Termination-of-resuscitation rule in the emergency department for patients with refractory out-of-hospital cardiac arrest: a nationwide, population-based observational study.

BACKGROUND: In Japan, emergency medical service (EMS) providers are prohibited from field termination-of-resuscitation (TOR) in out-of-hospital cardiac arrest (OHCA) patients. In 2013, we developed a TOR rule for emergency department physicians (Goto's TOR rule) immediately after hospital arrival. However, this rule is subject to flaws, and there is a need for revision owing to its relatively low specificity for predicting mortality compared with other TOR rules in the emergency department. Therefore, this study aimed to develop and validate a modified Goto's TOR rule by considering prehospital EMS cardiopulmonary resuscitation (CPR) duration. METHODS: We analysed the records of 465,657 adult patients with OHCA from the All-Japan Utstein registry from 2016 to 2019 and divided them into two groups: development (n = 231,363) and validation (n = 234,294). The primary outcome measures were specificity, false-positive rate (FPR), and positive predictive value (PPV) of the revised TOR rule in the emergency department for predicting 1-month mortality. RESULTS: Recursive partitioning analysis for the development group in predicting 1-month mortality revealed that a modified Goto's TOR rule could be defined if patients with OHCA met the following four criteria: (1) initial asystole, (2) unwitnessed arrest by any laypersons, (3) EMS-CPR duration > 20 min, and (4) no prehospital return of spontaneous circulation (ROSC). The specificity, FPR, and PPV of the rule for predicting 1-month mortality were 99.2% (95% confidence interval [CI], 99.0-99.4%), 0.8% (0.6-1.0%), and 99.8% (99.8-99.9%), respectively. The proportion of patients who fulfilled the rule and the area under the receiver operating curve (AUC) was 27.5% (95% CI 27.3-27.7%) and 0.904 (0.902-0.905), respectively. In the validation group, the specificity, FPR, PPV, proportion of patients who met the rule, and AUC were 99.1% (95% CI 98.9-99.2%), 0.9% (0.8-1.1%), 99.8% (99.8-99.8%), 27.8% (27.6-28.0%), and 0.889 (0.887-0.891), respectively. CONCLUSION: The modified Goto's TOR rule (which includes the following four criteria: initial asystole, unwitnessed arrest, EMS-CPR duration > 20 min, and no prehospital ROSC) with a > 99% predictor of 1-month mortality is a reliable tool for physicians treating refractory OHCAs immediately after hospital arrival.

Dispatcher-assisted conventional cardiopulmonary resuscitation and outcomes for paediatric out-of-hospital cardiac arrests.

AIM: As asphyxial cardiac arrest is more common than cardiac arrest from a primary cardiac event in paediatric cardiac arrest, effective ventilation is important during paediatric cardiopulmonary resuscitation (CPR). We aimed to determine optimal dispatcher-assisted CPR instructions for bystanders after paediatric out-of-hospital cardiac arrest (OHCA). METHODS: We analysed the records of 8172 children who received bystander dispatcher-assisted CPR. Data were obtained from an All-Japan Utstein-style registry from 2005 to 2017. Patients were divided into conventional CPR and compression-only CPR groups. The primary study endpoint was 1-month neurologically intact survival, defined as a Cerebral Performance Category score of 1 or 2 (CPC 1-2). RESULTS: The 1-month CPC 1-2 rate was significantly higher in the dispatcher-assisted conventional CPR group than in the dispatcher-assisted compression-only CPR group (before propensity score matching, 5.7% [175/3077] vs. 3.1% [160/5095], p < 0.0001, adjusted odds ratio 2.48, 95% confidence interval 1.19-3.22; after propensity score matching, 6.0% [156/2618] vs. 2.6% [69/2618], p < 0.0001, adjusted odds ratio 2.42, 95% confidence interval 1.76-3.32). In most subgroup analyses after matching, dispatcher-assisted conventional CPR had a higher CPC 1-2 rate than dispatcher-assisted compression-only CPR; however, CPC 1-2 rates were similar between the two groups for patients with an initial shockable rhythm, those with total prehospital CPR time ≥ 20 min, those receiving public access defibrillation, advanced airway management, or adrenaline administration. CONCLUSION: Within the limitations of this retrospective observational study, dispatcher-assisted conventional CPR was preferable to dispatcher-assisted compression-only CPR as optimal CPR instructions for coaching callers to perform bystander CPR.

Association of dispatcher-assisted cardiopulmonary resuscitation with initial shockable rhythm and survival after out-of-hospital cardiac arrest.

BACKGROUND AND IMPORTANCE: Bystander cardiopulmonary resuscitation (CPR) and initial shockable rhythm are crucial predictors of survival after out-of-hospital cardiac arrest (OHCA). However, the relationship between dispatcher-assisted CPR (DA-CPR) and initial shockable rhythm is not completely elucidated. OBJECTIVE: To examine the association of DA-CPR with initial shockable rhythm and outcomes. DESIGN, SETTING AND PARTICIPANTS: This nationwide population-based observational study conducted in Japan included 59 688 patients with witnessed OHCA of cardiac origin after excluding those without bystander CPR. Patients were divided into DA-CPR (n = 42 709) and CPR without dispatcher assistance (unassisted CPR, n = 16 979) groups. OUTCOME MEASURES AND ANALYSIS: The primary outcome measure was initial shockable rhythm, and secondary outcome measures were 1-month survival and neurologically intact survival. A Cox proportional hazards model adjusted for collapse-to-first-rhythm-analysis time and multivariable logistic regression models were used after propensity score (PS) matching to compare the incidence of initial shockable rhythm and outcomes, respectively. MAIN RESULTS: Among all patients (mean age 76.7 years), the rates of initial shockable rhythm, 1-month survival and neurologically intact survival were 20.8, 10.7 and 7.0%, respectively. The incidence of initial shockable rhythm in the DA-CPR group (20.4%, 3462/16 979) was significantly higher than that in the unassisted CPR group (18.5%, 3133/16 979) after PS matching (P < 0.0001). However, no significant differences were found between the two groups with respect to the incidence of initial shockable rhythm in the Cox proportional hazards model [adjusted hazard ratio of DA-CPR for initial shockable rhythm compared with unassisted CPR, 0.99; 95% confidence interval (CI), 0.97-1.02, P = 0.56]. No significant differences were observed in the survival rates in the two groups after PS matching [10.8% (1833/16 979) vs. 10.3% (1752/16 979), P = 0.16] and neurologically intact survival rates [7.3% (1233/16 979) vs. 6.8% (1161/16 979), P = 0.13]. The multivariable logistic regression model showed no significant differences between the groups with regard to survival (adjusted odds ratio of DA-CPR compared with unassisted CPR: 1.00; 95% CI, 0.89-1.13, P = 0.97) and neurologically intact survival (adjusted odds ratio: 1.12; 95% CI, 0.98-1.29, P = 0.14). CONCLUSION: DA-CPR after OHCA had the same independent association with the likelihood of initial shockable rhythm and 1-month meaningful outcome as unassisted CPR.

Dispatcher instructions for bystander cardiopulmonary resuscitation and neurologically intact survival after bystander-witnessed out-of-hospital cardiac arrests: a nationwide, population-based observational study.

BACKGROUND: The International Liaison Committee on Resuscitation recommends that dispatchers provide instructions to perform compression-only cardiopulmonary resuscitation (CPR) to callers responding to adults with out-of-hospital cardiac arrest (OHCA). This study aimed to determine the optimal dispatcher-assisted CPR (DA-CPR) instructions for OHCA. METHODS: We analysed the records of 24,947 adult patients (aged ≥ 18 years) who received bystander DA-CPR after bystander-witnessed OHCA. Data were obtained from a prospectively recorded Japanese nationwide Utstein-style database for a 2-year period (2016-2017). Patients were divided into compression-only DA-CPR (n = 22,778) and conventional DA-CPR (with a compression-to-ventilation ratio of 30:2, n = 2169) groups. The primary outcome measure was 1-month neurological intact survival, defined as a cerebral performance category score of 1-2 (CPC 1-2). RESULTS: The 1-month CPC 1-2 rate was significantly higher in the conventional DA-CPR group than in the compression-only DA-CPR group (before propensity score (PS) matching, 7.5% [162/2169] versus 5.8% [1309/22778], p < 0.01; after PS matching, 7.5% (162/2169) versus 5.7% (123/2169), p < 0.05). Compared with compression-only DA-CPR, conventional DA-CPR was associated with increased odds of 1-month CPC 1-2 (before PS matching, adjusted odds ratio 1.39, 95% confidence interval [CI] 1.14-1.70, p < 0.01; after PS matching, adjusted odds ratio 1.34, 95% CI 1.00-1.79, p < 0.05). CONCLUSION: Within the limitations of this retrospective observational study, conventional DA-CPR with a compression-to-ventilation ratio of 30:2 was preferable to compression-only DA-CPR as an optimal DA-CPR instruction for coaching callers to perform bystander CPR for adult patients with bystander-witnessed OHCAs.

Association of subsequent treated shockable rhythm with outcomes after paediatric out-of-hospital cardiac arrests: A nationwide, population-based observational study.

AIM: Among patients with paediatric out-of-hospital cardiac arrests (OHCAs), most have an initial non-shockable rhythm with poor outcomes. There is a subset who developed shockable rhythms. This study aimed to investigate the association between subsequent shock delivery and outcomes after paediatric OHCAs. METHODS: We analysed records of 19,095 children (aged <18 years) with OHCA and initial non-shockable rhythm. Data were obtained from a Japanese nationwide database for 13 years (2005-2017). The primary outcome measure was 1-month neurologically intact survival, defined as cerebral performance category 1-2. RESULTS: Among patients with pulseless electrical activity (PEA, n = 3,326), there was no significant difference between those with subsequent treated shockable rhythm (10.0% [11/109]) and those with sustained non-shockable rhythm (6.0% [192/3,217], p = 0.10) with respect to the neurologically intact survival rate. Among asystole patients (n = 15,769), the neurologically intact survival rate was significantly higher in the subsequent treated shockable rhythm group (4.4% [10/227]) than in the sustained non-shockable rhythm group (0.7% [106/15,542], p < 0.0001). Subsequent treated shockable rhythm with a shock delivery time (time from emergency medical services [EMS]-initiated cardiopulmonary resuscitation [CPR] to shock delivery) ≤9 min was associated with increased odds of neurologically intact survival compared with sustained non-shockable rhythm (PEA, adjusted odds ratio, 2.45 [95% confidence interval, 1.16-5.16], p = 0.018; asystole, 9.77 [4.2-22.5], p < 0.0001). CONCLUSION: After paediatric OHCAs, subsequent treated shockable rhythm was associated with increased odds of 1-month neurologically intact survival regardless of whether the initial rhythm was PEA or asystole, only when the shock was delivered ≤9 min of EMS-initiated CPR.

Time boundaries of the three-phase time-sensitive model for ventricular fibrillation cardiac arrest.

AIM: Ventricular fibrillation (VF) cardiac arrest may consist of three time-sensitive phases: electrical, circulatory, and metabolic. However, the time boundaries of these phases are unclear. We aimed to determine the time boundaries of the three-phase model for VF cardiac arrest. METHODS: We reviewed 20,741 out-of-hospital cardiac arrest cases with initial VF and presumed cardiac origin from the All-Japan Utstein-style registry between 2013 and 2017. The study endpoint was 1-month neurologically intact survival. The collapse-to-shock interval was defined as the time from collapse to the first shock delivery by emergency medical service personnel. The patients were divided into the bystander cardiopulmonary resuscitation (CPR, n = 11,606) and non-bystander CPR (n = 9135) groups. RESULTS: In the bystander CPR group, the collapse-to-shock times that were associated with increased adjusted 1-month neurologically intact survival, compared with those in the non-bystander CPR group, ranged from 7 min (42.9% [244/4999] vs. 26.0% [119/458], adjusted odds ratio [aOR], 1.95; 95% confidence interval [CI], 1.44-2.63; P < 0.0001) to 17 min (17.1% [70/410] vs. 7.3% [21/288], aOR, 2.82; 95% CI, 1.62-4.91; P = 0.0002). However, the neurologically intact survival rate of the bystander CPR group was statistically insignificant compared with that of the non-bystander CPR group when the collapse-to-shock time was outside this range. CONCLUSIONS: The time boundaries of the three-phase time-sensitive model for VF cardiac arrest may be defined as follows: electrical phase, from collapse to <7 min; circulatory phase, from 7 to 17 min; and metabolic phase, from >17 min onward.

Temporal trends in neurologically intact survival after paediatric bystander-witnessed out-of-hospital cardiac arrest: A nationwide population-based observational study.

AIM: Trends in neurologically intact survival after paediatric out-of-hospital cardiac arrest (OHCA) remain unclear. In the present study, we aimed to determine trends in 1-month neurologically intact survival after paediatric OHCA over time. METHODS: We reviewed the data of 5461 children (aged < 18 years) who experienced bystander-witnessed OHCA and were included in the nationwide Japanese registry from 2005 to 2017. Patients were divided into three groups according to study period: 2005-2010, 2011-2015, and 2016-2017. We analysed the trends in 1-month neurologically intact survival rates over time. RESULTS: The risk-adjusted odds of 1-month neurologically intact survival (odds ratio, 1.86; 95% confidence interval, 1.41-2.44) were significantly improved by 2016-2017 compared with baseline. Similar improvements in 1-month neurologically intact survival rates were observed with both standard bystander cardiopulmonary resuscitation (CPR) with rescue breaths and chest compression-only bystander CPR (P for trend < 0.05 and < 0.001, respectively). In the subgroup analyses by aetiology, the 1-month neurologically intact survival rate in patients with OHCA of non-traumatic origin significantly increased from 11.8%-15.1% to 19.7% (P for trend < 0.001) but not in those with OHCA of traumatic origin (from 4.9% to 3.4% to 4.1%; P for trend = 0.29). CONCLUSION: The 1-month neurologically intact survival rate significantly increased from 2005 to 2017 in Japanese children with bystander-witnessed OHCA, regardless of bystander CPR type; This increase was noted in patients with OHCA of non-traumatic origin but not in those with OHCA of traumatic origin.

A Risk Prediction Flowchart of Vancomycin-Induced Acute Kidney Injury to Use When Starting Vancomycin Administration: A Multicenter Retrospective Study.

We previously constructed a risk prediction model of vancomycin (VCM)-associated nephrotoxicity for use when performing initial therapeutic drug monitoring (TDM), using decision tree analysis. However, we could not build a model to be used at the time of initial administration due to insufficient sample size. Therefore, we performed a multicenter study at four hospitals in Japan. We investigated patients who received VCM intravenously at a standard dose from the first day until the initial TDM from November 2011 to March 2019. Acute kidney injury (AKI) was defined according to the criteria established by the "Kidney disease: Improving global outcomes" group. We extracted potential risk factors that could be evaluated on the day of initial administration and constructed a flowchart using a chi-squared automatic interaction detection algorithm. Among 843 patients, 115 (13.6%) developed AKI. The flowchart comprised three splitting variables (concomitant drugs (vasopressor drugs and tazobactam/piperacillin) and body mass index ≥ 30) and four subgroups. The incidence rates of AKI ranged from 9.34 to 36.8%, and they were classified as low-, intermediate-, and high-risk groups. The accuracy of flowchart was judged appropriate (86.4%). We successfully constructed a simple flowchart predicting VCM-induced AKI to be used when starting VCM administration.

Postmortem computed tomography of gas gangrene with aortic gas in a dialysis patient.

Recently, postmortem imaging is sometimes used as an alternative to conventional autopsy. However, there are few case reports of postmortem imaging of dialysis patients. Here, we report a fatal case of gas gangrene involving a 76-year-old man who underwent dialysis. He died suddenly before a diagnosis could be established. Immediately after his death, postmortem computed tomography (PMCT) revealed gas accumulation in his right upper extremity and ascending aorta. Gas gangrene progresses rapidly and may sometimes result in sudden death before it is diagnosed. In this case, PMCT findings were useful to diagnose gas gangrene. Intravascular gas is a common finding on PMCT and is generally caused by cardiopulmonary resuscitation and decomposition. However, the detection of gas in the ascending aorta by PMCT was not described previously. Moreover, Gram stain and culture of the exudate showed anaerobic Gram-positive bacilli which suggested that the gas generation in the blood was caused by Clostridia species. To the best our knowledge, this is the first report of a dialysis patient whose cause of death was determined as gas gangrene using PMCT.

Hemodialysis as a Risk Factor for Ceftriaxone-Associated Pseudolithiasis in Adults.

Ceftriaxone-associated biliary pseudolithiasis is common among children; however, there are only a few reports of pseudolithiasis in adult patients on HD. This retrospective cohort study included 278 adult patients on ceftriaxone therapy from 1 February 2016 to 1 September 2018. Pseudolithiasis was defined as a new development of sludge or stones in the gallbladder within 60 days of ceftriaxone therapy. After excluding patients with preexisting gallstones and a history of cholecystectomy, 113 patients on maintenance HD, and another 98 patients were enrolled as the HD and control group, respectively. Thirteen patients developed pseudolithiasis. Its incidence was significantly higher in the HD group than that in the control group. Multivariate logistic regression analyses showed that development of pseudolithiasis was significantly associated with HD and ceftriaxone dose. Therefore, HD in patients receiving ceftriaxone therapy appears to be associated with a risk of pseudolithiasis. These findings highlight the need for careful follow-up.

Sex-specific differences in survival after out-of-hospital cardiac arrest: a nationwide, population-based observational study.

BACKGROUND: It remains unclear whether men have more favorable survival outcomes after out-of-hospital cardiac arrest (OHCA) than women. METHODS: We reviewed a total of 386,535 patients aged ≥ 18 years with OHCA who were included in the Japanese registry from 2013 to 2016. The study endpoints were the rates of 1-month survival and neurologically intact survival (Cerebral Performance Category Scale score = 1 or 2). Based on age, the reviewed patients were categorized into the following eight groups: < 30, 30-39, 40-49, 50-59, 60-69, 70-79, 80-89, and ≥ 90 years. The survival outcomes in men and women were compared using hierarchical propensity score matching. RESULTS: The crude survival rate was significantly higher in men than in women in five groups: 30-39, 40-49, 50-59, 60-69, and 70-79 years (all P < 0.001). Similarly, the crude neurologically intact survival rate was significantly higher in men than in women in seven groups: < 30, 30-39, 40-49, 50-59, 60-69, 70-79, and 80-89 years (all P < 0.005). However, multivariate logistic regression analysis of each group revealed no significant sex-specific differences in 1-month survival outcomes (all P > 0.02). Moreover, after hierarchical propensity score matching, the survival outcomes did not significantly differ between both sexes (all P > 0.05). CONCLUSIONS: No significant sex-specific differences were found in the rates of 1-month survival and neurologically intact survival after OHCA.

Impact of prehospital physician-led cardiopulmonary resuscitation on neurologically intact survival after out-of-hospital cardiac arrest: A nationwide population-based observational study.

AIM: The impact of prehospital physician care for out-of-hospital cardiac arrest (OHCA) on long-term neurological outcome is unclear. We aimed to determine the association between emergency medical services (EMS) physician-led cardiopulmonary resuscitation (CPR) versus paramedic-led CPR and neurologically intact survival after OHCA. METHODS: We assessed 613,251 patients using All-Japan Utstein Registry data from 2011 to 2015 retrospectively. The main outcome measure was 1-month neurologically intact survival after OHCA, defined as Cerebral Performance Category 1 or 2 (CPC 1-2). RESULTS: Before propensity score matching, the 1-month CPC 1-2 rate was significantly higher in EMS physician-led CPR than in paramedic-led CPR [5.7% (1114/19,551) vs. 2.5% (14,859/593,700), P < 0.001; adjusted odds ratio (aOR), 1.50; 95% confidence interval (CI), 1.40-1.61]. After propensity score matching, EMS physician-led CPR showed more favourable neurological outcomes than paramedic-led CPR [6.0% (996/16,612) vs. 4.6% (766/16,612), P < 0.001; aOR, 1.44; 95% CI, 1.29-1.60]. In most subgroup analyses after matching, physician-led CPR had higher 1-month CPC 1-2 rates than paramedic-led CPR did; however, 1-month CPC 1-2 rates were similar between the two CPR configurations for patients aged <18 years (5.6% vs. 8.2%, P = 0.10; aOR, 0.82; 95% CI, 0.46-1.47) and those who received bystander defibrillation (26.3% vs. 21.5%; P = 0.10; aOR, 1.07; 95% CI, 0.74-1.53). CONCLUSION: Within the limitations of this retrospective observational research, EMS physician-led CPR for OHCA was associated with improved 1-month neurologically intact survival compared with paramedic-led CPR. However, neurologically intact survival was similar for patients aged <18 years and those receiving bystander defibrillation.

Hepcidin-25/erythroferrone ratio predicts improvement of anaemia in haemodialysis patients treated with ferric citrate hydrate.

BACKGROUND/AIMS: Hepcidin-25 (HEP-25) and erythroferrone (ERFE) are key regulators of iron homeostasis. Correlations among serum ferritin, ERFE and HEP-25 levels and improvements in anaemia have not been evaluated after administration of ferric citrate hydrate (FCH). METHODS: This retrospective observational study investigated 24 patients on haemodialysis with both anaemia (haemoglobin (Hb) < 12 g/dL) and hyperphosphatemia (inorganic phosphorus ≥6 mg/dL). The patients who were administered FCH (1500 mg/day) for 12 consecutive weeks and 12 control patients who were administered a phosphate binder other than FCH were included. Correlations among Hb, HEP-25 and ERFE levels were studied. We then stratified the FCH group into two subgroups using the median baseline values of ferritin, HEP-25, ERFE and HEP-25/ERFE ratio to predict whether these markers could serve as prognostic indicators in the treatment of anaemia. RESULTS: In the FCH group, Hb, transferrin saturation, ferritin, HEP-25 and ERFE levels were all significantly increased, while inorganic phosphorus levels, dosage of erythropoietin-stimulating agent, and erythropoietin resistance index were all significantly decreased after drug administration. A significant inverse correlation was apparent between Hb and HEP-25 levels, and a significant positive correlation was seen between Hb and ERFE levels. A significant inverse correlation was found between HEP-25 and serum ERFE levels. Compared with the high HEP-25/ERFE ratio group, only the low HEP-25/ERFE ratio group exhibited significantly increased Hb levels at 12 weeks. CONCLUSION: HEP-25/ERFE ratio could be a novel prognostic marker for increases in Hb levels following FCH administration.

Field termination-of-resuscitation rule for refractory out-of-hospital cardiac arrests in Japan.

BACKGROUND: Guidelines for cardiopulmonary resuscitation (CPR) recommend using the universal termination-of-resuscitation (TOR) rule to identify out-of-hospital cardiac arrest (OHCA) patients eligible for field termination of resuscitation, thus avoiding medically futile transportation to the hospital. However, in Japan, emergency medical services (EMS) personnel are forbidden from terminating CPR in the field and transport almost all patients with OHCA to hospitals. We aimed to develop and validate a novel TOR rule to identify patients eligible for field termination of CPR. METHODS: We analyzed 540,478 patients with OHCA from 2011 to 2015 using a Japanese registry. Main outcome measures were specificity and positive predictive value (PPV) of the newly developed TOR rule in predicting 1-month mortality after OHCA. RESULTS: Recursive partitioning analysis in the development group (n=434,208) showed that EMS personnel could consider TOR if patients with OHCA met all of the following five criteria: (1) initial asystole, (2) arrest unwitnessed by a bystander, (3) age ≥81 years, (4) no bystander-administered CPR or automated external defibrillator use before EMS arrival, and (5) no return of spontaneous circulation after EMS-initiated CPR for 14min. For patients meeting these criteria, specificity and PPV for predicting 1-month mortality were 99.2% [95% confidence interval (CI), 99.0-99.3%] and 99.7% (95% CI, 99.6-99.7%), respectively, for the development group and were 99.5% (95% CI, 99.3-99.7%) and 99.8% (95% CI, 99.7-99.9%), respectively, for the validation group. Implementation of this novel rule would reduce patient transports to hospitals by 10.6% in the development group and 10.4% in the validation group. CONCLUSIONS: Having both high specificity and PPV of >99% for predicting 1-month mortality, our developed TOR rule may be applied in the field for Japanese patients with OHCA who meet all five criteria. Prospective validation studies and establishment of prehospital EMS protocol are required before implementing this rule.

Linagliptin inhibits lipopolysaccharide-induced inflammation in human U937 monocytes.

BACKGROUND: Atherosclerosis and inflammation are more common in patients with diabetes than in patients without diabetes, and atherosclerosis progression contributes to inflammation. Therefore, anti-inflammatory therapy is important for the prognosis of patients with diabetes. Linagliptin is the only bile-excreted, anti-diabetic oral dipeptidyl peptidase-4 (DPP-4) inhibitor. Although the anti-inflammatory effects of DPP-4 inhibitors in vivo and in vitro have been reported, few in vitro studies have examined the effects of linagliptin using monocytes, which play a central role in arteriosclerosis-related inflammation. Herein, we assessed the anti-inflammatory effects of linagliptin in human U937 monocytes. METHODS: U937 cells at densities of 1 × 106 cells/mL were cultured in Roswell Park Memorial Institute medium supplied with 10% fetal bovine serum and treated with 100 nM phorbol myristate acetate for 48 h for differentiation into macrophages. The media were replaced, and the cells were pretreated with 1, 5, 10, 50, and 100 nM linagliptin for 1 h or were left untreated. The media were then replaced again, and the cells were treated with 1 µg/mL lipopolysaccharide (LPS) or 10 nM interleukin (IL)-1ß only, in combination with 1, 5, 10, 50, and 100 nM linagliptin or were left untreated. The extracted media were used to measure IL-6 and tumor necrosis factor (TNF)-α levels using enzyme-linked immunosorbent assay kits. RESULTS: LPS alone significantly increased IL-6 and TNF-α production compared with the control treatment. The treatment of cells with linagliptin at all concentrations significantly inhibited the LPS-stimulated IL-6 and TNF-α production. Meanwhile, IL-1ß alone significantly increased IL-6 production compared with the control treatment. No significant difference in IL-6 production was noted between the cells treated with IL-1ß and simultaneous treatment with IL-1ß and linagliptin. CONCLUSIONS: Linagliptin inhibited LPS-induced inflammation in human monocytic U937 cells.

Effects of prehospital epinephrine administration on neurologically intact survival in bystander-witnessed out-of-hospital cardiac arrest patients with non-shockable rhythm depend on prehospital cardiopulmonary resuscitation duration required to hospital arrival.

The effects of prehospital epinephrine administration on post-arrest neurological outcome in out-of-hospital cardiac arrest (OHCA) patients with non-shockable rhythm remain unclear. To examine the time-dependent effectiveness of prehospital epinephrine administration, we analyzed 118,396 bystander-witnessed OHCA patients with non-shockable rhythm from the prospectively recorded all-Japan OHCA registry between 2011 and 2014. Patients who achieved prehospital return of spontaneous circulation without prehospital epinephrine administration were excluded. Patients with prehospital epinephrine administration were stratified according to the time from the initiation of cardiopulmonary resuscitation (CPR) by emergency medical service (EMS) providers to the first epinephrine administration (≤ 10, 11-19, and ≥ 20 min). Patients without prehospital epinephrine administration were stratified according to the time from CPR initiation by EMS providers to hospital arrival (≤ 10, 11-19, and ≥ 20 min). The primary outcome was 1-month neurologically intact survival (cerebral performance category 1 or 2; CPC 1-2). Multivariate logistic regression analysis demonstrated that there was no significant difference in the chance of 1-month CPC 1-2 between patients who arrived at hospital in ≤ 10 min without prehospital epinephrine administration and patients with time to epinephrine administration ≤ 19 min. However, compared to patients who arrived at hospital in ≤ 10 min without prehospital epinephrine administration, patients with time to epinephrine administration ≥ 20 min and patients who arrived at hospital in 11-19, and ≥ 20 min without prehospital epinephrine administration were significantly associated with decreased chance of 1-month CPC 1-2 (p < 0.05, < 0.05, and < 0.001, respectively). In conclusion, when prehospital CPR duration from CPR initiation by EMS providers to hospital arrival estimated to be ≥ 11 min, prehospital epinephrine administered ≤ 19 min from CPR initiation by EMS providers could improve neurologically intact survival in bystander-witnessed OHCA patients with non-shockable rhythm.

Relationship Between Emergency Medical Services Response Time and Bystander Intervention in Patients With Out-of-Hospital Cardiac Arrest.

BACKGROUND: The response time of emergency medical services (EMS) is an important determinant of survival after out-of-hospital cardiac arrest. We sought to identify upper limits of EMS response times and bystander interventions associated with neurologically intact survival. METHODS AND RESULTS: We analyzed the records of 553 426 patients with out-of-hospital cardiac arrest in a Japanese registry between 2010 and 2014. The primary study end point was 1-month neurologically intact survival (Cerebral Performance Category scale 1 or 2). Increased EMS response time was associated with significantly decreased adjusted odds of 1-month neurologically intact survival (adjusted odds ratio [aOR] for each 1-minute increase, 0.89; 95% confidence interval [CI], 0.89-0.90), although this relationship was modified by bystander interventions. The bystander interventions and the ranges of EMS response times that were associated with increased adjusted 1-month neurologically intact survival were as follows: bystander defibrillation, from ≤2 minutes (aOR, 3.10 [95% CI, 1.25-7.31]) to 13 minutes (aOR, 5.55 [95% CI, 2.66-11.2]); bystander conventional cardiopulmonary resuscitation, from 3 minutes (aOR 1.48 [95% CI, 1.02-2.12]) to 11 minutes (aOR 2.41 [95% CI, 1.61-3.56]); and bystander chest-compression-only cardiopulmonary resuscitation, from ≤2 minutes (aOR 1.57 [95% CI, 1.01-2.25]) to 11 minutes (aOR 1.92 [95% CI, 1.45-2.56]). However, the increase in neurologically intact survival of those receiving bystander interventions became statistically insignificant compared with no bystander interventions when the EMS response time was outside these ranges. CONCLUSIONS: The upper limits of the EMS response times associated with improved 1-month neurologically intact survival were 13 minutes when bystanders provided defibrillation (typically with cardiopulmonary resuscitation) and 11 minutes when bystanders provided cardiopulmonary resuscitation without defibrillation.