Yoon Sun Jung

Prolonged therapeutic hypothermia is more effective in attenuating brain apoptosis in a Swine cardiac arrest model.

Objectives:To investigate whether 48 hours of therapeutic hypothermia is more effective to attenuate brain apoptosis than 24 hours and to determine whether the antiapoptotic effects of therapeutic hypothermia are associated with the suppressions of the cleavage of protein kinase C-&dgr;, the cytosolic release of cytochrome c, and the cleavage of caspase 3 in a swine cardiac arrest model. Design:Prospective laboratory study. Setting:University laboratory. Subjects:Male domestic pigs (n = 24). Interventions:After 6 minutes of no-flow time that was induced by ventricular fibrillation, cardiopulmonary resuscitation was provided, and the return of spontaneous circulation was achieved. The animals were randomly assigned to the following groups: sham, normothermia, 24 hours of therapeutic hypothermia, or 48 hours of therapeutic hypothermia. Therapeutic hypothermia (core temperature, 32–34°C) was maintained for 24 or 48 hours post return of spontaneous circulation, and the animals were rewarmed for 8 hours. At 60 hours post return of spontaneous circulation, the animals were killed, and brain tissues were harvested. Measurements and Main Results:We examined cellular apoptosis and neuronal damage in the brain hippocampal cornu ammonis 1 region. We also measured the cleavage of protein kinase C-&dgr;, the cytosolic release of cytochrome c, and the cleavage of caspase 3 in the hippocampus. The 48 hours of therapeutic hypothermia attenuated cellular apoptosis and neuronal damage when compared with normothermia. There was also a decrease in the cleavage of protein kinase C-&dgr;, the cytosolic release of cytochrome c, and the cleavage of caspase 3. However, 24 hours of therapeutic hypothermia did not significantly attenuate cellular apoptosis or neuronal damage. Conclusions:We found that 48 hours of therapeutic hypothermia was more effective in attenuating brain apoptosis than 24 hours of therapeutic hypothermia. We also found that the antiapoptotic effects of therapeutic hypothermia were associated with the suppressions of the cleavage of protein kinase C-&dgr;, the cytosolic release of cytochrome c, and the cleavage of caspase 3.

The therapeutic effect and mechanism of niacin on acute lung injury in a rat model of hemorrhagic shock: Down-regulation of the reactive oxygen species-dependent nuclear factor κB pathway.

BACKGROUND The purpose of the current study was to investigate the protective effect of niacin on acute lung injury by the down-regulation of the nuclear factor &kgr;B (NF-&kgr;B) pathway in hemorrhagic shock (HS) rats. METHODS HS was induced in male Sprague-Dawley rats by withdrawing blood to maintain a mean arterial pressure of 20 mm Hg to 25 mm Hg for 40 minutes. The rats were resuscitated by the reinfusion of the drawn blood, and a vehicle (HS), a low-dose of niacin (360 mg/kg, HS + LD-NA), or a high dose of niacin (1,080 mg/kg, HS + HD-NA) were administered orally. The survival of the subjects was observed for 72 hours, and a separate set of animals was killed at 6 hours after HS induction. We measured cytoplasmic phosphorylated inhibitor &kgr;B-&agr; and inhibitor &kgr;B-&agr; expressions, nuclear NF-&kgr;B p65 expression, NF-&kgr;B p65 DNA-binding activity, MEK partner 1 activity, tumor necrosis factor &agr; (TNF-&agr;), interleukin 6 (IL-6), IL-8, nicotinamide adenine dinucleotide (NAD+), reduced nicotinamide adenine dinucleotide phosphate, reduced glutathione, glutathione disulfide, malondialdehyde levels, and histologic damage in the lung tissue. We also measured TNF-&agr;, IL-6, and IL-8 levels in the serum. RESULTS The survival rates of the sham, HS, HS + LD-NA, and HS + HD-NA groups were 6 of 6 (100%), 0 of 9 (0%), 1 of 9 (11.1%), and 3 of 9 (33.3%), respectively. A high dose of niacin increased lung NAD+, nicotinamide adenine dinucleotide phosphate levels, and glutathione–glutathione disulfide ratios; decreased lung malondialdehyde levels; down-regulated the NF-&kgr;B pathway; suppressed TNF-&agr;, IL-6, and IL-8 levels in the lung tissue and serum; and attenuated histologic lung damage. CONCLUSION A high dose of niacin attenuated lung inflammation, suppressed proinflammatory cytokine release, reduced histologic lung damage, and improved survival after HS in rats. Its therapeutic benefits were associated with the down-regulation of the reactive oxygen species–dependent NF-&kgr;B pathway.

Niacin and Selenium Attenuate Sepsis-Induced Lung Injury by Up-Regulating Nuclear Factor Erythroid 2-Related Factor 2 Signaling.

Objectives:To determine whether the combination therapy of niacin and selenium attenuates lung injury and improves survival during sepsis in rats and whether its benefits are associated with the activation of the glutathione redox cycle and up-regulation of nuclear factor erythroid 2–related factor 2. Design:Prospective laboratory study. Setting:University laboratory. Subjects:Human lung microvascular endothelial cells and male Sprague-Dawley rats (n = 291). Intervention:In lipopolysaccharide-exposed cells, the dose-related effects of niacin and selenium were assessed, and the therapeutic effects of the combination therapy of niacin (0.9 mM) and selenium (1.5 &mgr;M) were evaluated. The role of nuclear factor erythroid 2–related factor 2 was determined using nuclear factor erythroid 2–related factor 2 knockdown cells. In endotoxemic and cecal ligation and puncture with antibiotics rats, the therapeutic effects of the posttreatments of clinically relevant doses of niacin (360 mg/kg) and selenium (60 &mgr;g/kg) were evaluated. Measurements and Main Results:Combination therapy reduced the hydrogen peroxide level via the synergistic activation of the glutathione redox cycle, which involves niacin-induced increases in glutathione reductase activity, and reduced the glutathione level and a selenium-induced increase in glutathione peroxidase activity. Combination therapy contributed to the up-regulation of nuclear factor erythroid 2–related factor 2, enhancement of glutathione synthesis, and down-regulation of nuclear factor &kgr;B signaling, but nuclear factor erythroid 2–related factor 2 knockdown inhibited the enhancement of glutathione synthesis and down-regulation of the nuclear factor &kgr;B pathway. The therapeutic effects of combination therapy on endotoxemic rats were consistent with those on lipopolysaccharide-exposed cells. In addition, the posttreatment of combination therapy attenuated lung injury and improved survival in endotoxemic and cecal ligation and puncture with antibiotics rats. However, individual therapies of niacin or selenium failed to achieve these benefits. Conclusions:The combination therapy of niacin and selenium attenuated lung injury and improved survival during sepsis. Its therapeutic benefits were associated with the synergistic activation of the glutathione redox cycle, reduction of hydrogen peroxide level, and up-regulation of nuclear factor erythroid 2–related factor 2.

Prognostic performance of Emergency Severity Index (ESI) combined with qSOFA score

Objective We conducted this study to investigate whether ESI combined with qSOFA score (ESI + qSOFA) predicts hospital outcome better than ESI alone in the emergency department (ED). Methods This was a retrospective study for patients aged over 15 years who visited an ED of a tertiary referral hospital from January 1st, 2015 to December 31st, 2015. We calculated and compared predictive performances of ESI alone and ESI + qSOFA for prespecified outcomes. The primary outcome was hospital mortality, and the secondary outcome was composite outcome of in‐hospital mortality and ICU admission. We calculated in‐hospital mortality rates by positive qSOFA in each subgroup divided according to ESI levels (1, 2, 3, 4 + 5). Results 43,748 patients were enrolled. The area under receiver‐operating characteristics curves were higher in ESI + qSOFA than in ESI alone for both mortality and composite outcome (0.786 vs. 0.777, P < .001 for mortality; 0.778 vs. 0.774, P < .001 for composite outcome). In each subgroup divided by ESI levels, patients with positive qSOFA had significantly higher in‐hospital mortality rate compared to those with negative qSOFA (20.4% vs. 14.7%, P = .117 in ESI level 1 subgroup; 11.3% vs. 2.7%, P = .001 in ESI level 2 subgroup; 2.3% vs. 0.4%, P < .001 in ESI level 3 subgroup; 0.0% vs. 0.0% in ESI level 4 or 5 subgroup). Conclusion The prognostic performance of ESI + qSOFA for in‐hospital mortality was significantly higher than that of ESI alone. Within each subgroup, patients with positive qSOFA had higher in‐hospital mortality compared to those with negative qSOFA.

End-tidal CO 2 -guided automated robot CPR system in the pig. Preliminary communication

BACKGROUND Our aim was to compare the efficacy of the end-tidal CO2-guided automated robot CPR (robot CPR) system with manual CPR and mechanical device CPR. METHODS We developed the algorithm of the robot CPR system which automatically finds the optimal compression position under the guidance of end-tidal CO2 feedback in swine models of cardiac arrest. Then, 18 pigs after 11 min of cardiac arrest were randomly assigned to one of three groups, robot CPR, LUCAS CPR, and manual CPR groups (n = 6 each group). Return of spontaneous circulation (ROSC) and Neurological Deficit Score 48 h after ROSC were compared. RESULTS A ROSC was achieved in 5 pigs, 4 pigs, and 3 pigs in the robot CPR, LUCAS CPR, and manual CPR groups, respectively (p = 0.47). Robot CPR showed a significant difference in Neurological Deficit Score 48 h after ROSC compared to manual CPR, whereas LUCAS CPR showed no significant difference over manual CPR. (p = 0.01; Robot versus Manual adjusted p = 0.04, Robot versus LUCAS adjusted p = 0.07, Manual versus LUCAS adjusted p = 1.00). CONCLUSIONS The end-tidal CO2-guided automated robot CPR system did not significantly improve ROSC rate in a swine model of cardiac arrest. However, robot CPR showed significant improvement of Neurological Deficit Score 48 h after ROSC compared to Manual CPR while LUCAS CPR showed no significant improvement compared to Manual CPR.

Low serum Kallistatin level was associated with poor neurological outcome of out-of-hospital cardiac arrest survivors: Proteomics study

AIM OF THE STUDY To identify proteins of which depletion are associated with the poor 6-month neurological outcome of out-of-hospital cardiac arrest survivors. METHODS Seven healthy volunteers and 34 out-of-hospital cardiac arrest survivors admitted to the intensive care unit (ICU) and underwent targeted-temperature management were enrolled. According to the 6-month cerebral performance category (CPC) scale, patients were divided into the good (CPC 1-2) and poor (CPC 3-5) outcome groups. Blood samples were obtained at 0, 24, and 72 h after admission to the ICU. RESULTS With proteomic approaches, we found 23 proteins that showed group-differences between the sera pooled from 7 study groups: healthy volunteers, the good outcome groups (0, 24, and 72 h), and the poor outcome groups (0, 24, and 72 h). We selected 7 candidate proteins of which intensities were different between the good and poor outcome groups (>2-fold change) and excluded 5 proteins related to haemolysis or remaining high abundant proteins. To confirm the 2 identified proteins: retinal dehydrogenase 1 and Kallistatin, we performed enzyme-linked immunosorbent assay with individual serum. Finally, old age (odds ratio = 1.055; 95% confidence interval, 1.002-1.112; p = 0.043) and low serum kallistatin level at 0 h (odds ratio = 0.784; 95% confidence interval, 0.618-0.995; p = 0.046) were independently associated with the poor 6-month neurological outcome. CONCLUSION The depletion of serum kallistatin at admission to the ICU was associated with the poor neurological outcome of out-of-hospital cardiac arrest survivors.

Prediction of neurological outcomes following the return of spontaneous circulation in patients with out-of-hospital cardiac arrest: Retrospective fast-and-frugal tree analysis

AIM Although various quantitative methods have been developed for predicting neurological prognosis in patients with out-of-hospital cardiac arrest (OHCA), they are too complex for use in clinical practice. We aimed to develop a simple decision rule for predicting neurological outcomes following the return of spontaneous circulation (ROSC) in patients with OHCA using fast-and-frugal tree (FFT) analysis. METHODS We performed a retrospective analysis of prospectively collected data archived in a multi-centre registry. Good neurological outcomes were defined as cerebral performance category (CPC) values of 1 or 2 at 28-day. Variables used for FFT analysis included age, sex, witnessed cardiac arrest, bystander cardiopulmonary resuscitation, initial shockable rhythm, prehospital defibrillation, prehospital ROSC, no flow time, low flow time, cause of arrest (cardiac or non-cardiac), pupillary light reflex, and Glasgow Coma Scale score after ROSC. RESULTS Among the 456 patients enrolled, 86 (18.9%) experienced good neurological outcomes. Prehospital ROSC (true = good), prompt or sluggish light reflex response after ROSC (true = good), and presumed cardiac cause (true = good, false = poor) were selected as nodes for the decision tree. Sensitivity, specificity, positive predictive value, and negative predictive value of the decision tree for predicting good neurological outcomes were 100% (42/42), 64.0% (119/186), 38.5% (42/109), and 100% (119/119) in the training set and 95.5% (42/44), 57.6% (106/184), 35.0% (42/120), and 98.1% (106/108) in the test set, respectively. CONCLUSION A simple decision rule developed via FFT analysis can aid clinicians in predicting neurological outcomes following ROSC in patients with OHCA.

Lower serum kallistatin level is associated with 28-day mortality in patients with septic shock

Purpose: Investigation for whether serum levels of kallistatin, vascular cell adhesion molecule‐1 (VCAM‐1), and E‐selectin are associated with outcomes in patients with septic shock Material and methods: Biomarker levels were measured using blood samples from patients with septic shock at admission, 24 h, and 72 h and from healthy volunteers. The primary outcome was 28‐day mortality. Results: Fifty‐eight survivors, fourteen non‐survivors, and six healthy volunteers were enrolled. Serum kallistatin level was lower and serum VCAM‐1 and E‐selectin levels were higher in patients at admission compared with healthy volunteers. Serum kallistatin levels were higher in survivors compared with non‐survivors at all time points (4.4 &mgr;g/mL [2.9–6.1] vs. 2.5 &mgr;g/mL [2.1–5.0], P = 0.019 at admission; 4.3 &mgr;g/mL [3.3–5.2] vs. 3.2 &mgr;g/mL [2.2–3.8], P = 0.004 at 24 h; 3.1 &mgr;g/mL [2.5–4.2] vs. 2.3 &mgr;g/mL [1.7–3.1], P = 0.012 at 72 h), while VCAM‐1 and E‐selectin levels showed no difference. In the multivariable analysis, serum kallistatin level at 24 h was independently associated with 28‐day mortality (OR, 0.29; 95% CI, 0.08–0.69, P = 0.024). Conclusions: Lower serum kallistatin level at 24 h was independently associated with 28‐day mortality in patients with septic shock

Delayed endoscopy is associated with increased mortality in upper gastrointestinal hemorrhage

Objectives: To determine the association between delayed (>24h) endoscopy and hospital mortality in patients with upper gastrointestinal hemorrhage (UGIH). Methods: We retrospectively analyzed all adult patients with UGIH who underwent endoscopy in a single emergency room for 2years. The primary exposure was defined as >24h from the ED visit to the first endoscopy. The primary outcome was defined as all cause hospital mortality. Secondary outcomes were intensive care unit admission rate, ED length of stay, and hospital length of stay. Results: Among 1101 patients enrolled, 898 received endoscopy within 24h (early group) and 203 received endoscopy after 24h (delayed group). The hospital mortality of early and delayed group was 2.8% and 6.4%, respectively (unadjusted relative risk [RR] 2.30: 95% CI, 1.20–4.42, p=0.012). This was significant after adjusting covariates including AIMS65 and Glasgow‐Blatchford score (adjusted RR 2.23: 95% CI, 1.18–4.20, p=0.013). Intensive care unit admission rate was not different between two groups. ED and hospital length of stay were significantly longer in delayed group. Conclusions: Endoscopy performed after 24h was associated with increased hospital mortality in UGIH. Patients in the delayed group stayed longer in the ED and in the hospital.

Relative tachycardia is associated with poor outcomes in post-cardiac arrest patients regardless of therapeutic hypothermia

Background: To investigate whether the relationship between heart rate and neurological outcome is independent of therapeutic hypothermia (TH) and whether heart rate is related to hemodynamic instability post‐cardiac arrest. Methods: Retrospective review of an out‐of‐hospital cardiac arrest registry was performed. The primary exposure was heart rate quartiles at 24 h post‐cardiac arrest. The primary outcome was a poor neurological outcome, which was defined as having a cerebral performance category (CPC) of 3–5 at 28 days. Secondary outcomes were mean blood pressure and serum lactate at 24 h and Sequential Organ Failure Assessment (SOFA) scores at admission. Results: In total, 155 patients were enrolled. The proportion of patients with a poor CPC was significantly greater in higher heart rate quartiles; similar results were observed in patients who did and did not undergo TH. Serum lactate levels at 24 h were significantly higher in the 3rd and 4th quartile groups than in the 1st quartile group. Additionally, SOFA scores were significantly higher in the 4th quartile group than in the 1st and 3rd quartile groups. Conclusions: Relative tachycardia is associated with poor neurological outcomes in post‐cardiac arrest patients, independent of TH, and with higher serum lactate levels and admission SOFA scores.