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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. Conclusions 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.

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.

Background: To investigate the clinical features of coinfection due to Mycoplasma pneumoniae ( M. pneumoniae ), a common copathogen in influenza, in influenza pneumonia patients. Methods: We reviewed 4,465 patients with influenza who visited a tertiary care hospital emergency department in Seoul (Korea) from 2010 through 2016, and underwent immunoglobulin M (IgM) serology or polymerase chain reaction (PCR) for M. pneumoniae . Influenza pneumonia was defined as laboratory-confirmed influenza plus radiographic pneumonia. Patients with healthcare-associated pneumonia or non-mycoplasma bacterial coinfection were excluded. Clinical, laboratory, and radiographic findings and outcomes of the influenza pneumonia patients with and without M. pneumoniae coinfection were compared. Multivariable logistic regression analysis was performed to identify factors associated with the coinfection. Results: Of 244 influenza pneumonia patients, 41 (16.8%) had M. pneumoniae coinfection. These patients were younger with a higher frequency of age of 5–10 years, and had higher white blood cell (WBC) and lymphocyte counts; lower concentration of C-reactive protein (CRP). The coinfection had no association with specific radiographic findings and poor outcome. Multivariable analysis showed the age of 5–10 years (adjusted odds ratio, 18.83; 95% confidence interval, 5.899–60.08; P

Background We hypothesised that lactate concentrations are independently associated with massive transfusion in patients with primary postpartum haemorrhage. Moreover, combining lactate concentrations with the shock index, defined as the ratio of heart rate to systolic arterial blood pressure, can improve the predictive performance for massive transfusion. Methods We retrospectively analysed patients with primary postpartum haemorrhage in the emergency department of a tertiary referral centre in Korea between January 1, 2004 and December 31, 2015. Results Of the 302 patients, 101 (33.4%) patients required massive transfusion. Lactate concentration was independently associated with the requirement for massive transfusion [odds ratio, 1.56; 95% confidence interval (CI), 1.31–1.87; P 4.0 mM L−1) was associated with 86.1% specificity and 67.8% positive predictive value for massive transfusion. When combining elevated lactate concentrations (>4.0 mM L−1) with a shock index >1.0, the specificity and positive predictive value increased to 95.5% and 82.4%, respectively. Conclusions Point-of-care testing of lactate concentrations in the emergency department may be useful to predict massive transfusion requirements in primary postpartum haemorrhage. Combining initial lactate concentrations with the shock index improves the predictive performance for massive transfusion requirements and may contribute to rapid risk stratification of patients with primary postpartum haemorrhage in need of transfusion and further focus on early interventions to control bleeding.

Objectives The aim of this study was to identify risk factors for recurrent intussusception after a successful reduction by fluoroscopy-guided air enema, the time required for recurrence, and the association between delayed reduction and the recurrence. Methods Medical records of 479 consecutive children with intussusception who underwent fluoroscopy-guided air enema between January 2004 and September 2014 were reviewed. Recurrent intussusception was defined as a recurrence within 48 hours of a reduction. Symptom-to-door time was defined as the time from symptom onset to emergency department arrival. Door-to-reduction time was defined as the time from emergency department arrival to reduction. Time-to-recurrence was defined as the time required for recurrence from the first ultrasound diagnosis. Results Of the 360 eligible children, 32 had recurrent intussusceptions (8.9%). Multivariable logistic regression showed that age 2 years or older is an independent predictor of recurrent intussusception (odds ratio, 2.39; 95% confidence interval, 1.13-5.02; P = 0.02). Median time to recurrence was 25 hours (18.0-36.0 hours). Although symptom-to-door and door-to-reduction times tended to be longer in the recurrence group, these differences were not significant (12.5 vs 7.0 hours, P = 0.18; 154.0 vs 143.0 minutes, P = 0.67, respectively). Conclusions Our data suggest that provision for early recurrence and extended observation may be beneficial for children 2 years or older. Delayed reduction was not associated with recurrent intussusception, but further studies with larger sample sizes are needed to explain this issue.

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.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.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.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.

We investigated clinical outcomes in high-risk patients with acute nonvariceal upper gastrointestinal bleeding (UGIB), and determined if urgent endoscopy is effective.Consecutive patients with a Glasgow-Blatchford score greater than 7 who underwent endoscopy for acute nonvariceal UGIB at the emergency department from January 1, 2005, to December 31, 2014, were included. Urgent (6 h) and elective (6-48 h) endoscopies were defined according to the time to endoscopy after the initial presentation. The primary outcomes were mortality and rebleeding within 28 days of admission.Among 961 patients, 571 patients underwent urgent endoscopy. The 28-day mortality rate was 2.5%, and the rebleeding rate was 10.4%. There were significant differences in mortality rate (1.6% vs 3.8%), the number of transfused packed red blood cells (2.6 ± 2.5 vs 2.3 ± 2.1 packs), need for intervention (69.5% vs 53.5%), and embolization (2.8% vs 0.5%), but no differences in rebleeding, intensive care unit admission, vasopressor use, and length of stay between the urgent and elective endoscopy groups. Mortality was associated with malignancy (odds ratio [OR], 3.58; 95% confidence interval [CI], 1.33-9.62), cirrhosis (OR, 4.67; 95% CI, 1.85-11.76), urgent endoscopy (OR, 0.36; 95% CI, 0.14-0.95), failed primary endoscopic treatment (OR, 15.03; 95% CI, 4.63-48.82), and rebleeding (OR, 2.77; 95% CI, 1.03-7.45). Rebleeding was associated with Forrest I ulcers (OR, 7.67; 95% CI, 2.71-21.69), Forrest II ulcers (OR, 2.34; 95% CI, 1.51-3.60), and coagulopathy (OR, 2.34; 95% CI, 1.51-3.60).Urgent endoscopy was an independent predictor of lower mortality rate but was not associated with rebleeding in high-risk patients with acute nonvariceal UGIB.

Background: There is a lack of data regarding the incidence and associated factors of pneumothorax following thoracentesis conducted in emergency department (ED) settings. The present study aims to determine the incidence of pneumothorax following thoracentesis in ED settings and evaluate the association of specific demographics, clinical, and procedure factors with thoracentesis-related pneumothorax. Methods: We retrospectively reviewed the medical records of 3,067 thoracentesis cases in the ED of a tertiary care, university-affiliated hospital between January 2009 and December 2014. To evaluate the factors associated with the occurrence of pneumothorax following thoracentesis, matched controls were used with a case to control ratio of 1:5. Results: Of the 3,067 cases that received thoracentesis, 19 cases of pneumothorax were observed (0.62%). Patients with pneumothorax had significantly lower weight and body mass index (BMI) than those without pneumothorax (51.0 vs . 61.2 kg, 20.0 vs . 22.6; P Conclusions: The incidence of pneumothorax following thoracentesis was very low in the present study. However, clinicians should be aware of the risk of pneumothorax in underweight patients during thoracentesis. Further prospective studies are required to clarify the results of the present study.

Kyungho Jang,1,2,* Min-Kyoung Kim,3,4,* Jaeseong Oh,1 SeungHwan Lee,1 Joo-Youn Cho,1 Kyung-Sang Yu,1 Tai Kiu Choi,3 Sang-Hyuk Lee,3,4 Kyoung Soo Lim4 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 2Center for Clinical Pharmacology and Biomedical Research Institute, Chonbuk National University Medical School, Jeonju, 3Department of Psychiatry, 4Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, Republic of Korea *These authors contributed equally to this work Purpose: Oseltamivir is widely used in the treatment and prophylaxis of influenza A and B viral infections. It is ingested as an oral prodrug that is rapidly metabolized by carboxylesterase 1 (CES1) to its active form, oseltamivir carboxylate. Dexamethasone is also used in the treatment of acute respiratory distress syndrome, a severe complication of influenza; however, its influence on the pharmacokinetics (PK) of oseltamivir is controversial. The aim of this study was to investigate the effects of coadministering oseltamivir and dexamethasone on the PK of oseltamivir in healthy volunteers. Methods: An open-label, two-period, one-sequence, multiple-dose study was conducted in 19 healthy male volunteers. Oseltamivir (75mg) was orally administered on Day 1 and Day 8, and dexamethasone (1.5mg) was administered once daily from Day 3 to Day 8. Serial blood and urine samples were collected for PK analysis of oseltamivir and oseltamivir carboxylate on Day 1 and Day 8. Oseltamivir and oseltamivir carboxylate concentrations in plasma and urine were determined using liquid chromatography–tandem mass spectrometry. Results: Area under the plasma concentration–time curve (AUC) of oseltamivir and oseltamivir carboxylate decreased after dexamethasone treatment for 6 days. The geometric mean ratio (90% confidence interval) of the metabolic ratio (oseltamivir carboxylate AUC0–48h/oseltamivir AUC0–48h) was 0.92 (0.87–0.97). The amount of unchanged oseltamivir excreted in urine increased by 14% after dexamethasone treatments. Conclusion: Coadministration of dexamethasone with oseltamivir slightly decreased systemic exposure to oseltamivir and oseltamivir carboxylate in healthy volunteers. This result suggests that CES1 is inhibited by dexamethasone in humans. However, coadministration of oseltamivir and dexamethasone did not appear to have a clinically relevant effect on the PK of oseltamivir; based on these results, dexamethasone can be coadministered with oseltamivir. Keywords: carboxylesterase, steroid, influenza, ARDS

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.

Wonsuk Shin,1 Kyoung Soo Lim,1 Min-Kyoung Kim,1 Hyun Sook Kim,2 Jihwa Hong,3 Stanford Jhee,3 Joseph Kim,3 Sungeun Yoo,4 Yeon-Tae Chung,4 Jae Moon Lee,4 Doo-Yeoun Cho1 1Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea; 2Department of Neurology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea; 3Department of Scientific Affairs, PAREXEL International, Waltham, MA, USA; 4Kainos Medicine Inc., Seongnam, Republic of Korea 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 10–400mg. 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. Keywords: first-in-human, KM-819, pharmacokinetics, pharmacodynamics, safety &nbsp

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.

Acquired methemoglobinemia is a potentially fatal condition that leads to tissue hypoxia. Although the clinical features of methemoglobinemia depend on the methemoglobin levels, the clinical course would differ depending on the causative agents.We attempted to clarify this issue by comparing the clinical course of methemoglobinemia caused by dapsone and that caused by other toxic agents.A retrospective case-control study was performed. All patients with methemoglobinemia and who were admitted to the emergency department (ED) of our hospital from 1 January 2002 to 31 December 2014 were included.Of the 34 patients with methemoglobinemia, 15 ingested dapsone (14 with acute overdose and one with chronic therapeutic use) and 19 had been exposed to other toxic agents, such as sodium nitrites, indoxacarb, primaquine, and lidocaine. The clinical characteristics and the course of dapsone-induced and other toxic-agent-induced methemoglobinemia were compared. There was no significant difference in clinical presentation and methemoglobin level (38.5% vs. 35.0%, p = 0.456) upon their ED arrival between the two groups. However, the methemoglobin level after use of methylene blue and the total dose of methylene blue were higher in patients with dapsone-induced methemoglobinemia than in those with other agent-induced methemoglobinemia (11.9% vs. 1.7%, p = 0.001, 455 mg vs. 144 mg, p = 0.006). The majority of dapsone-induced methemoglobinemia (93.3%) required more than 72 h for normalization of the methemoglobin level, despite the use of methylene blue. Five of the study patients died due to multiorgan failure, and all of whom were inpatients with dapsone-induced methemoglobinemia.The clinical course of dapsone-induced methemoglobinemia was worse than that of other toxic-agent-induced methemoglobinemia despite no significant difference in their initial clinical presentation. Continuous treatment with serial monitoring of the serum methemoglobin is necessary for patients with dapsone-induced methemoglobinemia.

To investigate the clinical features of coinfection due toWe reviewed 4,465 patients with influenza who visited a tertiary care hospital emergency department in Seoul (Korea) from 2010 through 2016, and underwent immunoglobulin M (IgM) serology or polymerase chain reaction (PCR) forOf 244 influenza pneumonia patients, 41 (16.8%) had

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 &ge, 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 &lt, 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&mdash, 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&ndash, 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 &le, 2 had a negative predictive value of 99.5% and an LBS score of &ge, 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.

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

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

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.

Background Although the incidence of anaphylaxis is rapidly increasing, the clinical characteristics and associated factors of a biphasic reaction are unclear. Objective To determine the incidence and clinical characteristics of biphasic reactions in patients with anaphylaxis treated with corticosteroids. Methods A total of 655 patients with anaphylaxis visiting the emergency department of a tertiary teaching hospital from January 2007 through December 2014 were analyzed. Patient characteristics, triggers, symptoms and signs, in-hospital management, and disposition were recorded. A biphasic reaction was defined as the development of anaphylaxis after complete resolution of the initial reaction without further exposure to the offending agent within 7 days. Univariate and multivariate analyses on the predictors of the biphasic reaction were performed. Results Of the 415 patients with anaphylaxis treated with corticosteroids, 9 patients (2.2%) developed a biphasic reaction. The mean age was 48.4 years, and 221 patients (54.4%) were women. The median time from complete resolution of initial clinical symptoms to occurrence of the biphasic reaction was 15 hours (range 1–45). History of drug anaphylaxis (odds ratio 14.3, 95% confidence interval 2.4–85.8) was a contributing factor to the development of the biphasic reaction. Conclusion The incidence of biphasic reactions was 2.2% in patients treated with corticosteroids and those with a history of drug anaphylaxis were at greater risk.

Purpose Rotigotine, a nonergolinic dopamine receptor agonist, is a once-daily transdermal patch developed for the treatment of Parkinson's disease and restless legs syndrome. The objective of the present study was to determine the pharmacokinetic characteristics and tolerability of rotigotine transdermal patch after repeated-dose application in healthy male and female Korean subjects. Methods In this randomized, double-blind, placebo-controlled, repeated-dose study, subjects were randomly assigned to receive either rotigotine or placebo (ratio, 20 rotigotine to 4 placebo, per sex). Rotigotine patches were applied once daily at a dose of 2 mg/24 h on days 1 to 3, followed by 4 mg/24 h on days 4 to 6. Serial blood and urine samples were collected on days 1 to 9 for the determination of the concentrations of rotigotine and its metabolites. Tolerability was evaluated by adverse events determined using physical examination, including vital signs with orthostatic measurements; ECG; and clinical laboratory testing. Findings A total of 48 healthy Korean subjects were enrolled (24 men, 24 women; mean age, 24 years). Approximately 50% of the total drug content was delivered within 24 hours. The mean plasma concentration of unconjugated rotigotine increased proportionally with dose. At the 2 mg/24 h dose at steady state, the geometric mean AUC 0–24h and C max values of unconjugated rotigotine were 5.88 ng·h/mL and 0.347 ng/mL, respectively; at the 4 mg/24 h dose, the corresponding values were 13.74 ng·h/mL and 0.838 ng/mL. The mean t ½ of rotigotine was 4.96 hours. At the 2 mg/24 h dose at steady state, the geometric mean AUC 0–24h and C max values of total rotigotine were 14.02 ng·h/mL and 0.776 ng/mL; at the 4-mg/24 h dose, 32.38 ng·h/mL and 1.867 ng/mL. Common adverse events reported in the rotigotine-treated subjects included nausea (17 subjects, 42.5%), headache (11, 27.5%), and dizziness (9, 22.5%). No clinically significant changes in blood pressure, ECG, or laboratory values were observed. Implications The mean plasma exposures of unconjugated rotigotine increased proportionally with dose. Repeated daily application of the rotigotine patch was well tolerated in these healthy Korean volunteers. ClinicalTrials.gov identifier: NCT01964573.

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.This retrospective study was performed from a prospective septic shock registry.This study was performed at single urban tertiary center. And, all patients were treated with protocol-driven resuscitation bundle therapy between 2010 and 2016.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.Serum lactate levels were measured at initial and 6 hours from septic shock recognition.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%; p0.01). 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; p0.01). The prognostic value of subsequent lactate levels (≥ 2, ≥ 3, and ≥ 4 mmol/L) and lactate clearances (10%,20%, and30%) was not significantly differed. However, lactate levels of greater than or equal to 2 mmol/L had the greatest sensitivity (85.3%).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.

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

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.To determine whether acute brain lesions on diffusion-weighted imaging are related to subsequent development of delayed neurological sequelae after acute carbon monoxide poisoning.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.The presence of unambiguous, high-signal-intensity, acute brain lesions on diffusion-weighted imaging (b = 1000 s/mm2).Development of delayed neurological sequelae defined as any neurological symptoms or signs that newly developed within 6 weeks of discharge.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%] had1 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.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.

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.

Taegon Hong,1,2 Seunghoon Han,1,2 Jongtae Lee,1,2 Sangil Jeon,1,2 Gab-Jin Park,1,2 Wan-Su Park,1,2 Kyoung Soo Lim,3 Jae-Yong Chung,4 Kyung-Sang Yu,3 Dong-Seok Yim1,2 1Department of Pharmacology, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea; 2PIPET (Pharmacometrics Institute for Practical Education and Training), the Catholic University of Korea, Seoul, Republic of Korea; 3Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 4Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of Korea Abstract: A single 400 mg dose of moxifloxacin has been the standard positive control for thorough QT (TQT) studies. However, it is not clearly known whether a 400 mg dose is also applicable to TQT studies in Asian subjects, including Koreans. Thus, we aimed to develop a pharmacokinetic (PK)-pharmacodynamic (PD) model for moxifloxacin, to evaluate the time course of its effect on QT intervals in Koreans. Data from three TQT studies of 33 healthy male Korean subjects who received 400 and 800 mg of moxifloxacin and placebo (water) were used. Twelve-lead electrocardiograms were taken for 2 consecutive days: 1 day to record diurnal changes and the next day to record moxifloxacin or placebo effects. Peripheral blood samples were also obtained for PK analysis. The PK-PD data obtained were analyzed using a nonlinear mixed-effects method (NONMEM ver. 7.2). A two-compartment linear model with first-order absorption provided the best description of moxifloxacin PK. Individualized QT interval correction, by heart rate, was performed by a power model, and the circadian variation of QT intervals was described by two mixed-effect cosine functions. The effect of moxifloxacin on QT interval prolongation was well explained by the nonlinear dose-response (Emax) model, and the effect by 800 mg was only slightly greater than that of 400 mg. Although Koreans appeared to be more sensitive to moxifloxacin-induced QT prolongation than were Caucasians, the PK-PD model developed suggests that a 400 mg dose of moxifloxacin is also applicable to QT studies in Korean subjects. Keywords: thorough QT study, PK-PD model, NONMEM, Emax model

The purposes of this study were to investigate the clinical presentation, cause and outcome of drug-induced liver injury (DILI) and to evaluate the predictive value of the model for end-stage liver disease (MELD) score in DILI.Patients diagnosed with DILI between January 1, 2010 and December 31, 2012 in the Emergency Department at Asan Medical Center in Seoul, Korea were analyzed retrospectively. The primary end point was poor outcome, defined as liver transplantation or death within 30 days of the initial hospital visit.Of 213 patients, 13.1% had a 30-day poor outcome. Folk remedies were the most common cause of DILI in 147 patients (69%). Univariate logistic regression analysis showed that multiple drugs (odds ratio [OR] 2.30, 95% confidence interval [CI]: 1.03-5.15), concurrent alcohol consumption (OR 3.69, 95% CI: 1.03-13.18), white blood cell (WBC) count (OR 1.17, 95% CI: 1.07-1.28), hemoglobin (Hb) (OR 0.60, 95% CI: 0.49-0.74), platelet count (OR 0.993, 95% CI: 0.987-0.998), total bilirubin (OR 1.09, 95% CI: 1.06-1.13) and MELD (OR 1.23, 95% CI: 1.15-1.32) were significantly associated with 30-day poor outcomes. Multivariate analysis showed that the MELD (OR 1.21, 95% CI: 1.12-1.30) and Hb (OR 0.77, 95% CI: 0.61-0.98) were independent predictors of poor outcome. For 30-day mortality, the c-statistics for MELD alone and for combination of MELD and Hb were 0.93 (95% CI: 0.89-0.97) and 0.94 (95% CI: 0.90-0.97), respectively.The outcome of patients with DILI was poor. MELD score and Hb were reliable predictors of short-term outcome in patients with DILI.

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 Escudie’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 ± 6.6 days. Eight patients fulfilled Ganzert's criteria, while 10 patients fulfilled the King's College and Escudie’s criteria for emergency liver transplantation. King's College and Escudie’s criteria had 100% accuracy in predicting 28-day mortality; however, Escudie’s criteria were able to identify fatal cases earlier. Conclusions Escudie’s criteria demonstrated the best performance with 100% accuracy and the ability to promptly identify fatal cases of mushroom-induced acute liver failure.

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.

Aspiration pneumonia is associated with significant morbidity and mortality; however, little is known about aspiration pneumonia in patients with carbon monoxide intoxication, which is the leading cause of poisoning-related death. This study aimed to evaluate the prevalence, clinical impacts, and risk factors for developing aspiration pneumonia in patients with carbon monoxide poisoning with loss of consciousness.A retrospective analysis of a carbon monoxide poisoning registry was performed at our emergency department for the period January 2008 to December 2015. All adult carbon monoxide poisoning patients with loss of consciousness were included.Aspiration pneumonia developed in 103 (19.2%) of 537 patients. It was associated with increased ventilator use (52.4% vs 3.2%), length of hospital stay (median [interquartile range], 3.6 [2.1-5.1] vs 1.3 [0.6-2.1] days), and in-hospital mortality (5.8% vs 0.0%) (all P .001). Altered mental status on emergency department arrival, white blood cell count, and increased exposure duration were the independent factors associated with development of aspiration pneumonia; odds ratios were 9.46 (95% confidence interval [CI] 4.92-18.19; P .001), 1.19 (95% CI 1.13-1.26; P .001), and 1.12 (95% CI 1.06-1.19; P .001), respectively. For painful or unresponsive mental status and white blood cell count 12,000/mmThe prevalence of aspiration pneumonia was 19.2% in carbon monoxide poisoning patients with loss of consciousness and was associated with poor outcomes. Additionally, altered mental status on emergency department arrival, white blood cell count, and increased exposure duration were independently associated with the development of aspiration pneumonia.

Antidotes for toxicological emergencies can be life-saving. However, there is no nationwide estimation of the antidotes stocking amount in Korea. This study tried to estimate the quantities of stocking antidotes at emergency department (ED). An expert panel of clinical toxicologists made a list of 18 emergency antidotes. The quantity was estimated by comparing the antidote utilization frequency in a multicenter epidemiological study and the nation-wide EDs' data of National Emergency Department Information System (NEDIS). In an epidemiological study of 11 nationwide EDs from January 2009 to December 2010, only 92 (1.9%) patients had been administered emergency antidotes except activated charcoal among 4,870 cases of acute adult poisoning patients. Comparing with NEDIS data, about 1,400,000 patients visited the 124 EDs nationwide due to acute poisoning and about 103,348 adult doses of the 18 emergency antidotes may be required considering poisoning severity score. Of these, 13,224 (1.9%) adult doses of emergency antidotes (575 of atropine, 144 of calcium gluconate or other calcium salts, 2,587 of flumazenil, 3,450 of N-acetylcysteine, 5,893 of pralidoxime, 287 of hydroxocobalamin, 144 of sodium nitrite, and 144 of sodium thiosulfate) would be needed for maintaining the present level of initial treatment with emergency antidotes at EDs in Korea. Graphical Abstract

Namyi Gu,1,3,* Min Kyu Park,1,4,* Tae-Eun Kim,1,5 Mi Young Bahng,2 Kyoung Soo Lim,1 Sang-Heon Cho,1 Seo Hyun Yoon,1 Joo-Youn Cho,1 In-Jin Jang,1 Kyung-Sang Yu1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Clinical Development Department, Dong-A ST Co, Ltd, Seoul, Republic of Korea; 3Department of Clinical Pharmacology and Therapeutics, Dongguk University College of Medicine and Ilsan Hospital, Goyang, Gyeonggi-do, Republic of Korea; 4Department of Clinical Pharmacology and Therapeutics, Dong-A University College of Medicine and Hospital, Busan, Republic of Korea; 5Department of Clinical Pharmacology and Therapeutics, Kunkuk University Medical Center, Seoul, Republic of Korea *These authors contributed equally to this work Purpose: Evogliptin (DA-1229) is a novel, potent, and selective dipeptidyl peptidase IV (DPP-IV) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study aimed to investigate the pharmacokinetic and pharmacodynamic profiles and tolerability of evogliptin after repeated oral administration in healthy subjects.Patients and methods: A block-randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study was performed in a total of 30 subjects. Repeated once-daily doses of 5, 10, or 20 mg evogliptin or the same doses of placebo were orally administered to ten subjects in each dosage group for 10 days. Subjects in each group were randomized to receive evogliptin or placebo with a ratio of 8:2. Pharmacokinetics of evogliptin were evaluated, with its concentrations in serial plasma and urine samples collected following the first and last administrations. DPP-IV activity and glucagon-like peptide-1, glucose, and insulin levels were quantified to evaluate evogliptin's pharmacodynamics on the first and last dosing days.Results: All participants completed the study without any serious or severe adverse event. The evogliptin plasma concentration reached its peak within 4–5 hours and decreased relatively slowly, with a terminal elimination half-life of 33–39 hours. Repeated administration resulted in a 1.4- to 1.5-fold accumulation. Evogliptin's systemic exposure and inhibition of plasma DPP-IV activity increased in a dose-dependent manner. Inhibition of DPP-IV activity >80% was sustained over 24 hours in all evogliptin dose groups and provided an increase in postprandial active glucagon-like peptide-1 levels by 1.5- to 2.4-fold. Postprandial glucose levels in the evogliptin-treated groups were reduced 20%–35% compared to placebo, but were not accompanied by increased insulin levels.Conclusion: Repeated administration of evogliptin in healthy subjects was well tolerated and exhibited linear pharmacokinetics within the 5–20 mg dose range. A once-daily regimen of 5–20 mg evogliptin effectively inhibited DPP-IV activity.Keywords: DPP-IV, GLP-1, insulin, glucagon-like peptide-1, glucose

Aims HM30181 is a third generation P-glycoprotein (P-gp) inhibitor currently under development. The objectives of this study were to evaluate the effects of a single dose of HM30181 on the pharmacodynamics and pharmacokinetics of loperamide, a P-gp substrate, and to compare them with those of quinidine. Methods Eighteen healthy male subjects were administered loperamide alone (period 1) or with loperamide plus quinidine or HM30181 in period 2 or 3, respectively. In period 3, subjects randomly received one of three HM30181 doses: 15, 60 or 180 mg. Changes in pupil size, alertness, oxygen saturation and the oral bioavailability of loperamide were assessed in each period. In addition, the pharmacokinetics of HM30181 were determined. Results Pupil size, alertness and oxygen saturation did not change over time when loperamide alone or loperamide plus HM30181 was administered while HM30181 significantly increased the systemic exposure to loperamide, i.e. the geometric mean ratio (90% confidence interval) of AUC(0,tlast) for loperamide with and without HM30181 was 1.48 (1.08, 2.02). Co-administered quinidine significantly increased the systemic exposure to loperamide 2.2-fold (1.53, 3.18), which also markedly reduced pupil size, resulting in a decrease of 24.7 mm h in the area under the effect curve of pupil size change from baseline compared with loperamide alone. Conclusions HM30181 inhibits P-gp mainly in the intestinal endothelium, which can be beneficial because pan-inhibition of P-gp, particularly in the brain, could lead to detrimental adverse events. Further studies are warranted to investigate adequately the dose–exposure relationship of HM30181, along with its duration of effect.