Cost-Effectiveness of Juluca for Human Immunodeficiency Virus Infection Treatment in Virologically Suppressed Adults in Taiwan.

OBJECTIVES: Although the efficacy of traditional 3-drug regimens for the treatment of HIV is well established, tolerability and toxicity concerns remain. New 2-drug regimens such as Juluca (dolutegravir [DTG]/rilpivirine [RPV]) offer noninferior efficacy versus 3-drug regimens (SWORD-1 and SWORD-2 studies), while reducing cumulative drug exposure and potentially long-term toxicities and drug-drug interactions. Here, we assess the cost-effectiveness of DTG/RPV for the treatment of HIV-1 for virologically suppressed adults in Taiwan. METHODS: A hybrid decision tree and Markov cohort state transition model was used to evaluate the expected economic costs and clinical outcomes associated with DTG/RPV and comparators. Model health states were defined by viral load and CD4 cell count. Efficacy and safety data were informed from SWORD-1 and SWORD-2 studies and the literature. The risk of long-term toxicities (cardiovascular disease, bone fractures, and chronic kidney disease) were included. Current branded drug acquisition prices were included, and healthcare costs informed by a bespoke costing study using National Health Insurance Research Database data. Incremental cost-effectiveness ratios were calculated and compared with a willingness-to-pay threshold of 2 times Taiwan's gross domestic product (NT$1 550 000). RESULTS: DTG/RPV was found to be a cost-saving regimen compared to 3 comparators (rilpivirine [RPV]/emtricitabine [FTC]/tenofovir disoproxil fumarate [TDF], dolutegravir [DTG]/abacavir [ABC]/lamivudine [3TC], and elvitegravir [EVG]/cobicistat [c]/emtricitabine [FTC]/tenofovir alafenamide [TAF]) and fell in the southwest quadrant of the cost-effectiveness plane where it is generating significant savings with a small decrement in lifetime quality-adjusted life-years (-0.005). It was, however, more expensive than efavirenz [EFV]/emtricitabine [FTC]/ tenofovir disoproxil fumarate [TDF]. CONCLUSIONS: DTG/RPV is cost-saving compared to RPV/FTC/TDF, DTG/ABC/3TC, and EVG/c/FTC/TAF, and provides comparable efficacy with reduced cumulative drug exposure.

Hypothermia treatment preserves mitochondrial integrity and viability of cardiomyocytes after ischaemic reperfusion injury.

BACKGROUND: Haemorrhagic shock after traumatic injury carries a high mortality. Therapeutic hypothermia has been widely used in critical illness to improve the outcome in haemorrhagic shock by activation of cardiac pro-survival signalling pathways. However, the role played by the mitochondria in the cardioprotective effects of therapeutic hypothermia remains unclear. We investigated the effects of therapeutic hypothermia on mitochondrial function and integrity after haemorrhagic shock using an in vitro ischaemia-reperfusion model. METHODS: H9c2 cardiomyocytes received a simulated ischaemic reperfusion injury under normothermic (37 °C) and hypothermic (31 °C) conditions. The cardiomyocytes were treated with hypoxic condition for 18 h in serum-free, glucose-free culture medium at pH 6.9 and then shifted to re-oxygenation status for 6h in serum-containing cell culture medium at pH 7.4. Cellular survival, mitochondrial integrity, energy metabolism and calcium homeostasis were studied. RESULTS: Hypothermia treatment lessened cell death (15.0 ± 12.7 vs. 31.9 ± 11.8%, P=0.025) and preserved mitochondrial number (81.3 ± 17.4 vs. 45.2 ± 6.6, P=0.03) against simulated ischaemic reperfusion injury. Hypothermia treatment ameliorated calcium overload in the intracellular (1.5 ± 0.2 vs. 9.5 ± 2.8, P<0.001) and intra-mitochondrial (1.0 ± 0.3 vs. 1.6 ± 0.3, P=0.014) compartments against the injury. Mitochondrial integrity was more preserved by hypothermia treatment (50.1 ± 26.6 vs. 14.8 ± 13.0%, P<0.01) after the injury. Mitochondrial ATP concentrations were maintained with hypothermia treatment after injury (16.7 ± 9.5 vs. 6.1 ± 5.1 µM, P<0.01). CONCLUSIONS: Hypothermia treatment at 31 °C can ameliorate cardiomyocyte damage caused by simulated ischaemic reperfusion injuries. Mitochondrial calcium homeostasis, energy metabolism, and membrane integrity are preserved and play critical roles during therapeutic hypothermia treatment.

Effects of an Al(3+)- and Mg(2+)-containing antacid, ferrous sulfate, and calcium carbonate on the absorption of nemonoxacin (TG-873870) in healthy Chinese volunteers.

AIM: To evaluate the effects of an Al(3+)- and Mg(2+)-containing antacid, ferrous sulfate, and calcium carbonate on the absorption of nemonoxacin in healthy humans. METHODS: Two single-dose, open-label, randomized, crossover studies were conducted in 24 healthy male Chinese volunteers (12 per study). In Study 1, the subjects orally received nemonoxacin (500 mg) alone, or an antacid (containing 318 mg of Al(3+) and 496 mg of Mg(2+)) plus nemonoxacin administered 2 h before, concomitantly or 4 h after the antacid. In Study 2, the subjects orally received nemonoxacin (500 mg) alone, or nemonoxacin concomitantly with ferrous sulfate (containing 60 mg of Fe(2+)) or calcium carbonate (containing 600 mg of Ca(2+)). RESULTS: Concomitant administration of nemonoxacin with the antacid significantly decreased the area under the concentration-time curve from time 0 to infinity (AUC0-∞) for nemonoxacin by 80.5%, the maximum concentration (Cmax) by 77.8%, and urine recovery (Ae) by 76.3%. Administration of nemonoxacin 4 h after the antacid decreased the AUC0-∞ for nemonoxacin by 58.0%, Cmax by 52.7%, and Ae by 57.7%. Administration of nemonoxacin 2 h before the antacid did not affect the absorption of nemonoxacin. Administration of nemonoxacin concomitantly with ferrous sulfate markedly decreased AUC0-∞ by 63.7%, Cmax by 57.0%, and Ae by 59.7%, while concomitant administration of nemonoxacin with calcium carbonate mildly decreased AUC0-∞ by 17.8%, Cmax by 14.3%, and Ae by 18.4%. CONCLUSION: Metal ions, Al(3+), Mg(2+), and Fe(2+) markedly decreased the absorption of nemonoxacin in healthy Chinese males, whereas Ca(2+) had much weaker effects. To avoid the effects of Al(3+) and Mg(2+)-containing drugs, nemonoxacin should be administered ≥2 h before them.

Prognostic relevance of plasma heart-type fatty acid binding protein after out-of-hospital cardiac arrest.

OBJECTIVE: Heart-type fatty acid binding protein (H-FABP) is a tissue-specific protein which is rapidly released into the circulation when cardiomyocyte injury occurs. The aim of the study is to investigate the prognostic relevance of H-FABP for out-of-hospital cardiac arrest (OHCA) patients in the early post-cardiac arrest period. DESIGN AND METHODS: This is a prospective cohort study enrolling non-traumatic resuscitated OHCA patients. RESULTS: A total of 106 patients were enrolled. The H-FABP level at 24h was correlated to the duration from collapse to return of spontaneous circulation (p<0.001, R(2)=0.549). The outcomes of survival to discharge were worse in the patient group with the higher tertile of plasma H-FABP level at 24h after the event (p=0.011). Multivariate analysis demonstrated that the significant predictors for in-hospital mortality were APACHE II score (p=0.010), gender (p=0.025) and the tertiles of H-FABP at 24h with hazard ratios for the lowest, middle, and highest tertiles being 1.0, 1.157 (95% confidence interval 0.435-3.075, p=0.770), and 2.840 (95% confidence interval 1.137-7.092, p=0.025), respectively. CONCLUSION: The plasma level of H-FABP at 24h after the event may be an early and independent factor associated with survival to discharge in OHCA patients.

Combination of intravenous ascorbic acid administration and hypothermia after resuscitation improves myocardial function and survival in a ventricular fibrillation cardiac arrest model in the rat.

OBJECTIVES: Intravenous (IV) administration of ascorbic acid during cardiopulmonary resuscitation (CPR) was reported to facilitate defibrillation and improves survival in ventricular fibrillation (VF) cardiac arrest. We investigated whether IV administration of ascorbic acid after return of spontaneous circulation (ROSC) can improve outcomes in VF cardiac arrest in a rat model and its interaction with therapeutic hypothermia. METHODS: Ventricular fibrillation-induced cardiac arrest followed by CPR and defibrillation was performed in male Wistar rats. After ROSC, the animals were equally randomized to the normothermia (NormoT), hypothermia (HypoT), ascorbic acid (AA+NormoT), and ascorbic acid plus hypothermia (AA+HypoT) groups. The AA+NormoT and AA+HypoT groups received IV ascorbic acid (100 mg/kg). In the HypoT and AA+HypoT groups, therapeutic hypothermia was maintained at 32°C for 2 hours. RESULTS: There were 12 rats in each group. Within 4 hours after ROSC, the HypoT, AA+NormoT, and AA+HypoT groups had significantly lower myocardial lipid peroxidation than the NormoT group. Within 4 hours following ROSC, the AA+NormoT group had a significantly better systolic function (dp/dt40 ) than the NormoT group (6887.9 mm Hg/sec, SD ± 1049.7 mm Hg/sec vs. 5953.6 mm Hg/sec, SD ± 1161.9 mm Hg/sec; p < 0.05). The AA+HypoT group also showed a significantly better diastolic function (-dp/dtmax ) than the HypoT group (dp/dt40 : 8524.8, SD ± 1166.7 mm Hg/sec vs. 7399.8 mm Hg/sec, SD ± 1114.5 mmHg/sec; dp/dtmax : -8183.4 mm Hg/sec, SD ± 1359.0 mm Hg/sec vs. -6573.7 mm Hg/sec, SD ± 1110.9 mm Hg/sec; p < 0.05) at the fourth hour following ROSC. Also at 4 hours, there was less myocytolysis in the HypoT, AA+NormoT, and AA+HypoT groups than the NormoT group. The HypoT, AA+NormoT, and AA+HypoT groups had significantly better survival rates and neurologic outcomes than the NormoT group. Compared with only five surviving animals in the NormoT group, there were nine, eight, and 10 in the HypoT, AA+NormoT, and AA+HypoT groups, respectively, with good neurologic outcomes at 72 hours. CONCLUSIONS: Intravenous ascorbic acid administration after ROSC in normothermia may mitigate myocardial damage and improve systolic function, survival rate, and neurologic outcomes in VF cardiac arrest of rat. Combination of ascorbic acid and hypothermia showed an additive effect in improving both systolic and diastolic functions after ROSC.

Induction of cardiac fibrosis and transforming growth factor-ß1 by motorcycle exhaust in rats.

Motorcycle exhaust (ME) is a major source of air pollution and a potential health hazard in urban areas where motorcycles are a popular means of transportation. The main objectives of this study were to determine the ability of ME to cause cardiotoxicity in rats and investigate the possible mechanisms of toxicity. Male rats were exposed to 1:10 diluted ME by inhalation 2 h daily and Monday through Friday for 8 weeks. Exposure to ME increased heart weight and decreased cardiac antioxidant enzymes glutathione S-transferase (GST), superoxide dismutase and glutathione peroxidase activities in a concentration- and time-dependent manner. Analysis of echocardiographic parameters indicated that ME increased left ventricle posterior wall thickness, interventricular septum thickness and left ventricle mass. Histopathological examinations of the hearts revealed that ME exposure caused focal cardial degeneration and necrosis, mononuclear cell infiltration, and fibrosis. The results of reverse transcriptase-polymerase chain reaction studies showed that ME decreased GST-M1 and GST-P1 mRNA expression and increased the expression of proinflammatory cytokine interleukin-1ß, hypertrophy marker atrial natriuretic peptide, fibrosis markers type I and III collagen, profibrotic cytokine connective tissue growth factor, and hypertrophy and fibrosis mediator transforming growth factor (TGF)-ß1 in the heart. The data of Western blot analysis showed that cardiac TGF-ß1 protein was induced by ME. These findings demonstrate that subchronic ME exposure caused hypertrophy and fibrosis, and modulated GST and TGF-ß1 expression in rat heart possibly by mechanisms involving oxidative stress and inflammation.

The difference in myocardial injuries and mitochondrial damages between asphyxial and ventricular fibrillation cardiac arrests.

INTRODUCTION: Ventricular fibrillation (VF) and asphyxia account for most cardiac arrests but differ in cardiac arrest course, neurologic deficit, and myocardial damage. In VF resuscitation, cardiac mitochondria were known to be damaged via excess generation of reactive oxygen species. This study evaluated the difference of cardiac mitochondrial damages between VF and asphyxial cardiac arrests. METHODS: In the VF + electrical shock (ES) group, VF was induced and untreated for 5 minutes, followed by 1 minute of cardiopulmonary resuscitation (CPR) and 1 ES of 5 J. Animals were killed immediately after ES. In the asphyxia group, cardiac arrest was induced by airway obstruction, and then pulselessness was maintained for 5 minutes, followed by 1 minute of CPR. The animals were killed immediately after CPR. The histology and ultrastructural changes of myocardium and complex activities and respiration of mitochondria were evaluated. The mitochondrial permeability transition pore opening was measured based on mitochondrial swelling rate. RESULTS: The histopathologic examinations showed myocardial necrosis and mitochondrial damage in both cardiac arrests. Instead of regional damages of myocardium in the VF + ES group, the myocardial injury in the asphyxia group distributed diffusely. The asphyxia group demonstrated more severe mitochondrial damage than the VF + ES group, which had a faster mitochondrial swelling rate, more decreased cytochrome c oxidase activity, and more impaired respiration. CONCLUSIONS: Both VF and asphyxial cardiac arrests caused myocardial injuries and mitochondrial damages. Asphyxial cardiac arrest presented more diffuse myocardial injuries and more severe mitochondrial damages than VF cardiac arrest.

Circulating cell-free DNA levels correlate with postresuscitation survival rates in out-of-hospital cardiac arrest patients.

Early prediction of prognosis is helpful in cardiac arrest patients. Plasma cell-free DNA, which increases rapidly after cell death, is a novel biomarker for the prognosis of critical ill patients. Changes in the plasma cell-free DNA level and its role for the early prognosis of cardiac arrest patients remain unclear. We prospectively enrolled adult out-of-hospital cardiac arrest (OHCA) patients with sustained return of spontaneous circulation. The resuscitation variables were recorded following the Utstein recommendation. The plasma cell-free DNA concentration was determined by quantitative real-time polymerase chain reaction assay of ß-globin gene. A total of 42 patients were enrolled for the study. The plasma cell-free DNA level within 2h after cardiac arrest was higher in the non-survival group than the survival-to-discharge group (median level 1659.9 g.e./mL vs. 1121.6g.e./mL, p=0.003 by non-parametric test). The plasma cell-free DNA level at 72 h became no difference between these two groups. The optimal cutoff value of plasma cell-free DNA for predicting survival-to-discharge was 1,170 g.e./mL by ROC curve analysis (area under curve 0.752, p=0.010). A plasma cell-free DNA level higher than 1,170 g.e./mL and was an independent predictor for in-hospital mortality by multiple logistic regression analysis (adjusted odds ratio of 12.35, p=0.023) and was also associated with higher 90 day mortality (p=0.021 by log-rank test). In conclusion, the plasma cell-free DNA level increases during the early post-cardiac arrest phase and can be an early prognostic factor for OHCA patients.

Ultrasonographic lung sliding sign in confirming proper endotracheal intubation during emergency intubation.

AIM OF STUDY: Unrecognized one-lung intubations (also known as main-stem intubation) can lead to hypoventilation, atelectasis, barotrauma, and even patient death. Many traditional methods can be employed to detect one-lung intubation; however, each of these methods has limitations and is not consistently reliable in emergency settings. This study aimed to assess the accuracy and timeliness of ultrasound to confirm proper endotracheal intubation. METHODS: This was a prospective, single-center, observational study conducted at the emergency department of a national university teaching hospital. Patients received emergency tracheal intubation because of respiratory failure or cardiac arrest. After intubation, bedside ultrasound was performed with a transducer placed on the chest bilaterally at the mid-axillary line, to identify lung sliding over the lungs bilaterally during ventilation. Chest radiography was used as the criterion standard for confirmation of endotracheal tube position. RESULTS: One hundred and fifteen patients needing tracheal intubation were included, and nine (7.8%) had one-lung intubations. The overall accuracy of ultrasound to confirm proper endotracheal intubation was 88.7% (95% confidence interval (CI): 81.6-93.3%). The positive predictive value was 94.7% (95% CI: 87.1-97.9%) in the non-cardiac-arrest group and 100% (95% CI: 87.1-100.0%) in the cardiac-arrest group. The median operating time of ultrasound was 88 s (interquartile range [IQR]: 55.0, 193.0), and of chest radiography was 1349 s (IQR: 879.0, 2221.0) post intubation. CONCLUSIONS: In this study, the positive predictive value of bilateral lung sliding in confirming proper endotracheal intubation was high, especially among patients with cardiac arrest. Considerable time advantage of ultrasound over chest radiography was demonstrated.

Ascorbic acid mitigates the myocardial injury after cardiac arrest and electrical shock.

PURPOSE: To examine the effects of ascorbic acid (AA) administrated during cardiopulmonary resuscitation (CPR) on the myocardial injury in a rat model of ventricular fibrillation (VF) and electrical shock (ES). METHODS: VF was induced in male Wistar rats and left untreated for 5 min, followed by 1 min of CPR, and then one ES of 5 J. At the start of CPR, animals received either intravenous administration of AA (100 mg/kg) or Tempol (30 mg/kg), two antioxidants, or 0.9% saline (VF + ES group). After ES, animals were immediately killed. Myocardial lipoxidation was determined by malondialdehyde (MDA) assay. The histology and ultrastructural changes of myocardium were also evaluated. The mitochondrial permeability transition pore (mPTP) opening was measured based on the mitochondrial swelling rate. The complex activities and respiration of mitochondria were assessed, too. RESULTS: Increased myocardial injury and mitochondrial damage in the VF + ES group were noted. AA and Tempol alleviated such damages. Both AA and Tempol improved accelerated mitochondrial swelling; decreased complex activities and respiratory dysfunction occurred in the VF + ES group. The animals receiving AA and Tempol during CPR had better successful resuscitation rates and 72-h survival than the VF + ES group. CONCLUSIONS: Intravenous administration of AA and Tempol at the start of CPR may reduce lipid peroxidation and myocardial necrosis, diminish mitochondrial damage, facilitate resuscitation, and improve outcomes after VF + ES.

Tracheal rapid ultrasound exam (T.R.U.E.) for confirming endotracheal tube placement during emergency intubation.

OBJECTIVES: This study aimed to assess the diagnostic accuracy and timeliness of using tracheal ultrasound to examine endotracheal tube placement during emergency intubation. METHODS: This was a prospective, observational study, conducted at the emergency department of a national university teaching hospital. Patients received emergency intubation because of impending respiratory failure, cardiac arrest, or severe trauma. The tracheal rapid ultrasound exam (T.R.U.E.) was performed during emergency intubation with the transducer placed transversely at the trachea over the suprasternal notch. Quantitative waveform capnography was used as the criterion standard for confirmation of tracheal intubation. The main outcome was the concordance between the T.R.U.E. and the capnography. RESULTS: A total of 112 patients were included in the analysis, and 17 (15.2%) had esophageal intubations. The overall accuracy of the T.R.U.E. was 98.2% (95% confidence interval [CI]: 93.7-99.5%). The kappa (κ) value was 0.93 (95% CI: 0.84-1.00), indicating a high degree of agreement between the T.R.U.E. and capnography. The sensitivity, specificity, positive predictive value, and negative predictive value of the T.R.U.E. were 98.9% (95% CI: 94.3-99.8%), 94.1% (95% CI: 73.0-99.0%), 98.9% (95% CI: 94.3-99.8%) and 94.1% (95% CI: 73.0-99.0%). The median operating time of the T.R.U.E. was 9.0s (interquartile range [IQR]: 6.0, 14.0). CONCLUSIONS: The application of the T.R.U.E. to examine endotracheal tube placement during emergency intubation is feasible, and can be rapidly performed.

Post-cardiac arrest myocardial dysfunction is improved with cyclosporine treatment at onset of resuscitation but not in the reperfusion phase.

AIM OF STUDY: Significant myocardial dysfunction and high mortality occur after whole-body ischaemia-eperfusion injuries in the post-cardiac arrest status. The inhibition of mitochondrial permeability transition pore (mPTP) opening during ischaemia-reperfusion can ameliorate injuries in the specific organs. We investigated the effect and therapeutic window of pharmacological inhibition of mPTP opening in cardiac arrest. METHODS: Forty male Wistar rats were resuscitated after cardiac arrest induced by 8.5 min of asphyxia. Cyclosporine (10 mg/kg) was administered intravenously at onset of resuscitation in protocol 1 study and administered 3 min after ROSC in protocol 2 with placebo control in both. RESULTS: Left ventricular systolic (dP/dt 40), diastolic (maximal negative dP/dt) functions and cardiac output were improved in the group with cyclosporine treatment at onset of resuscitation compared to control group (p < 0.01, respectively). Seventy-two hour survival was better in the group with cyclosporine treatment at onset of resuscitation compared to control (p = 0.046). Left ventricular systolic and diastolic function, cardiac output and 72 h survival were not improved in the group with cyclosporine treatment 3 min after ROSC. The severity of mitochondrial damage under electronic microscopy, mPTP opening, mitochondrial respiratory control ratio and ADP:O ratio were ameliorated in the group with cyclosporine treatment at onset of resuscitation (p< 0.05, respectively) but not in the group with cyclosporine treatment at 3 min after ROSC. CONCLUSIONS: Post-cardiac arrest myocardial dysfunction and survival can be improved by cyclosporine treatment at onset of resuscitation, but not by the cyclosporine treatment at 3 min after ROSC.

Acute cardiac dysfunction after short-term diesel exhaust particles exposure.

Epidemiological studies show an association between particulate matter exposure and acute heart failure. However, underlying mechanisms remain unclear. In this study, we investigated acute cardiac hemodynamic effects and related mechanisms after 1 day exposure to diesel exhaust particles (DEPs). Male Sprague-Dawley rats were randomized and instilled with 250 microg (low dose) or 500 microg (high dose) of DEP or saline placebo intra-tracheally. The cardiac systolic function by dP/dt(40) and diastolic functions by maximal negative dP/dt were both worse in DEP low dose and DEP high dose groups than the control group, respectively. In the heart rate variability analysis, SDNN in DEP low dose and DEP high dose groups were both lower than the control group. The low frequency heart rate variability was higher in the DEP groups compared to the control group. The cardiac IL-1beta expression and circulating cardiac troponin I level were higher in the DEP group than the control group. Plasma IL-1beta and IL-6 protein were significantly higher in the DEP groups than the control group. In conclusion, DEP exposure causes acute cardiac systolic and diastolic dysfunction. The changes may be related to decreased heart rate variability, increased cardiac inflammatory reaction and myocardial damage.

Antiapoptotic cardioprotective effect of hypothermia treatment against oxidative stress injuries.

OBJECTIVES: The effect of hypothermia on cardiomyocyte injury induced by oxidative stress remains unclear. The authors investigated the effects of hypothermia on apoptosis and mitochondrial dysfunction in cardiomyocytes exposed to oxidative stress. METHODS: Cardiomyocytes (H9c2) derived from embryonic rat heart cell culture were exposed to either normothermic (37 degrees C) or hypothermic (31 degrees C) environments before undergoing oxidative stress via treatment with hydrogen peroxide (H(2)O(2)). The degree of apoptosis was determined by annexin V and terminal deoxynucleotidyl transferase (TUNEL) staining. The amount of reactive oxygen species (ROS) was compared after H(2)O(2) exposure between normo- and hypothermic-pretreated groups. Mitochondrial dysfunction in both groups was measured by differential reductase activity and transmembrane potential (DeltaPsim). RESULTS: Hydrogen peroxide induced significant apoptosis in both normothermic and hypothermic cardiomyocytes. Hypothermia ameliorated apoptosis as demonstrated by decreased annexin V staining (33 +/- 1% vs. 49 +/- 4%; p < 0.05) and TUNEL staining (27 +/- 17% vs. 80 +/-25%; p < 0.01). The amount of intracellular ROS increased after H(2)O(2) treatment and was higher in the hypothermic group than that in the normothermic group (237.9 +/- 31.0% vs. 146.6 +/- 20.6%; p < 0.05). In the hypothermic group, compared with the normothermic group, after H(2)O(2) treatment mitochondrial reductase activity was greater (72.0 +/- 17.9% vs. 27.0 +/- 13.3%; p < 0.01) and the mitochondria DeltaPsim was higher (101.0 +/- 22.6% vs. 69.7 +/- 12.9%; p < 0.05). Pretreatment of cardiomyocytes with the antioxidant ascorbic acid diminished the hypothermia-induced increase in intracellular ROS and prevented the beneficial effects of hypothermia on apoptosis and mitochondrial function. CONCLUSIONS: Hypothermia at 31 degrees C can protect cardiomyocytes against oxidative stress-induced injury by decreasing apoptosis and mitochondrial dysfunction through intracellular ROS-dependent pathways.

Who survives cardiac arrest in the intensive care units?

OBJECTIVE: The aim of this study was to evaluate the factors related to outcome regarding in-intensive care unit (ICU) cardiac arrest (IICA) in a university hospital. PATIENTS AND METHODS: Adult nontraumatic ICU patients who sustained IICA were prospectively enrolled. Several patient and event-related variables, as well as outcomes, were recorded and summarized based on the revised Utstein-style template. RESULTS: A total of 202 episodes of IICA happened during the study period. Return of spontaneous circulation (ROSC) was achieved in 127 patients (62.9%), whereas the overall survival-to-discharge rate was 15.3% (31 patients). In univariate analysis, a shorter duration of resuscitation and pulseless ventricular tachycardia/ventricular fibrillation (VT/VF) as initial arrest rhythm represented better outcomes. Independent predictors of survival to hospital discharge were VT/VF as the initial rhythm (odds ratio [OR], 3.81; 95% confidence interval [CI], 1.50-9.67; P = .005), lower Acute Physiology and Chronic Health Evaluation II score (OR 0.92, 95% CI 0.87-0.98, P = .008), and shorter resuscitation durations (OR 0.91, 95% CI 0.87-0.96, P < .001). CONCLUSION: Shorter resuscitation duration and initial VT/VF are predictors for both ROSC and hospital survival, whereas lower Acute Physiology and Chronic Health Evaluation II scores predict the latter.

Cardioprotective effect of therapeutic hypothermia for postresuscitation myocardial dysfunction.

Mild-to-moderate therapeutic hypothermia after resuscitation from cardiac arrest is neuroprotective, but its effect on postresuscitation myocardial dysfunction is not clear. We hypothesized that therapeutic hypothermia is cardioprotective in postresuscitation. Male adult Wistar rats underwent asphyxia-induced cardiac arrest and manual resuscitation with epinephrine. Therapeutic hypothermia is induced immediately after successful resuscitation and the return of spontaneous circulation (ROSC). One hour after ROSC, the rats achieved a target temperature of 30 degrees C to 31 degrees C, which was maintained for 1.5 h and then transitioned to the passive rewarming process in the hypothermia group. A temperature between 36.5 degrees C and 37.5 degrees C was maintained in the normothermia group. Echocardiography revealed that hypothermia resulted in significantly better systolic function of fractional shortening in 60 and 120 min after ROSC (both P < 0.05). The benefit of cardioprotection was also confirmed by the general linear mixed-models analysis of dP/dt, which revealed significantly better systolic function in positive dP/dtR(40) and diastolic function in maximal negative dP/dt (both P < 0.001). The 4-h and 3-day survival analyses both revealed better outcomes in the hypothermia groups in the log-rank test (P < 0.001 for the 4-h analysis, and P < 0.05 for the 3-day analysis). Serum level of heart-type, fatty acid-binding protein at 4 h after resuscitation as the myocardium damage marker was also significantly lower in the hypothermia group (52.4 ng/mL vs 186.5 ng/mL in the normothermia group; P < 0.05). Western blotting of myocardium showed that myocardial Akt and ERK1/2 were more activated in the hypothermia group 2 h after spontaneous circulation returned. In conclusion, postresuscitation mild-to-moderate therapeutic hypothermic is cardioprotective in the asphyxia-induced cardiac arrest animal model. It stabilizes hemodynamics, improves short-term survival, and decreases myocardial damage. The cardioprotective effect is associated with Akt and ERK1/2 activation in signal transduction.

Cardioprotective effects of erythropoietin on postresuscitation myocardial dysfunction in appropriate therapeutic windows.

OBJECTIVE: Erythropoietin has been noted for its cardioprotective effects. The objective of the study is to investigate its effects on postresuscitation myocardial dysfunction and therapeutic windows. DESIGN: Randomized animal study. SETTING: Animal research laboratory. SUBJECTS: Adult male adult Wistar rats. INTERVENTIONS: Cardiopulmonary resuscitation was started after 6.5 or 9.5 mins of asphyxia-induced cardiac arrest. The resuscitated animals received either erythropoietin (1000, 3000, or 5000 U/kg) or placebo intravenously 3 mins after return of spontaneous circulation. MEASUREMENTS AND MAIN RESULTS: Erythropoietin treatment improved the 3-day survival and left ventricular dP/dt40 and peak negative dP/dt after 6.5 mins asphyxia-induced cardiac arrest. The cardioprotective effects of erythropoietin decreased after 9.5 mins asphyxia-induced cardiac arrest with worse postresuscitation left ventricular dP/dt40 and peak negative dP/dt (p < .01 for both). The erythropoietin showed a dose-dependent response for its cardioprotective effects. The 3-day survival rates were higher in the group treated with erythropoietin 5000 U/kg than with 3000 and 1000 U/kg groups (p = .045 and .003, respectively). Postresuscitation left ventricular dP/dt40 and peak negative dP/dt were more preserved in the group treated with erythropoietin 5000 U/kg than the groups with lower doses (p < .05 for both). CONCLUSIONS: Erythropoietin has the potential to improve postresuscitation myocardial dysfunction and short-term survival in appropriate therapeutic windows.

How much would you be willing to pay for preventing a new dangerous infectious disease: a willingness-to-pay study in medical personnel working in the emergency department.

BACKGROUND: The risk of developing nosocomial infectious diseases among medical personnel in the emergency department (ED) can result in tremendous psychologic stress. The objective of this study was to estimate the median amount of money ED personnel would be willing to pay for preventing nosocomial severe acute respiratory syndrome (SARS). METHODS: A contingent valuation approach with close-ended format was used. During the study period from June 15, 2003 through June 30, 2003, a convenience sample of all medical personnel working in the ED of National Taiwan University Hospital was carried out. Participants were interviewed by a standard questionnaire and were asked to choose whether or not they would pay at a specified price to purchase a hypothetical SARS vaccine. A logistic regression model was created to evaluate the relationship between willingness-to-pay and the log of the price offered in the bid questions. The median and mean amounts of willingness-to-pay were calculated. RESULTS: A total of 115 subjects were interviewed and most were nurses (68.7%). The median and mean amount subjects reported being willing to pay for a SARS vaccine was US $1762 and US $720, respectively. Subject responses were significantly related to the price of vaccination and their type of job. CONCLUSIONS: Medical personnel in the ED reported that they would be willing to pay substantial monetary amounts for preventing nosocomial SARS.

Erythropoietin improves the postresuscitation myocardial dysfunction and survival in the asphyxia-induced cardiac arrest model.

To investigate the effect of erythropoietin for the management of postresuscitation myocardial dysfunction following asphyxia-induced cardiac arrest. Male adult Wistar rats were used for the prospective controlled animal study. Asphyxia-induced cardiac arrest was performed by turning-off the ventilator and clamping the endotracheal tube. Cardiopulmonary resuscitation with an intravenous injection of 0.01 mg/kg epinephrine and mechanical ventilation were started after 6.5 minutes of asphyxia. The resuscitated animals received either erythropoietin (5000 U/kg) or equivalent volume of 0.9% saline as placebo intravenously 3 minutes after return of spontaneous circulation. The erythropoietin treatment produced better left ventricular dP/dt40 and -dP/dt in the invasive hemodynamic measurements, and left ventricular fraction shortening by echocardiography. Administration of erythropoietin also improved three days survival among those successfully resuscitated. The molecular effects of erythropoietin were shown by activation of its down streaming Akt and ERK 42/44 signaling pathways. EPO has the potential to improve postresuscitation myocardial dysfunction and short term survival in rats after asphyxia-induced cardiac arrest.