Prediction of Neurologically Intact Survival in Cardiac Arrest Patients without Pre-Hospital Return of Spontaneous Circulation: Machine Learning Approach.

Current multimodal approaches for the prognostication of out-of-hospital cardiac arrest (OHCA) are based mainly on the prediction of poor neurological outcomes; however, it is challenging to identify patients expected to have a favorable outcome, especially before the return of spontaneous circulation (ROSC). We developed and validated a machine learning-based system to predict good outcome in OHCA patients before ROSC. This prospective, multicenter, registry-based study analyzed non-traumatic OHCA data collected between October 2015 and June 2017. We used information available before ROSC as predictor variables, and the primary outcome was neurologically intact survival at discharge, defined as cerebral performance category 1 or 2. The developed models' robustness were evaluated and compared with various score metrics to confirm their performance. The model using a voting classifier had the best performance in predicting good neurological outcome (area under the curve = 0.926). We confirmed that the six top-weighted variables predicting neurological outcomes, such as several duration variables after the instant of OHCA and several electrocardiogram variables in the voting classifier model, showed significant differences between the two neurological outcome groups. These findings demonstrate the potential utility of a machine learning model to predict good neurological outcome of OHCA patients before ROSC.

First-in-Human, Double-Blind, Randomized Controlled Trial of an Oral Dose of GnRH Antagonist TU2670 in Healthy Women.

OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TU2670, a novel orally active, nonpeptide gonadotropin-releasing hormone (GnRH) antagonist administered to healthy female participants. METHODS: This was a first-in-human, multicenter, phase 1, randomized, double-blind, placebo-controlled, single-dose ascending trial that took place in multiple medical centers. A total of 16 healthy premenopausal women (23 to 45 years of age) were randomized and received 20, 40, 80, and 160 mg TU2670 (GnRH antagonist) or placebo 7 days (±1 day) after the onset of menstrual bleeding. We performed a noncompartmental analysis for pharmacokinetic parameters and calculated relative minimum concentration values (Cmin, % Baseline) of serum pharmacodynamic (PD) markers (luteinizing hormone [LH], follicle-stimulating hormone [FSH], and estradiol). RESULTS: There were no significant differences among treatments with respect to vital signs, electrocardiography, adverse events, ovulation test results, and ultrasonography. The median Tmax of TU2670 occurred 0.75 to 1.00 hours after dosing, and concentrations then declined, with a mean apparent half-life (t1/2) of 3.0 to 5.9 hours. AUClast (17.7-417.9 ng·h/mL) and Cmax (8.1-95.4 ng/mL) increased in a dose-dependent manner. The PD analysis after a single administration of TU2670 revealed dose-dependent suppression of LH, FSH, and estradiol. Maximal suppression of the pre-dose baseline (%) was 58% to 82% at 6 to 8 hours for LH, 28% to 39% at 6 to 12 hours for FSH, and 34% to 82% at 12 to 24 hours for estradiol. CONCLUSION: The single administration of TU2670 in healthy premenopausal women was well tolerated and resulted in the dose-dependent suppression of LH, FSH, and estradiol, suggesting rapid and significant inhibition of pituitary and ovarian hormones.

Implications of Increased Weight Status for the Occurrence of Fall-Induced Intracranial Hemorrhage in Children Aged 4 Years or Younger.

OBJECTIVES: The aim of this study was to investigate the association between increased weight status (IWS), a weight for age/sex at greater than the 95th percentile, and fall-induced intracranial hemorrhage (ICH) in children aged 4 years or younger. METHODS: In 7072 children aged 4 years or younger with head injury who visited a tertiary care hospital emergency department in Korea from 2013 through 2015, the presence of fall-induced ICH was reviewed. The association between IWS and ICH was investigated by multivariable logistic regression. We retrospectively validated the Pediatric Emergency Care Applied Research Network rule alone and in combination with IWS for predicting ICH. RESULTS: Of 7072 children, 547 (7.7%) underwent computed tomography, of whom 451 (6.4%) were enrolled. Of these, 41 (9.1%; estimated event rate, 0.6%) had ICHs, and 26 (5.8%) had IWS. Increased weight status was more common in the children with ICH (P = 0.023). The association between IWS and ICH remained significant after adjustment (odds ratio, 5.24; 95% confidence interval [CI], 1.49-18.46; P = 0.010). The validation of the rule in combination with IWS showed no significant increases in a sensitivity (92.7% [95% CI, 80.1%-98.5%] to 95.7% [95% CI, 83.5%-99.4%]) and negative predictive value (98.2% [95% CI, 94.7%-99.4%] to 98.8% [95% CI, 95.4%-99.8%]). CONCLUSIONS: Increased weight status is associated with fall-induced ICH in children aged 4 years or younger. Information on weight status could be potentially helpful in predicting ICH in young children with fall-induced head injury.

Cancer patients with neutropenic septic shock: etiology and antimicrobial resistance.

BACKGROUND/AIMS: Among patients with febrile neutropenia that developed after chemotherapy, high-risk patients, such as those having clinical instability or Multinational Association of Supportive Care in Cancer score of < 21, require hospitalization for intravenous empiric antibiotic therapy. Monotherapy with an anti-pseudomonal ß-lactam agent is recommended. Although many studies reported the microbial etiology of infections and resistant patterns of febrile neutropenia, the patients were not well characterized as having neutropenic septic shock. Therefore, this study aimed to determine the microbial spectrum of infections and resistance patterns of their isolates in patients with chemotherapy-induced neutropenic septic shock. METHODS: Data of adult patients diagnosed with neutropenic septic shock in the emergency department between June 2012 and December 2016 were extracted from a prospectively compiled septic shock registry at a single academic medical center. Thereafter, microbiological studies and antimicrobial susceptibility tests were conducted. RESULTS: In total, 109 bacteria were found in patients with neutropenic septic shock. Gram-negative bacteria were the predominant causative organisms (84, 77.1%). Moreover, 33 microorganisms (30.3%) were multidrug-resistant (MDR) bacteria with extended-spectrum ß-lactamase-producing Escherichia coli (17, 50%) being the commonest. The most commonly affected sites in patients with MDR bacterial infections were the gastrointestinal tract (45%) and unknown (43.5%). Approximately 48.5% of MDR bacteria were resistant to cefepime but not to piperacillin-tazobactam or carbapenem. CONCLUSION: MDR bacteria were prevalent in patients with chemotherapy-induced neutropenic septic shock. Therefore, piperacillin-tazobactam or carbapenem may be considered as empiric antibiotics if MDR bacteria are suspected to be causative agents.

A first-in-human study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of KM-819 (FAS-associated factor 1 inhibitor), a drug for Parkinson's disease, in healthy volunteers.

BACKGROUND: KM-819 is a novel FAS-associated factor 1 (FAF1) inhibitor, and a neuroprotective agent, under clinical development for the treatment of Parkinson's disease as a disease-modifying drug. METHODS: This first-in-human, single and multiple ascending dose study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of KM-819 in healthy volunteers. Additionally, the effect of age on safety and pharmacokinetics were assessed. The starting dose was determined considering the no observed adverse effect level based on preclinical studies, and the dose escalations in subsequent cohorts were decided based on safety, tolerability, and pharmacokinetic data from previous dose cohorts. RESULTS: After a single dose, the KM-819 plasma exposure showed a less than dose-proportional increase across a dose range of 10-400 mg. After repeated dosing, KM-819 plasma exposure increased in an approximately dose-proportional manner across the evaluated dose range (30-400 mg once daily for 7 days). The mean elimination half-life was 1.8 to 4.8 h with the lower KM-819 doses (≤30 mg), which increased to around 9 h with the higher doses (100-400 mg). When administered to the elderly population, KM-819 plasma exposure increased to 102% after a 200 mg once-daily dosing for 7 days. No clear treatment-related effects on the estimated pharmacodynamic variables were observed. Single or multiple doses of KM-819 were generally well tolerated. CONCLUSION: The data from this study can be used to guide rational drug dosing and choose therapeutic regimens in subsequent clinical studies.

Risk Factors for Same Pathogen Sepsis Readmission Following Hospitalization for Septic Shock.

(1) Background: Septic shock survivors frequently readmit because of subsequent infection. This study aimed to determine the rate and risk factors for same pathogen sepsis readmissions following hospitalization for septic shock. (2) Methods: We performed this retrospective study using data from a prospective septic shock registry at a single urban tertiary center. All the patients were treated with a protocol-driven resuscitation bundle therapy between 2011 and 2016. We collected data from adult (older than 18 years) patients readmitted with sepsis within 90 days of discharge following hospitalization for septic shock. (3) Results: Among 2062 septic shock patients, 690 were readmitted within 90 days of discharge. After excluding scheduled and non-sepsis admissions, we analyzed the data from 274 (13.3%) patients readmitted for sepsis. Most of the readmissions following septic shock were new infections rather than relapses of the initial infection. The culture-negative rate was 51.4% (141/274), while the same pathogen was isolated in 25% of cases (69/274). Multivariate analysis revealed that previous gram-negative bacteremia (OR, 9.902; 95% CI, 2.843⁻34.489), urinary tract infection (OR, 4.331; 95% CI, 1.723⁻10.882) and same site infection (OR, 6.894; 95% CI, 2.390⁻19.886) were significantly associated with readmission for sepsis caused by the same pathogen. (4) Conclusions: The sepsis readmission rate following the previous hospitalization for septic shock was 13.3% and one-quarter of those patients had the same pathogen isolated. Previous gram-negative bacteremia, and/or same site infection are predisposing factors for recurrent same-pathogen sepsis.

Early Risk Score for Predicting Hypotension in Normotensive Patients with Non-Variceal Upper Gastrointestinal Bleedin.

Risk assessment for upper gastrointestinal bleeding (UGIB) is important; however, current scoring systems are insufficient. We aimed to develop and validate a prediction model for rapidly determining the occurrence of hypotension in non-variceal UGIB patients with normotension (systolic blood pressure ≥90 mmHg) at emergency department presentation. In this prospective observational cohort study, consecutive non-variceal UGIB patients between January 2012 and April 2017 were enrolled. We developed and validated a new prediction model through logistic regression, with the occurrence of hypotension <24 h as the primary outcome. Among 3363 UGIB patients, 1439 non-variceal UGIB patients were included. The risk factors for the occurrence of hypotension were lactate level, blood in nasogastric tube, and systolic blood pressure. The area under the curve (AUC) of the new scoring model (LBS-Lactate, Blood in nasogastric tube, Systolic blood pressure) in the development cohort was 0.74, higher than the value of 0.64 of the Glasgow⁻Blatchford score for predicting the occurrence of hypotension. The AUC of the LBS score in the validation cohort was 0.83. An LBS score of ≤2 had a negative predictive value of 99.5% and an LBS score of ≥7 had a specificity of 97.5% in the validation cohort. The new LBS score stratifies normotensive patients with non-variceal UGIB at risk for developing hypotension.

Risk factors for extended-spectrum beta-lactamase-producing Enterobacteriaceae infection causing septic shock in cancer patients with chemotherapy-induced febrile neutropenia.

Patients with chemotherapy-induced febrile neutropenia (FN) are vulnerable to extended-spectrum b-lactamase-producing Enterobacteriaceae (ESBL-PE) infection. Early identification of patients suspected to have ESBL-PE infection for empirical carbapenem administration is crucial; nevertheless, risk factors for ESBL-PE causing septic shock remain unclear. We identify factors to predict ESBL-PE in septic shock patients with chemotherapy-induced FN. In this observational, prospectively collected registry-based study, consecutive adult chemotherapy-induced FN patients with septic shock who were admitted to the emergency department between June 2012 and June 2018 were enrolled. Clinical and laboratory data extracted from the septic shock registry were assessed to identify risk factors for ESBL-PE. Of 179 chemotherapy-induced FN septic shock patients, ESBL-PE is isolated in 23 (12.8%). ESBL-PE infection is frequently seen in patients with hepatobiliary cancer (17.4% vs. 4.5%, P = 0.037), leukemia (13.0% vs. 2.6%, P = 0.046), and those with profound neutropenia (defined as absolute neutrophil count < 100) (73.9% vs. 43.6%, P = 0.007) in contrast to those with lung cancer (0% vs. 14.7%, P = 0.048) and other solid cancer (0% vs. 19.2%, P = 0.016). Multivariate logistic regression reveals that profound neutropenia (adjusted OR 3.67; 95% CI 1.372-9.799; P = 0.010) is an independent risk factor for ESBL-PE infection after adjusting age, the presence of solid tumor, and the parameters of sepsis severity scores. ESBL-PE is rare (12.9%) in chemotherapy-induced FN patients with septic shock. Early empirical carbapenem therapy might be considered in chemotherapy-induced FN patients with profound neutropenia.

Clinical Predictors of Acute Brain Injury in Carbon Monoxide Poisoning Patients With Altered Mental Status at Admission to Emergency Department.

OBJECTIVES: Objective screening tool for patients at a high risk of developing acute brain injury (ABI) is necessary for the proper treatment of carbon monoxide (CO) poisoning patients. The aim of this study is to identify clinical factors that could predict ABI due to CO poisoning in patients with an altered mental status. METHODS: A prospectively collected CO poisoning registry at a single academic medical center was retrospectively analyzed. CO poisoning patients with an altered mental status at the emergency department, defined as unalert on the alert/responsive to voice/responsive to pain/unresponsive scale and underwent diffusion-weighted magnetic resonance imaging (DW-MRI) between January 1, 2013, and December 31, 2015, were included. ABI was defined as the presence of acute hypoxic brain lesions. Clinical predictors of ABI were identified by multivariate logistic regression analysis. RESULTS: Of 180 patients, 67 (37.2%) had ABI as revealed by DW-MRI. Multivariate analysis showed that CO exposure duration > 5 hours (adjusted odds ratio [AOR] = 7.082; 95% confidence interval [CI] = 3.463-15.014; p < 0.001) defined as the time between CO exposure and rescue, abnormal white blood cell count (AOR = 2.568, 95% CI = 1.188-5.700, p = 0.02), and abnormal creatinine concentration (AOR = 2.667, 95% CI = 1.110-6.605, p = 0.03) were predictors of ABI. CO exposure duration had the highest predictive value (area under the curve, 0.815), and the optimal cutoff value was 5 hours. Moreover, increasing exposure durations (quartile) indicated a stepwise increase in the risk of ABI. CONCLUSIONS: In CO poisoning patients with an altered mental status, CO exposure duration was useful for predicting ABI, which may help clinicians or paramedics identify high-risk patients and provide treatment on priority.

One--Year Progression and Risk Factors for the Development of Chronic Kidney Disease in Septic Shock Patients with Acute Kidney Injury: A Single-Centre Retrospective Cohort Study.

(1) Background: Sepsis-associated acute kidney injury (AKI) can lead to permanent kidney damage, although the long-term prognosis in patients with septic shock remains unclear. This study aimed to identify risk factors for the development of chronic kidney disease (CKD) in septic shock patients with AKI. (2) Methods: A single-site, retrospective cohort study was conducted using a registry of adult septic shock patients. Data from patients who had developed AKI between January 2011 and April 2017 were extracted, and 1-year follow-up data were analysed to identify patients who developed CKD. (3) Results: Among 2208 patients with septic shock, 839 (38%) had AKI on admission (stage 1: 163 (19%), stage 2: 339 (40%), stage 3: 337 (40%)). After one year, kidney function had recovered in 27% of patients, and 6% had progressed to CKD. In patients with stage 1 AKI, 10% developed CKD, and mortality was 13% at one year; in patients with stage 2 and 3 AKI, the CKD rate was 6%, and the mortality rate was 42% and 47%, respectively. Old age, female, diabetes, low haemoglobin levels and a high creatinine level at discharge were seen to be risk factors for the development of CKD. (4) Conclusions: AKI severity correlated with mortality, but it did not correlate with the development of CKD, and patients progressed to CKD, even when initial AKI stage was not severe. Physicians should focus on the recovery of renal function, and ensure the careful follow-up of patients with risk factors for the development of CKD.

Lack of a Clinically Significant Pharmacokinetic Interaction Between Pregabalin and Thioctic Acid in Healthy Volunteers.

PURPOSE: Pregabalin and thioctic acid are likely to be used concomitantly for the treatment of painful diabetic neuropathy. In this study, the pharmacokinetic interaction between pregabalin and thioctic acid was investigated at steady state. METHODS: A randomized, open-label, 6-sequence, 3-period, 3-treatment crossover study was conducted in 42 healthy male volunteers. The volunteers randomly received pregabalin 300 mg BID for 6 times, thioctic acid 600 mg once daily for 3 times, or the combination of pregabalin and thioctic acid. Serial blood samples were collected up to 24 hours after the last dosing in each period. Pharmacokinetic parameters were calculated by using noncompartmental analysis methods. FINDINGS: The mean concentration-time curves were similar between each drug alone and in combination with the other drug. The 90% CIs of the geometric mean ratios with and without the co-administered drug for Cmax at steady state and AUC during the dosing interval were well within the conventional bioequivalence range of 0.8 to 1.25, except for Cmax at steady state for thioctic acid, which barely exceeded only the lower bound (0.78-1.15). Co-administered pregabalin and thioctic acid was well tolerated. IMPLICATIONS: Repeatedly administered pregabalin and thioctic acid do not interact pharmacokinetically. This study suggests that the combination of pregabalin and thioctic acid can safely be administered concomitantly without dose adjustment. ClinicalTrials.gov identifier: NCT01808300.

Sodium bicarbonate on severe metabolic acidosis during prolonged cardiopulmonary resuscitation: a double-blind, randomized, placebo-controlled pilot study.

BACKGROUND: Sodium bicarbonate administration during cardiopulmonary resuscitation (CPR) is controversial. Current guidelines recommend sodium bicarbonate injection in patients with existing metabolic acidosis, but clinical trials, particularly, those involving patients with acidosis, are limited. We aimed to evaluate the efficacy of sodium bicarbonate administration in out-of-hospital cardiac arrest (OHCA) patients with severe metabolic acidosis during prolonged CPR. METHODS: Prospective, double-blind, randomized placebo-controlled pilot trial was conducted between January 2015 and December 2015, at a single center emergency department (ED). After 10 minutes of CPR, patients who failed to achieve return of spontaneous circulation (ROSC) and with severe metabolic acidosis (pH<7.1 or bicarbonate <10 mEq/L) were enrolled. Sodium bicarbonate (n=25) or normal saline (n=25) were administered. The primary end point was sustained ROSC. The secondary end points were the change of acidosis and good neurologic survival. RESULTS: Sodium bicarbonate group had significant effect on pH (6.99 vs. 6.90, P=0.038) and bicarbonate levels (21.0 vs. 8.0 mEq/L, P=0.007). However, no significant differences showed between sodium bicarbonate and placebo groups in sustained ROSC (4.0% vs. 16.0%, P=0.349) or good neurologic survival at 1 month (0.0% vs. 4.0%, P=1.000). CONCLUSIONS: The use of sodium bicarbonate improved acid-base status, but did not improve the rate of ROSC and good neurologic survival. We could not draw a conclusion, but our pilot data could be used to design a larger trial to verify the efficacy of sodium bicarbonate. TRIAL REGISTRATION: NCT02303548 (http://www.ClinicalTrials.gov).

Prognostic value of decision criteria for emergency liver transplantation in patients with wild mushroom induced acute liver injury.

BACKGROUND: The reported mortality rate of mushroom-induced acute liver failure with conventional treatment is 1.4%-16.9%. Emergency liver transplantation may be indicated and can be the only curative treatment option. This study aimed to assess the prognostic value of criteria for emergency liver transplantation in predicting 28-day mortality in patients with mushroom-induced acute liver injury. METHODS: A retrospective cohort study was performed between January 2005 and December 2015. All adult patients aged≥18 years admitted with mushroom intoxication at our emergency department were evaluated. All patients with acute liver injury, defined as elevation of serum liver enzymes (>5 times the upper limit of normal, ULN) or moderate coagulopathy (INR > 2.0) were included. The ability of the King's College, Ganzert's, and Escudié's criteria to predict 28-day mortality was evaluated. RESULTS: Of the 23 patients with acute liver injury following mushroom intoxication, 10 (43.5%) developed acute liver failure and subsequently died. The mean time interval from ingestion to death was 11.3 ±â€¯6.6 days. Eight patients fulfilled Ganzert's criteria, while 10 patients fulfilled the King's College and Escudié's criteria for emergency liver transplantation. King's College and Escudié's criteria had 100% accuracy in predicting 28-day mortality; however, Escudié's criteria were able to identify fatal cases earlier. CONCLUSIONS: Escudié's criteria demonstrated the best performance with 100% accuracy and the ability to promptly identify fatal cases of mushroom-induced acute liver failure.

Serial evaluation of SOFA and APACHE II scores to predict neurologic outcomes of out-of-hospital cardiac arrest survivors with targeted temperature management.

OBJECTIVE: This study was aimed at a serial evaluation and comparison of the prognostic values of Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE) II scores for neurologic outcomes in comatose, out-of-hospital cardiac arrest (OHCA) survivors, treated with targeted temperature management (TTM). METHODS: We analysed a prospective cohort of comatose OHCA patients, with TTM, admitted to an emergency intensive care unit (ICU), between January 2010 and December 2015. SOFA and APACHE II scores were calculated initially, and then at day 1, 2, 3, 5, and 7 after ICU admission. Primary and secondary outcomes were the 28-day neurologic outcome and the 28-day mortality, respectively. Prognostic value of the SOFA and APACHE II scores was analysed using the receiver operating characteristic curve. RESULTS: Of the 143 selected patients, 62 survived and 34 had good neurologic outcomes at day 28. There was no significant difference in the SOFA and extracerebral SOFA scores between the good and poor neurologic outcome groups. However, the APACHE II scores were significantly higher in the good outcome group; they displayed good discriminatory power in predicting poor outcomes, unlike the SOFA scores. The APACHE II score at day 3 had the highest prognostic value for predicting poor neurologic outcomes with an area under the cure of 0.793, and with a cut-off value of 20, the APACHE II score predicted poor neurologic outcomes with a sensitivity of 43.75%, a specificity of 94.12%, a positive predictive value of 94.59%, and a negative predictive value of 41.56%. CONCLUSIONS: Identifying APACHE II score might assist as one piece of multimodal prognostic approach for the assessment of neurologic outcomes in OHCA survivors treated with TTM.

Incidence of intracranial injury in orbital wall fracture patients not classified as traumatic brain injury.

OBJECTIVE: The detection of intracranial injury in patients with facial injury rather than traumatic brain injury (TBI) remains a challenge for emergency physicians. This study aimed to evaluate the incidence and risk factors of intracranial injury in patients with orbital wall fracture (OWF), who were classified with a chief complaint of facial injury rather than TBI. METHODS: This retrospective case-control study enrolled adult OWF patients (age ≥18 years) who presented at the hospital between January 2004 and March 2016. Patients with definite TBI were excluded because non-contrast head computed tomography (CT) is recommended for such patients. RESULTS: A total of 1220 patients with OWF were finally enrolled. CT of the head was performed on 677 patients, and the incidence of concomitant intracranial injury was found to be 9% (62/677). Patients with definite TBI were excluded. Symptoms raising a suspicion of TBI, such as loss of consciousness, alcohol intoxication, or vomiting, were present in 347 of the patients, with 44 of these patients (13%) showing a concomitant intracranial injury. Of the 330 patients without such symptoms, 18 (6%) demonstrated a concomitant intracranial injury. In OWF patients, superior wall fracture (odds ratio [OR], 4.15; 95% confidence interval [CI], 2.06-8.34; P < 0.001), associated frontal bone fracture (OR, 4.38; 95% CI, 2.08-9.23; P < 0.001), and older age (decades) (OR, 1.03; 95% CI, 1.01-1.04; P = 0.002) were independent risk factors for concomitant intracranial injury. CONCLUSIONS: Emergency physicians should maintain a high degree of suspicion of TBI, even when their primary concern is facial trauma with OWF. Head CT is recommended for OWF patients with a superior OWF, frontal bone fracture, or increased age.

Lactate Level Versus Lactate Clearance for Predicting Mortality in Patients With Septic Shock Defined by Sepsis-3.

OBJECTIVES: This study aimed to compare the prognostic value of lactate level and lactate clearance at 6 hours after septic shock recognition. And, we performed it to determine lactate kinetics in the Sepsis-3 defined septic shock. DESIGN: This retrospective study was performed from a prospective septic shock registry. SETTINGS: This study was performed at single urban tertiary center. And, all patients were treated with protocol-driven resuscitation bundle therapy between 2010 and 2016. PATIENTS: We included septic shock patients who met the Sepsis-3 definition, which involves lactate levels greater than or equal to 2 mmol/L and vasopressor use. INTERVENTIONS: Serum lactate levels were measured at initial and 6 hours from septic shock recognition. MEASUREMENTS AND MAIN RESULTS: Lactate clearance was calculated as ([initial lactate - 6-hr lactate]/initial lactate) × 100. The prognostic value of measured lactate levels and lactate clearance for 28-day mortality was analyzed and compared with that of subsequent lactate levels greater than or equal to 2 mmol/L, greater than or equal to 3 mmol/L, and greater than or equal to 4 mmol/L and less than 10%, less than 20%, and less than 30% lactate clearance. A total of 1,060 septic shock patients by Sepsis-3, 265 patients died (28-d mortality: 25%). In survivor, groups had lower median 6-hour lactate level and higher lactate clearance than nonsurvivors (2.5 vs 4.6 mmol/L and 35.4% vs 14.8%; p < 0.01). Both lactate and lactate clearance were associated with mortality after adjusting for confounders (odd ratio, 1.27 [95% CI, 1.21-1.34] and 0.992 [95% CI, 0.989-0.995]), but lactate had a significantly higher prognostic value than lactate clearance (area under the curve, 0.70 vs 0.65; p < 0.01). The prognostic value of subsequent lactate levels (≥ 2, ≥ 3, and ≥ 4 mmol/L) and lactate clearances (< 10%, < 20%, and < 30%) was not significantly differed. However, lactate levels of greater than or equal to 2 mmol/L had the greatest sensitivity (85.3%). CONCLUSIONS: Our findings indicate lactate and lactate clearance are both useful targets in patients with septic shock defined by Sepsis-3. Serum lactate level at 6-hour can be an easier and more effective tool for prognosis of septic shock patients who were treated with protocol-driven resuscitation bundle therapy.

Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study.

BACKGROUND: The effect of intranasal esketamine on cognitive functioning in healthy participants is assessed in this study. METHODS: Twenty-four participants (19-49 years) were randomized to one of two treatment sequences in which either esketamine 84 mg or placebo was intranasally administered in a double-blind, two-period crossover design. Primary measures included five tests of Cogstate® computerized test battery assessed at 1 h predose and 40 min, 2, 4, and 6 h postdose. Secondary measures included the Mental Effort Scale, Karolinska Sleepiness Scale (KSS), and safety. RESULTS: Esketamine was associated with significant cognitive performance impairment at 40 min postdose for all five Cogstate® tests (Detection p = 0.0011, Identification p = 0.0006, One-Card Learning p = 0.0040, One Back p = 0.0017, and Groton Maze Learning Test p < 0.0001) versus placebo. In contrast, performance on these tests did not differ significantly between esketamine and placebo at 2, 4, or 6 h postdose. Secondary outcomes indicated a significant, transient increase from baseline under esketamine versus placebo at 40 min postdose on the Mental Effort Scale and at 40 min and 2 h postdose on KSS (p < 0.0001 for both); however, no significant difference was observed on these outcomes between esketamine and placebo at later timepoints. The most commonly reported adverse events were dizziness (67%), nausea (37.5%), disturbance in attention (29.2%), and fatigue (29.2%); the majority were considered mild in severity. CONCLUSIONS: Esketamine was associated with cognitive performance decline, and greater effort was required to complete the test battery versus placebo at 40 min postdose, which returned to placebo-comparable levels by 2 h postdose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02094378.

Acute Brain Lesions on Magnetic Resonance Imaging and Delayed Neurological Sequelae in Carbon Monoxide Poisoning.

Importance: Preventing delayed neurological sequelae is a major goal of treating acute carbon monoxide poisoning, but to our knowledge there are no reliable tools for assessing the probability of these sequelae. Objectives: To determine whether acute brain lesions on diffusion-weighted imaging are related to subsequent development of delayed neurological sequelae after acute carbon monoxide poisoning. Design, Setting, and Participants: This registry-based observational study was conducted at a university hospital in Seoul, Korea, between April 1, 2011, and December 31, 2015. Of 700 patients (aged ≥18 years) with acute carbon monoxide poisoning, 433 patients (61.9%) who underwent diffusion-weighted imaging at an emergency department were considered for the study. Patients who developed cardiac arrest before diffusion-weighted imaging (n = 3), had persistent neurological symptoms at discharge (n = 8), committed suicide soon after discharge (n = 1), and were lost to follow-up (n = 34) were excluded. Exposure: The presence of unambiguous, high-signal-intensity, acute brain lesions on diffusion-weighted imaging (b = 1000 s/mm2). Main Outcomes and Measures: Development of delayed neurological sequelae defined as any neurological symptoms or signs that newly developed within 6 weeks of discharge. Results: Of the 387 included patients (143 women [37.0%]; median age, 42.0 years [interquartile range, 32.0-56.0 years]), acute brain lesions on diffusion-weighted imaging were observed in 104 patients (26.9%). Among these, 77 patients (19.9%) had globus pallidus lesions, 13 (3.4%) had diffuse lesions, and 57 (14.7%) had focal lesions (37 patients [9.6%] had >1 pattern concurrently). Lesions were supratentorial and infratentorial in 101 and 23 patients, respectively. Delayed neurological sequelae occurred in 101 patients (26.1%). Multivariable logistic regression analysis indicated that the presence of acute brain lesions was independently associated with development of delayed neurological sequelae (adjusted odds ratio, 13.93; 95% CI, 7.16-27.11; P < .001). The sensitivity and specificity of acute brain lesions to assess the probability of delayed neurological sequelae were 75.2% (95% CI, 66.8%-83.7%) and 90.2% (95% CI, 86.8%-93.7%), respectively. In addition, the positive and negative predictive values were 73.1% (95% CI, 64.6%-81.6%) and 91.2% (95% CI, 87.9%-94.5%), respectively. Conclusions and Relevance: The presence of acute brain lesions was significantly associated with the development of delayed neurological sequelae. Diffusion-weighted imaging during the acute phase of carbon monoxide poisoning may therefore help identify patients at risk of developing these debilitating sequelae.

Analysis of the development and progression of carbon monoxide poisoning-related acute kidney injury according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria.

CONTEXT: Acute kidney injury (AKI) can occur after carbon monoxide (CO) intoxication; however, limited data are available. This study aimed to evaluate the prognostic value of the development and progression of AKI in patients with acute CO poisoning. MATERIALS AND METHODS: We conducted a retrospective cohort study using a prospective registry of CO poisoning between January 2010 and December 2015. AKI was defined and classified according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Multivariate logistic regression analysis was conducted to determine the association between AKI and adverse outcomes, defined as neurological deficits at discharge or 28-day mortality. RESULTS: A total of 661 patients were evaluated. According to KDIGO criteria, 114 patients (17.2%) had AKI (initial: stage 1, 70.2%; stage 2, 26.3%; stage 3, 3.5%) on admission and 119 (18.0%) finally developed AKI during their hospital stay (maximum: stage 1, 68.9%; stage 2, 23.5%; stage 3, 7.6%). Almost all patients (99.2%) were diagnosed as having their highest KDIGO stage within three days (median, one day). AKI development was associated with adverse outcomes (odds ratio (OR) 17.53, 95% confidence interval 45.00-77.14). Both initial and maximum AKI stages demonstrated a stepwise increase of adjusted OR for adverse outcomes. AKI stage progression occurred in 8.4% of patients with AKI and was an independent factor for adverse outcomes. CONCLUSION: CO poisoning- related AKI occurred in 18% and was mostly detected within one day after CO intoxication. The development and progression of AKI had a strong association with adverse outcomes and deserve further prospective investigation.

APACHE II Score Immediately after Cardiac Arrest as a Predictor of Good Neurological Outcome in Out-of-Hospital Cardiac Arrest Patients Receiving Targeted Temperature Management.

BACKGROUND: This study assessed the association between the initial Acute Physiology and Chronic Health Evaluation (APACHE) II score and good neurological outcome in comatose survivors of out-of-hospital cardiac arrest who received targeted temperature management (TTM). METHODS: Data from survivors of cardiac arrest who received TTM between January 2011 and June 2016 were retrospectively analyzed. The initial APACHE II score was determined using the data immediately collected after return of spontaneous circulation rather than within 24 hours after being admitted to the intensive care unit. Good neurological outcome, defined as Cerebral Performance Category 1 or 2 on day 28, was the primary outcome of this study. RESULTS: Among 143 survivors of cardiac arrest who received TTM, 62 (43.4%) survived, and 34 (23.8%) exhibited good neurological outcome on day 28. The initial APACHE II score was significantly lower in the patients with good neurological outcome than in those with poor neurological outcome (23.71 ± 4.39 vs. 27.62 ± 6.16, P = 0.001). The predictive ability of the initial APACHE II score for good neurological outcome, assessed using the area under the receiver operating characteristic curve, was 0.697 (95% confidence interval [CI], 0.599 to 0.795; P = 0.001). The initial APACHE II score was associated with good neurological outcome after adjusting for confounders (odds ratio, 0.878; 95% CI, 0.792 to 0.974; P = 0.014). CONCLUSIONS: In the present study, the APACHE II score calculated in the immediate post-cardiac arrest period was associated with good neurological outcome. The initial APACHE II score might be useful for early identification of good neurological outcome.