Rapidly progressive cognitive impairment resulting in heavy psychosocial burden in a patient with Fabry disease undergoing hemodialysis: a case report.

BACKGROUND: Long-term enzyme replacement therapy (ERT) may improve prognosis in the patients with Fabry disease (FD), however, detail psychosocial burden has not been focused on long life expectancy. We experienced a male case of FD under ERT, he was placed on hemodialysis and presented rapidly progressive cognitive function. CASE PRESENTATION: A 51-year-old male patient with FD has been receiving ERT from age of 38 years. Hemodialysis was initiated at the age of 47 years. The patient experienced several attacks of cerebral infarction, and brain images demonstrated wide-spread asymptomatic ischemic lesions. His behavior became problematic at the age of 51 years. He often exhibited restlessness during hemodialysis sessions and failure to communicate effectively. The patient experienced impairment of attention and executive function, topographical disorientation, and amnesia. Consequently, it was necessary for medical staff and family members to monitor his behavior for safe extracorporeal circulation and daily life activities. Annual standardized neuropsychiatric testing revealed worsening of cognitive performance. CONCLUSIONS: Despite treating with long-term ERT, it is necessary to determine the psychosocial burden derived from the progression of cognitive impairment in patients with FD undergoing hemodialysis.

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 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.

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.

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.

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.

Duration of Prehospital Cardiopulmonary Resuscitation and Favorable Neurological Outcomes for Pediatric Out-of-Hospital Cardiac Arrests: A Nationwide, Population-Based Cohort Study.

BACKGROUND: The appropriate duration of cardiopulmonary resuscitation (CPR) for pediatric out-of-hospital cardiac arrests (OHCAs) remains unclear and may differ based on initial rhythm. We aimed to determine the relationship between the duration of prehospital CPR by emergency medical services (EMS) personnel and post-OHCA outcomes. METHODS: We analyzed the records of 12 877 pediatric patients who experienced OHCAs (<18 years of age). Data were recorded in a nationwide Japanese database between 2005 and 2012. Study end points were 30-day survival and 30-day survival with favorable neurological outcomes (Cerebral Performance Category [CPC] scale 1-2). Prehospital EMS-initiated CPR duration was defined as the time from CPR initiation by EMS personnel to prehospital return of spontaneous circulation (ROSC) or to hospital arrival when prehospital ROSC was not achieved during prehospital CPR efforts. RESULTS: The rates of 30-day survival and 30-day CPC 1 to 2 were 9.1% (n=1167) and 2.5% (n=325), respectively. Prehospital EMS-initiated CPR duration was significantly and inversely associated with 30-day outcomes (adjusted odds ratio for 1-minute increments: 0.94, 95% confidence interval: 0.93-0.95 for survival; adjusted odds ratio: 0.90, 95% confidence interval: 0.88-0.92 for CPC 1-2). The duration of prehospital EMS-initiated CPR, beyond which the chance for favorable outcomes diminished to <1%, was 42 minutes for each key outcome, 30-day survival, and 30-day survival with CPC 1 to 2. When categorized by initial rhythm, the prehospital EMS-initiated CPR durations beyond which the chance for 30-day survival with CPC 1 to 2 diminished to <1% were 39 minutes for shockable rhythms, 42 minutes for pulseless electric activity, and 46 minutes for asystole, respectively. In patients with bystander-initiated CPR, the prehospital CPR duration, beyond which the chance for favorable outcome diminished to <1%, was 46 minutes from call receipt. CONCLUSIONS: Prehospital EMS-initiated CPR duration for pediatric OHCAs was independently and inversely associated with 30-day favorable outcomes. The duration of prehospital EMS-initiated CPR, beyond which the chance for 30-day favorable outcomes diminished to <1%, was 42 minutes. However, the CPR duration to achieve this proportion of outcomes differed based on initial rhythm. Further research is required to elucidate appropriate CPR duration for pediatric OHCAs, including in-hospital CPR time. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02432196.

Age-Specific Differences in the Duration of Prehospital Cardiopulmonary Resuscitation Administered by Emergency Medical Service Providers Necessary to Achieve Favorable Neurological Outcome After Out-of-Hospital Cardiac Arrest.

BACKGROUND: The appropriate duration of prehospital cardiopulmonary resuscitation (CPR)administered by emergency medical service (EMS) providers for patients with out-of-hospital cardiac arrest (OHCA) necessary to achieve 1-month survival with favorable neurological outcome (Cerebral Performance Category 1 or 2, CPC 1-2) is unclear and could differ by age.Methods and Results:We analyzed the records of 35,709 adult OHCA patients with return of spontaneous circulation (ROSC) before hospital arrival in a prospectively recorded Japanese registry between 2011 and 2014. The CPR duration was defined as the time from CPR initiation by EMS providers to prehospital ROSC. The rate of 1-month CPC 1-2 was 21.4% (7,650/35,709). The CPR duration was independently and inversely associated with 1-month CPC 1-2 (adjusted odds ratio, 0.93 per 1-min increment; 95% confidence interval, 0.93-0.94). The CPR duration increased with age (P<0.001). However, the CPR duration beyond which the proportion of OHCA patients with 1-month CPC 1-2 decreased to <1% declined with age: 28 min for patients aged 18-64 years, 25 min for 65-74 years, 23 min for 75-84 years, 20 min for 85-94 years, and 18 min for ≥95 years. CONCLUSIONS: In patients who achieved prehospital ROSC after OHCA, the duration of CPR administered by EMS providers necessary to achieve 1-month CPC 1-2 varied by age.

Vitamin E-Coated Dialyzer Inhibits Oxidative Stress.

AIM: To examine the effects of vitamin E-coated dialyzer on oxidative stress in vitro. METHODS: A dialyzer with a synthetic polymer membrane (APS-11SA) and vitamin E-coated dialyzer (VPS-11SA) were connected to a blood tubing line, and U937 cells were circulated in the device. The circulating fluid was collected at 1, 2, 5, 10, 25, and 50 cycles, which are estimated numbers of passes through the dialyzer. Intracellular reactive oxygen species (ROS) production, malondialdehyde (MDA), and Cu/Zn-superoxide dismutase (SOD) were quantified. RESULTS: Intracellular ROS production was increased in the first cycle by APS-11SA and was decreased throughout the experiment by VPS-11SA. Intracellular ROS production in the VPS-11SA device was lower, and MDA levels were decreased. MDA levels were lower during VPS-11SA processing than during APS-11SA processing. Cu/Zn-SOD levels remained unchanged. CONCLUSION: Our results highlight anti-oxidative-stress effects of a vitamin E-coated dialyzer.

Structural optimization and structure-functional selectivity relationship studies of G protein-biased EP2 receptor agonists.

The modification of the novel G protein-biased EP2 agonist 1 has been investigated to improve its G protein activity and develop a better understanding of its structure-functional selectivity relationship (SFSR). The optimization of the substituents on the phenyl ring of 1, followed by the inversion of the hydroxyl group on the cyclopentane moiety led to compound 9, which showed a 100-fold increase in its G protein activity compared with 1 without any increase in ß-arrestin recruitment. Furthermore, SFSR studies revealed that the combination of meta and para substituents on the phenyl moiety was crucial to the functional selectivity.

Improved Survival With Favorable Neurological Outcome in Elderly Individuals With Out-of-Hospital Cardiac Arrest in Japan　- A Nationwide Observational Cohort Study.

BACKGROUND: There is sparse data regarding the survival and neurological outcome of elderly patients with out-of-hospital cardiac arrest (OHCA). METHODS AND RESULTS: OHCA patients (334,730) aged ≥75 years were analyzed using a nationwide, prospective, population-based Japanese OHCA database from 2008 to 2012. The overall 1-month survival with favorable neurological outcome (Cerebral Performance Category Scale, category 1 or 2; CPC 1-2) rate was 0.88%. During the study period, the annual 1-month CPC 1-2 rate in whole OHCA significantly improved (0.73% to 0.96%, P for trend <0.001). In particular, outcomes of OHCA patients aged 75 to 84 years and those aged 85 to 94 years significantly improved (0.98% to 1.28%, P for trend=0.01; 0.46% to 0.70%, P for trend <0.001, respectively). However, in OHCA patients aged ≥95 years, the outcomes did not improve. Multivariate logistic regression analysis indicated that younger age, shockable first documented rhythm, witnessed arrest, earlier emergency medical service (EMS) response time, and cardiac etiology were significantly associated with the 1-month CPC 1-2. Under these conditions, elderly OHCA patients who had cardiac etiology, shockable rhythm and had a witnessed arrest had acceptable 1-month CPC1-2 rate; 7.98% in cases where OHCA was witnessed by family, 15.2% by non-family, and 25.6% by EMS. CONCLUSIONS: The annual 1-month CPC 1-2 rate after OHCA among elderly patients significantly improved, and the resuscitation of elderly patients in a selected population is not futile. (Circ J 2016; 80: 1153-1162).

Macroscopic Evidence for the Hibernating Behavior of Materials Stock.

Hibernating stock is defined as material stock that is no longer used, but is not yet recovered. Although hibernating stock plays a role in materials recoverability, its contribution to the overall material cycle is not clearly understood. Therefore, an analysis of the time-series potential generation of steel scrap in Japan was performed and compared against the actual recovery, proving that the steel scrap recovered each year exceeds the annual generation potential and providing the first macroscopic evidence of hibernating stock recovery. These results indicate that hibernation behavior should be considered when evaluating materials recoverability. The particular characteristics of hibernating stock were also identified. These materials tend to be located far from scrap yards and/or have low bulk density, while also minimally obstructing new activity. In fact, hibernating materials are typically only recovered when they obstruct new activity. Hence, in order to increase steel recoverability, the recovery cost must be reduced. The end-of-life recycling rates (EoL-RRs) were also evaluated, and were found to exhibit a significant change over time. Consequently, the annual EoL-RR cannot be considered as a representative value, and a value for the EoL-RR(s) of relevant year(s) that has been evaluated over the entire period should be used instead.

Neurological outcomes in children dead on hospital arrival.

INTRODUCTION: Obtaining favorable neurological outcomes is extremely difficult in children transported to a hospital without a prehospital return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA). However, the crucial prehospital factors affecting outcomes in this cohort remain unclear. We aimed to determine the prehospital factors for survival with favorable neurological outcomes (Cerebral Performance Category 1 or 2 (CPC 1-2)) in children without a prehospital ROSC after OHCA. METHODS: Of 9093 OHCA children, 7332 children (age <18 years) without a prehospital ROSC after attempting resuscitation were eligible for enrollment. Data were obtained from a prospectively recorded Japanese national Utstein-style database from 2008 to 2012. The primary endpoint was 1-month CPC 1-2 after OHCA. RESULTS: The 1-month survival and 1-month CPC 1-2 rates were 6.92 % (n = 508) and 0.99 % (n = 73), respectively. The proportions of the following prehospital variables were significantly higher in the 1-month CPC 1-2 cohort than in the 1-month CPC 3-5 cohort: age (median, 3 years (interquartile range (IQR), 0-14) versus 1 year (IQR, 0-11), p <0.05), bystander-witnessed arrest (52/73 (71.2 %) versus 1830/7259 (25.2 %), p <0.001), initial ventricular fibrillation (VF)/pulseless ventricular tachycardia (VT) rhythm (28/73 (38.3 %) versus 241/7259 (3.3 %), p <0.001), presumed cardiac causes (42/73 (57.5 %) versus 2385/7259 (32.8 %), p <0.001), and actual shock delivery (25/73 (34.2 %) versus 314/7259 (4.3 %), p <0.0001). Multivariate logistic regression analysis indicated that 2 prehospital factors were associated with 1-month CPC 1-2: initial non-asystole rhythm (VF/pulseless VT: adjusted odds ratio ( aOR), 16.0; 95 % confidence interval (CI), 8.05-32.0; pulseless electrical activity (PEA): aOR, 5.19; 95 % CI, 2.77-9.82) and bystander-witnessed arrest (aOR, 3.22; 95 % CI, 1.84-5.79). The rate of 1-month CPC 1-2 in witnessed-arrest children with an initial VF/pulseless VT was significantly higher than that in those with other initial cardiac rhythms (15.6 % versus 2.3 % for PEA and 1.2 % for asystole, p for trend <0.001). CONCLUSIONS: The crucial prehospital factors for 1-month survival with favorable neurological outcomes after OHCA were initial non-asystole rhythm and bystander-witnessed arrest in children transported to hospitals without a prehospital ROSC.

Prognostic implications of conversion from nonshockable to shockable rhythms in out-of-hospital cardiac arrest.

INTRODUCTION: The prognostic significance of conversion from nonshockable to shockable rhythms in patients with initial nonshockable rhythms who experience out-of-hospital cardiac arrest (OHCA) remains unclear. We hypothesized that the neurological outcomes in those patients would improve with subsequent shock delivery following conversion to shockable rhythms and that the time from initiation of cardiopulmonary resuscitation by emergency medical services personnel to the first defibrillation (shock delivery time) would influence those outcomes. METHODS: We analyzed the data of 569,937 OHCA adults with initial nonshockable rhythms. The data were collected in a nationwide Utstein-style Japanese database between 2005 and 2010. Patients were divided into subsequently shocked (n =21,944) and subsequently not-shocked (n =547,993) cohorts. The primary study endpoint was 1-month favorable neurological outcome (Cerebral Performance Categories scale, category 1 or 2). RESULTS: In the subsequently shocked cohort, the ratio of 1-month favorable neurological outcome was significantly higher than that in the subsequently not-shocked cohort (1.79% versus 0.60%, P <0.001). Multivariate logistic regression analysis for 11 prehospital variables revealed that when the shock delivery time was less than 20 minutes, subsequent shock delivery was significantly associated with increased odds of 1-month favorable neurological outcomes (adjusted odds ratios (95% confidence interval), 6.55 (5.21 to 8.22) and 2.97 (2.58 to 3.43) for shock delivery times less than 10 minutes and from 10 to 19 minutes, respectively). However, when the shock delivery time was more than or equal to 20 minutes, subsequent shock delivery was not associated with increased odds of 1-month favorable neurological outcomes. CONCLUSIONS: In patients with an initial nonshockable rhythm after OHCA, subsequent conversion to shockable rhythms during emergency medical services resuscitation efforts was associated with increased odds of 1-month favorable neurological outcomes when the shock delivery time was less than 20 minutes.

Decision tree model for predicting long-term outcomes in children with out-of-hospital cardiac arrest: a nationwide, population-based observational study.

INTRODUCTION: At hospital arrival, early prognostication for children after out-of-hospital cardiac arrest (OHCA) might help clinicians formulate strategies, particularly in the emergency department. In this study, we aimed to develop a simple and generally applicable bedside tool for predicting outcomes in children after cardiac arrest. METHODS: We analyzed data of 5,379 children who had undergone OHCA. The data were extracted from a prospectively recorded, nationwide, Utstein-style Japanese database. The primary endpoint was survival with favorable neurological outcome (Cerebral Performance Category (CPC) scale categories 1 and 2) at 1 month after OHCA. We developed a decision tree prediction model by using data from a 2-year period (2008 to 2009, n = 3,693), and the data were validated using external data from 2010 (n = 1,686). RESULTS: Recursive partitioning analysis for 11 predictors in the development cohort indicated that the best single predictor for CPC 1 and 2 at 1 month was the prehospital return of spontaneous circulation (ROSC). The next predictor for children with prehospital ROSC was an initial shockable rhythm. For children without prehospital ROSC, the next best predictor was a witnessed arrest. Use of a simple decision tree prediction model permitted stratification into four outcome prediction groups: good (prehospital ROSC and initial shockable rhythm), moderately good (prehospital ROSC and initial nonshockable rhythm), poor (prehospital non-ROSC and witnessed arrest) and very poor (prehospital non-ROSC and unwitnessed arrest). By using this model, we identified patient groups ranging from 0.2% to 66.2% for 1-month CPC 1 and 2 probabilities. The validated decision tree prediction model demonstrated a sensitivity of 69.7% (95% confidence interval (CI) = 58.7% to 78.9%), a specificity of 95.2% (95% CI = 94.1% to 96.2%) and an area under the receiver operating characteristic curve of 0.88 (95% CI = 0.87 to 0.90) for predicting 1-month CPC 1 and 2. CONCLUSIONS: With our decision tree prediction model using three prehospital variables (prehospital ROSC, initial shockable rhythm and witnessed arrest), children can be readily stratified into four groups after OHCA. This simple prediction model for evaluating children after OHCA may provide clinicians with a practical bedside tool for counseling families and making management decisions soon after patient arrival at the hospital.

Subanalgesic ketamine enhances morphine-induced antinociceptive activity without cortical dysfunction in rats.

PURPOSE: Ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, has been used for the treatment of cancer pain as an analgesic adjuvant to opioids. However, ketamine is known to produce psychotomimetic side effects including cognitive impairments under a high-dose situation, presumably as the result of cortical dysfunction. Here, we investigated whether low-dose ketamine was useful as an analgesic adjuvant to morphine for pain control, focusing on frontocortical function. METHODS: To assess the analgesic effects of ketamine with or without morphine, we performed behavioral and histochemical experiments, using the hot plate test and c-Fos expression analysis in rats. The effect on cortical function was also determined by prepulse inhibition (PPI) of the acoustic startle and evoked potentials in the hippocampal CA1-medial prefrontal cortex (mPFC) synapses as measures of synaptic efficacy. RESULTS: Coadministration of ketamine as a subanalgesic dose significantly enhanced intraperitoneal morphine-induced antinociceptive response, which was measured as the increased reaction latency in the hot plate test. In addition, the noxious thermal stimulus-induced c-Fos expression in the ventrolateral periaqueductal gray matter was significantly suppressed by concomitant ketamine and morphine. In contrast, the subanalgesic dose of ketamine did not impair PPI and synaptic efficacy in the mPFC. CONCLUSION: The present results indicate that the morphine-induced analgesic effect is enhanced by a concomitant subanalgesic dose of ketamine without affecting cortical function. Our findings possibly support the clinical notion that low-dose ketamine as an analgesic adjuvant has therapeutic potential to reduce opioid dosage, thereby improving the quality of life in cancer pain patients.

Change in Tacrolimus Concentration Measured in Whole Blood Correlates With Changes in Red Blood Cell Parameters After Red Blood Cell Transfusion in Kidney Transplant Recipients.

BACKGROUND: Tacrolimus (TAC) is a narrow therapeutic range drug that requires therapeutic drug monitoring. TAC concentration is measured using whole blood owing to its high red blood cell (RBC) transfer rate of 95%. The distribution and whole-blood TAC concentration may be affected by the transfusion of red cell concentrates (RCCs); however, this has not been studied in kidney transplant recipients (KTR). Therefore, we investigated the relationship between changes in whole-blood TAC concentration and RBC parameters before and after RCC transfusion in KTR. METHODS: Fifteen KTR who received TAC and RCC transfusions were enrolled. The change rates of RBC parameters (RBC count, hemoglobin [Hgb], hematocrit [Hct]), and TAC concentration/dose before and after transfusion were calculated. The correlation between each RBC parameter and the TAC rate was evaluated. RESULTS: The TAC concentration and rate increased after RCC transfusion. Moreover, the TAC rate showed a significant and strong correlation with RBC count, Hgb, and Hct, with RBC count showing the highest correlation coefficient (r = 0.811, 0.766, and 0.764, respectively; p < .01). Serum creatinine and potassium levels remained stable, suggesting the absence of typical adverse effects associated with TAC, such as acute kidney injury or hyperkalemia. CONCLUSION: Changes in whole-blood TAC concentration and RBC parameters were correlated, and whole-blood TAC concentration increased after RCC transfusion. Therefore, the TAC dose should be adjusted accordingly.

Effects of prehospital epinephrine during out-of-hospital cardiac arrest with initial non-shockable rhythm: an observational cohort study.

INTRODUCTION: Few clinical trials have provided evidence that epinephrine administration after out-of-hospital cardiac arrest (OHCA) improves long-term survival. Here we determined whether prehospital epinephrine administration would improve 1-month survival in OHCA patients. METHODS: We analyzed the data of 209,577 OHCA patients; the data were prospectively collected in a nationwide Utstein-style Japanese database between 2009 and 2010. Patients were divided into the initial shockable rhythm (n = 15,492) and initial non-shockable rhythm (n = 194,085) cohorts. The endpoints were prehospital return of spontaneous circulation (ROSC), 1-month survival, and 1-month favorable neurological outcomes (cerebral performance category scale, category 1 or 2) after OHCA. We defined epinephrine administration time as the time from the start of cardiopulmonary resuscitation (CPR) by emergency medical services personnel to the first epinephrine administration. RESULTS: In the initial shockable rhythm cohort, the ratios of prehospital ROSC, 1-month survival, and 1-month favorable neurological outcomes in the non-epinephrine group were significantly higher than those in the epinephrine group (27.7% vs. 22.8%, 27.0% vs. 15.4%, and 18.6% vs. 7.0%, respectively; all P < 0.001). However, in the initial non-shockable rhythm cohort, the ratios of prehospital ROSC and 1-month survival in the epinephrine group were significantly higher than those in the non-epinephrine group (18.7% vs. 3.0% and 3.9% vs. 2.2%, respectively; all P < 0.001) and there was no significant difference between the epinephrine and non-epinephrine groups for 1-month favorable neurological outcomes (P = 0.62). Prehospital epinephrine administration for OHCA patients with initial non-shockable rhythms was independently associated with prehospital ROSC (adjusted odds ratio [aOR], 8.83, 6.18, 4.32; 95% confidence interval [CI], 8.01-9.73, 5.82-6.56, 3.98-4.69; for epinephrine administration times ≤9 min, 10-19 min, and ≥20 min, respectively), with improved 1-month survival when epinephrine administration time was <20 min (aOR, 1.78, 1.29; 95% CI, 1.50-2.10, 1.17-1.43; for epinephrine administration times ≤9 min and 10-19 min, respectively), and with deteriorated 1-month favorable neurological outcomes (aOR, 0.63, 0.49; 95% CI, 0.48-0.80, 0.32-0.71; for epinephrine administration times 10-19 min and ≥20 min, respectively). CONCLUSIONS: Prehospital epinephrine administration for OHCA patients with initial nonshockable rhythms was independently associated with achievement of prehospital ROSC and had association with improved 1-month survival when epinephrine administration time was <20 min.

Decision-tree model for predicting outcomes after out-of-hospital cardiac arrest in the emergency department.

INTRODUCTION: Estimation of outcomes in patients after out-of-hospital cardiac arrest (OHCA) soon after arrival at the hospital may help clinicians guide in-hospital strategies, particularly in the emergency department. This study aimed to develop a simple and generally applicable bedside model for predicting outcomes after cardiac arrest. METHODS: We analyzed data for 390,226 adult patients who had undergone OHCA, from a prospectively recorded nationwide Utstein-style Japanese database for 2005 through 2009. The primary end point was survival with favorable neurologic outcome (cerebral performance category (CPC) scale, categories 1 to 2 [CPC 1 to 2]) at 1 month. The secondary end point was survival at 1 month. We developed a decision-tree prediction model by using data from a 4-year period (2005 through 2008, n = 307,896), with validation by using external data from 2009 (n = 82,330). RESULTS: Recursive partitioning analysis of the development cohort for 10 predictors indicated that the best single predictor for survival and CPC 1 to 2 was shockable initial rhythm. The next predictors for patients with shockable initial rhythm were age (<70 years) followed by witnessed arrest and age (>70 years) followed by arrest witnessed by emergency medical services (EMS) personnel. For patients with unshockable initial rhythm, the next best predictor was witnessed arrest. A simple decision-tree prediction mode permitted stratification into four prediction groups: good, moderately good, poor, and absolutely poor. This model identified patient groups with a range from 1.2% to 30.2% for survival and from 0.3% to 23.2% for CPC 1 to 2 probabilities. Similar results were observed when this model was applied to the validation cohort. CONCLUSIONS: On the basis of a decision-tree prediction model using four prehospital variables (shockable initial rhythm, age, witnessed arrest, and witnessed by EMS personnel), OHCA patients can be readily stratified into the four groups (good, moderately good, poor, and absolutely poor) that help predict both survival at 1 month and survival with favorable neurologic outcome at 1 month. This simple prediction model may provide clinicians with a practical bedside tool for the OHCA patient's stratification in the emergency department.

Termination-of-resuscitation rule for emergency department physicians treating out-of-hospital cardiac arrest patients: an observational cohort study.

INTRODUCTION: The 2010 cardiopulmonary resuscitation guidelines recommend emergency medical services (EMS) personnel consider prehospital termination-of-resuscitation (TOR) rules for out-of-hospital cardiac arrest (OHCA) following basic life support and/or advanced life support efforts in the field. However, the rate of implementation of international TOR rules is still low. Here, we aimed to develop and validate a new TOR rule for emergency department physicians to replace the international TOR rules for EMS personnel in the field. This rule aims to guide physicians in deciding whether to withhold further resuscitation attempts or terminate on-going resuscitation immediately after patient arrival. METHODS: We analyzed data prospectively collected in a nationwide Utstein-style Japanese database between 2005 and 2009, from 495,607 adult patients with OHCA. Patients were divided into development (n = 390,577) and validation (n = 105,030) groups. The main outcome measures were specificity, positive predictive value (PPV), and area under the receiver operating characteristic (ROC) curve for the newly developed TOR rule. RESULTS: We developed a new TOR rule that includes 3 criteria based on the results of multivariate logistic regression analysis for predicting a 1-month death after OHCA: no prehospital return of spontaneous circulation (adjusted odds ratio [OR], 25.8; 95% confidence interval [CI], 24.7-26.9), unshockable initial rhythm (adjusted OR, 2.76; 95% CI, 2.54-3.01), and unwitnessed by bystanders (adjusted OR, 2.18; 95% CI, 2.09-2.28). The specificity, PPV, and area under the ROC curve for this new TOR rule for predicting 1-month death in the validation group were 0.903 (95% CI, 0.894-0.911), 0.993 (95% CI, 0.992-0.993), and 0.874 (95% CI, 0.872-0.876), respectively. CONCLUSIONS: We developed and validated a new TOR rule for emergency department physicians consisting of 3 prehospital variables (no prehospital ROSC, unshockable initial rhythm, and unwitnessed by bystanders) that is a >99% predictor of very poor outcome. However, the implementation of this new rule in other countries or EMS systems requires further validation studies.