (11.5%) vs 12 of 113 patients (10.6%); RR, 1.08; 95%CI, 0.52-2.27. This lack of association between AAM strategy and survival was observed across a variety of subgroup and sensitivity analyses, and also for neurologically favorable survival (P = 0.5611) in the propensity score-matched analysis. CONCLUSIONS: In Japan, among pediatric OHCA patients, there was no significant difference in one-month survival between prehospital ETI and SGA insertion by EMS personnel. Although an adequately powered randomized controlled trial is needed, EMS personnel may choose their familiar strategy when prehospital AAM was performed during pediatric OHCA.