Inhaled gases as novel neuroprotective therapies in the postcardiac arrest period.

PURPOSE OF REVIEW: The purpose of this review is to summarize recent advances about inhaled gases as novel neuroprotective agents in the postcardiac arrest period. RECENT FINDINGS: Inhaled gases, as nitric oxide (NO) and molecular hydrogen (H2), and noble gases as xenon (Xe) and argon (Ar) have shown neuroprotective properties after resuscitation. In experimental settings, the protective effect of these gases has been demonstrated in both in-vitro studies and animal models of cardiac arrest. They attenuate neuronal degeneration and improve neurological function after resuscitation acting on different pathophysiological pathways. Safety of both Xe and H2 after cardiac arrest has been reported in phase 1 clinical trials. A randomized phase 2 clinical trial showed the neuroprotective effects of Xe, combined with targeted temperature management. Xe inhalation for 24 h after resuscitation preserves white matter integrity as measured by fractional anisotropy of diffusion tensor MRI. SUMMARY: Inhaled gases, as Xe, Ar, NO, and H2 have consistently shown neuroprotective effects in experimental studies. Ventilation with these gases appears to be well tolerated in pigs and in preliminary human trials. Results from phase 2 and 3 clinical trials are needed to assess their efficacy in the treatment of postcardiac arrest brain injury.

Airborne exposures associated with the typical use of an aerosol brake cleaner during vehicle repair work.

Many petroleum-based products are used for degreasing and cleaning purposes during vehicle maintenance and repairs. Although prior studies have evaluated chemical exposures associated with this type of work, most of these have focused on gasoline and exhaust emissions, with few samples collected solely during the use of an aerosol cleaning product. In this case study, we assess the type of airborne exposures that would be expected from the typical use of an aerosol brake cleaner during vehicle repair work. Eight exposure scenarios were evaluated over a 2-day study in which the benzene content of the brake cleaner and potential for dilution ventilation and air flow varied. Both short-term (15 min) and task-based (≥1 hr) charcoal tube samples were collected in the breathing zone and adjacent work area and analyzed for total hydrocarbons (THCs), toluene, and benzene. The majority of personal (N = 48) and area (N = 47) samples had detectable levels of THC and toluene, but no detections of benzene were found. For the personal short-term samples, average airborne concentrations ranged from 3.1-61.5 ppm (13.8-217.5 mg/m3) for THC and 2.2-44.0 ppm (8.2-162.5 mg/m3) for toluene, depending on the scenario. Compared to the personal short-term samples, average concentrations were generally 2-3 times lower for the personal task-based samples and 2-5 times lower for the area short-term samples. The highest exposures occurred when the garage bay doors were closed, floor fan was turned off, or greatest amount of brake cleaner was used. These findings add to the limited dataset on this topic and can be used to bound or approximate worker or consumer exposures from use of aerosol cleaning products with similar compositions and use patterns.

Mildly elevated lactate levels are associated with microcirculatory flow abnormalities and increased mortality: a microSOAP post hoc analysis.

BACKGROUND: Mildly elevated lactate levels (i.e., 1-2 mmol/L) are increasingly recognized as a prognostic finding in critically ill patients. One of several possible underlying mechanisms, microcirculatory dysfunction, can be assessed at the bedside using sublingual direct in vivo microscopy. We aimed to evaluate the association between relative hyperlactatemia, microcirculatory flow, and outcome. METHODS: This study was a predefined subanalysis of a multicenter international point prevalence study on microcirculatory flow abnormalities, the Microcirculatory Shock Occurrence in Acutely ill Patients (microSOAP). Microcirculatory flow abnormalities were assessed with sidestream dark-field imaging. Abnormal microcirculatory flow was defined as a microvascular flow index (MFI) < 2.6. MFI is a semiquantitative score ranging from 0 (no flow) to 3 (continuous flow). Associations between microcirculatory flow abnormalities, single-spot lactate measurements, and outcome were analyzed. RESULTS: In 338 of 501 patients, lactate levels were available. For this substudy, all 257 patients with lactate levels ≤ 2 mmol/L (median [IQR] 1.04 [0.80-1.40] mmol/L) were included. Crude ICU mortality increased with each lactate quartile. In a multivariable analysis, a lactate level > 1.5 mmol/L was independently associated with a MFI < 2.6 (OR 2.5, 95% CI 1.1-5.7, P = 0.027). CONCLUSIONS: In a heterogeneous ICU population, a single-spot mildly elevated lactate level (even within the reference range) was independently associated with increased mortality and microvascular flow abnormalities. In vivo microscopy of the microcirculation may be helpful in discriminating between flow- and non-flow-related causes of mildly elevated lactate levels. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01179243 . Registered on August 3, 2010.

International study on microcirculatory shock occurrence in acutely ill patients.

OBJECTIVES: Microcirculatory alterations are associated with adverse outcome in subsets of critically ill patients. The prevalence and significance of microcirculatory alterations in the general ICU population are unknown. We studied the prevalence of microcirculatory alterations in a heterogeneous ICU population and its predictive value in an integrative model of macro- and microcirculatory variables. DESIGN: Multicenter observational point prevalence study. SETTING: The Microcirculatory Shock Occurrence in Acutely ill Patients study was conducted in 36 ICUs worldwide. PATIENTS: A heterogeneous ICU population consisting of 501 patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic, hemodynamic, and laboratory data were collected in all ICU patients who were 18 years old or older. Sublingual Sidestream Dark Field imaging was performed to determine the prevalence of an abnormal capillary microvascular flow index (< 2.6) and its additional value in predicting hospital mortality. In 501 patients with a median Acute Physiology and Chronic Health Evaluation II score of 15 (10-21), a Sequential Organ Failure Assessment score of 5 (2-8), and a hospital mortality of 28.4%, 17% exhibited an abnormal capillary microvascular flow index. Tachycardia (heart rate > 90 beats/min) (odds ratio, 2.71; 95% CI, 1.67-4.39; p < 0.001), mean arterial pressure (odds ratio, 0.979; 95% CI, 0.963-0.996; p = 0.013), vasopressor use (odds ratio, 1.84; 95% CI, 1.11-3.07; p = 0.019), and lactate level more than 1.5 mEq/L (odds ratio, 2.15; 95% CI, 1.28-3.62; p = 0.004) were independent risk factors for hospital mortality, but not abnormal microvascular flow index. In reference to microvascular flow index, a significant interaction was observed with tachycardia. In patients with tachycardia, the presence of an abnormal microvascular flow index was an independent, additive predictor for in-hospital mortality (odds ratio, 3.24; 95% CI, 1.30-8.06; p = 0.011). This was not true for nontachycardic patients nor for the total group of patients. CONCLUSIONS: In a heterogeneous ICU population, an abnormal microvascular flow index was present in 17% of patients. This was not associated with mortality. However, in patients with tachycardia, an abnormal microvascular flow index was independently associated with an increased risk of hospital death.

Clinical evaluation of pazopanib eye drops versus ranibizumab intravitreal injections in subjects with neovascular age-related macular degeneration.

PURPOSE: To evaluate pazopanib eye drops in subjects with active subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). DESIGN: Multicountry, randomized, parallel-group, double-masked, active and placebo-controlled, dose-ranging study of eye drops. PARTICIPANTS: A total of 510 subjects (93% white; 58% female; mean age, 75.3 years) whose AMD was previously managed by anti-vascular endothelial growth factor intravitreal injections. METHODS: Treatments administered for 52 weeks included placebo eye drops instilled 4 times daily (n=73); pazopanib 5 mg/ml instilled 3 (n=72) or 4 times daily (n=74); pazopanib 10 mg/ml instilled 2 (n=73), 3 (n=73), or 4 times daily (n=72); or ranibizumab injection administered once every 4 weeks (n=73). In addition, for all eye drop treatment groups, open-label ranibizumab was administered as needed. MAIN OUTCOME MEASURES: The main outcome measures were best-corrected visual acuity (BCVA) and injection frequency assessed at week 52. Safety was assessed every 4 weeks and pazopanib plasma concentrations were determined at weeks 4 and 24. RESULTS: At week 52, pazopanib, with allowance for as-needed ranibizumab injections, was noninferior to monthly ranibizumab as well as to as-needed ranibizumab administered with placebo eye drops in maintaining BCVA (estimated BCVA gains of 0.3-1.8 vs. 1.4 vs. 0.2 letters, respectively). Pazopanib treatment did not reduce as-needed ranibizumab injections by ≥50% (prespecified efficacy criterion). At week 52, there were no clinically meaningful changes from baseline in retinal thickness or morphology, CNV size, or lesion characteristics on optical coherence tomography or fluorescein angiography. Complement factor H genotype had no effect on the responses to pazopanib and/or ranibizumab (BCVA, injection rate, or optical coherence tomography/fluorescein angiography changes). Steady-state concentrations of pazopanib in plasma seemed to be reached by week 4. The most common ocular adverse events related to pazopanib and ranibizumab were application site pain (3%) and injection site hemorrhage (1%), respectively. No treatment-related serious adverse events were reported. CONCLUSIONS: Pazopanib was well tolerated. Daily pazopanib eye drops in neovascular AMD subjects did not result in therapeutic benefit beyond that obtained with ranibizumab alone.

Brief inhalation of nitric oxide increases resuscitation success and improves 7-day-survival after cardiac arrest in rats: a randomized controlled animal study.

INTRODUCTION: Inhaled nitric oxide (iNO) improves outcomes when given post systemic ischemia/reperfusion injury. iNO given during cardiopulmonary resuscitation (CPR) may therefore improve return of spontaneous circulation (ROSC) rates and functional outcome after cardiac arrest (CA). METHODS: Thirty male Sprague-Dawley rats were subjected to 10 minutes of CA and at least 3 minutes of CPR. Animals were randomized to receive either 0 (n = 10, Control), 20 (n = 10, 20 ppm), or 40 (n = 10, 40 ppm) ppm iNO during CPR until 30 minutes after ROSC. A neurological deficit score was assessed daily for seven days following the experiment. On day 7, brains, hearts, and blood were sampled for histological and biochemical evaluation. RESULTS: During CPR, 20 ppm iNO significantly increased diastolic arterial pressure ( CONTROL: 57 ± 5.04 mmHg; 20 ppm: 71.57 ± 57.3 mmHg, p < 0.046) and decreased time to ROSC (CONTROL: 842 ± 21 s; 20 ppm: 792 ± 5 s, (p = 0.02)). Thirty minutes following ROSC, 20 ppm iNO resulted in an increase in mean arterial pressure ( CONTROL: 83 ± 4 mmHg; 20 ppm: 98 ± 4 mmHg, p = 0.035), a less pronounced rise in lactate and inflammatory cytokine levels, and attenuated cardiac damage. Inhalation of NO at 20 ppm improved neurological outcomes in rats 2 to 7 days after CA and CPR. This translated into increases in 7 day survival ( CONTROL: 4; 20 ppm: 10; 40 ppm 6, (p ≤ 0.05 20 ppm vs CONTROL and 40 ppm). CONCLUSIONS: Our study revealed that breathing NO during CPR markedly improved resuscitation success, 7-day neurological outcomes and survival in a rat model of VF-induced cardiac arrest and CPR. These results support the beneficial effects of NO inhalation after cardiac arrest and CPR.

Inhaled nitric oxide improves transpulmonary blood flow and clinical outcomes after prolonged cardiac arrest: a large animal study.

INTRODUCTION: The probability to achieve a return of spontaneous circulation (ROSC) after cardiac arrest can be improved by optimizing circulation during cardiopulomonary resuscitation using a percutaneous left ventricular assist device (iCPR). Inhaled nitric oxide may facilitate transpulmonary blood flow during iCPR and may therefore improve organ perfusion and outcome. METHODS: Ventricular fibrillation was electrically induced in 20 anesthetized male pigs. Animals were left untreated for 10 minutes before iCPR was attempted. Subjects received either 20 ppm of inhaled nitric oxide (iNO, n = 10) or 0 ppm iNO (Control, n = 10), simultaneously started with iCPR until 5 hours following ROSC. Animals were weaned from the respirator and followed up for five days using overall performance categories (OPC) and a spatial memory task. On day six, all animals were anesthetized again, and brains were harvested for neurohistopathologic evaluation. RESULTS: All animals in both groups achieved ROSC. Administration of iNO markedly increased iCPR flow during CPR (iNO: 1.81 ± 0.30 vs CONTROL: 1.64 ± 0.51 L/min, p < 0.001), leading to significantly higher coronary perfusion pressure (CPP) during the 6 minutes of CPR (25 ± 13 vs 16 ± 6 mmHg, p = 0.002). iNO-treated animals showed significantly lower S-100 serum levels thirty minutes post ROSC (0.26 ± 0.09 vs 0.38 ± 0.15 ng/mL, p = 0.048), as well as lower blood glucose levels 120-360 minutes following ROSC. Lower S-100 serum levels were reflected by superior clinical outcome of iNO-treated animals as estimated with OPC (3 ± 2 vs. 5 ± 1, p = 0.036 on days 3 to 5). Three out of ten iNO-treated, but none of the CONTROL animals were able to successfully participate in the spatial memory task. Neurohistopathological examination of vulnerable cerebral structures revealed a trend towards less cerebral lesions in neocortex, archicortex, and striatum in iNO-treated animals compared to CONTROLs. CONCLUSIONS: In pigs resuscitated with mechanically-assisted CPR from prolonged cardiac arrest, the administration of 20 ppm iNO during and following iCPR improved transpulmonary blood flow, leading to improved clinical neurological outcomes.

Doubling survival and improving clinical outcomes using a left ventricular assist device instead of chest compressions for resuscitation after prolonged cardiac arrest: a large animal study.

INTRODUCTION: Despite improvements in pre-hospital and post-arrest critical care, sudden cardiac arrest (CA) remains one of the leading causes of death. Improving circulation during cardiopulmonary resuscitation (CPR) may improve survival rates and long-term clinical outcomes after CA. METHODS: In a porcine model, we compared standard CPR (sCPR; n =10) with CPR using an intravascular cardiac assist device without additional chest compressions (iCPR; n =10) following 10 minutes of electrically induced ventricular fibrillation (VF). In a separate crossover experiment, 10 additional pigs were subjected to 10 minutes of VF and 6 minutes of sCPR; the iCPR device was then implanted if a return of spontaneous circulation (ROSC) was not achieved using sCPR. Animals were evaluated in respect to intra- and post-arrest hemodynamics, survival, functional outcome and cerebral and myocardial lesions following CPR. We hypothesized that iCPR would result in more frequent ROSC and better functional recovery than sCPR. RESULTS: iCPR produced a mean flow of 1.36 ± 0.02 L/min, leading to significantly higher coronary perfusion pressure (CPP) values during the early period of CPR (22 ± 10 mmHg vs. 9 ± 5 mmHg, P ≤0.01, 1 minute after start of CPR; 20 ± 11 mmHg vs. 10 ± 7 mmHg, P =0.03, 2 minutes after start of CPR), resulting in high ROSC rates (100% in iCPR vs. 50% in sCPR animals; P =0.03). iCPR animals showed significantly lower serum S100 levels at 10 and 30 minutes following ROSC (3.5 ± 0.6 ng/ml vs. 7.4 ± 3.0 ng/ml 30 minutes after ROSC; P ≤0.01), as well as superior clinical outcomes based on overall performance categories (2.9 ± 1.0 vs. 4.6 ± 0.8 on day 1; P ≤0.01). In crossover experiments, 80% of animals required treatment with iCPR after failed sCPR. Notably, ROSC was still achieved in six of the remaining eight animals (75%) after a total of 22.8 ± 5.1 minutes of ischemia. CONCLUSIONS: In a model of prolonged cardiac arrest, the use of iCPR instead of sCPR improved CPP and doubled ROSC rates, translating into improved clinical outcomes.

A systematic review and meta-analysis to compare the efficacy of acyclovir 3% ophthalmic ointment to idoxuridine in curing herpetic keratitis by Day 7 of treatment.

BACKGROUND: This objective of the review and analysis is to demonstrate that acyclovir (ACV) 3% ophthalmic ointment is superior to idoxuridine (IDU) in treating herpetic keratitis (HK) presenting as dendritic and geographic ulcer sub-types. DATA SOURCES: Publications in human subjects were identified by searching the Ovid MEDLINE database through April 2011, combining medical subject headings (MESH) "Keratitis, Herpetic/" AND "Acyclovir/" limiting by the key words "topical" OR "ointment" and also restricted to MESH "Administration, Topical/" OR "Ointments/". The results were cross checked with the references used in the Cochrane Database Syst Rev. 1:1-134, 2009 and GlaxoSmithKline clinical documents related to acyclovir. STUDY SELECTION: Randomized, double-masked studies in subjects diagnosed with HK with head to head comparator arms of ACV ophthalmic ointment and topical IDU that had actual or calculable healing rates at Day seven. DATA EXTRACTION: Data independently extracted from identified articles by two authors of this manuscript. DATA SYNTHESIS: Data from seven randomized, controlled trials (RCT) evaluating 432 subjects that met inclusion criteria (214 were treated with ACV and 218 were treated with IDU) and had Day seven healing rates calculable. All sub-classified lesions were identified as either dendritic ulcers (n = 185) or geographic ulcers (n = 35). The Cochran-Mantel-Haenszel (CMH) method in Biometrics 10:417-51, 1954 and JNCI 22:719-48, 1959, controlling for study, was performed as the primary analysis using SAS v9. Homogeneity was assessed using Breslow-Day-Tarone (BDT) test in IARC 1:1-32, 1980 and Biometrika 72:91-5, 1985. The analysis was performed with outliers removed to assess their impact. RESULTS: ACV showed statistically significant greater odds of healing HK at Day seven in all subjects (Odds Ratio 3.95, 95% CI2.60, 6.00, p < 0.0001), in dendritic ulcers (Odds Ratio 4.22, 95% CI: 2.14, 8.32; p < 0.0001) and geographic ulcers (Odds Ratio 5.31, 95% CI: 1.09, 25.93; p = 0.0244). CONCLUSION: ACV 3% ophthalmic ointment is a valuable intervention for dendritic and geographic corneal ulcers. ACV and IDU were generally well tolerated in the studies reviewed.

Delayed argon administration provides robust protection against cardiac arrest-induced neurological damage.

INTRODUCTION: Argon at a dosage of 70 % is neuroprotective, when given 1 h after cardiac arrest (CA) in rats. We investigated if a neuroprotective effect of argon would also be observed, when administration was delayed. METHODS: Twenty-four male Sprague-Dawley rats, weighing between 400 and 500 g were subjected to 7 min of CA and 3 min of cardiopulmonary resuscitation. Animals were randomized to receive either 1 h of 70 % argon ventilation 1 h (n = 8) or 3 h (n = 8) after return of spontaneous circulation or no argon treatment (n = 8). For all animals, a neurological deficit score (NDS) was calculated daily for 7 days following the experiment. On day 8, rats were re-anesthetized and transcardially perfused before brains were harvested for histopathological analyses. RESULTS: All animals survived. Control animals exhibited severe neurologic dysfunction at all time points as measured with the NDS. Argon-treated animals showed significant improvements in the NDS through all postoperative days, even when argon administration was delayed for 3 h. This was paralleled by a significant reduction in the neuronal damage index in the neocortex and the hippocampal CA 3/4 region in argon-treated animals, regardless of the timing of argon administration. However, animals of the delayed argon administration group additionally showed significant reductions in the basal ganglia in comparison with control animals. CONCLUSION: Our study demonstrates that a 1-h application of argon provided a significant reduction in histopathological damage, associated with a marked improvement in functional neurologic recovery even when treatment was delayed for 3 h. This is highly significant with regard to clinical situations, where argon treatment cannot be provided timely.

Accuracy and precision of calibrated arterial pulse contour analysis in patients with subarachnoid hemorrhage requiring high-dose vasopressor therapy: a prospective observational clinical trial.

INTRODUCTION: Calibrated arterial pulse contour analysis has become an established method for the continuous monitoring of cardiac output (PCCO). However, data on its validity in hemodynamically instable patients beyond the setting of cardiac surgery are scarce. We performed the present study to assess the validity and precision of PCCO-measurements using the PiCCO™-device compared to transpulmonary thermodilution derived cardiac output (TPCO) as the reference technique in neurosurgical patients requiring high-dose vasopressor-therapy. METHODS: A total of 20 patients (16 females and 4 males) were included in this prospective observational clinical trial. All of them suffered from subarachnoid hemorrhage (Hunt&Hess grade I-V) due to rupture of a cerebral arterial aneurysm and underwent high-dose vasopressor therapy for the prevention/treatment of delayed cerebral ischemia (DCI). Simultaneous CO measurements by bolus TPCO and PCCO were obtained at baseline as well as 2 h, 6 h, 12 h, 24 h, 48 h and 72 h after inclusion. RESULTS: PCCO- and TPCO-measurements were obtained at baseline as well as 2 h, 6 h, 12 h, 24 h, 48 h and 72 h after inclusion. Patients received vasoactive support with (mean ± standard deviation, SD) 0.57 ± 0.49 µg · kg-1 · min-1 norepinephrine resulting in a mean arterial pressure of 103 ± 13 mmHg and a systemic vascular resistance of 943 ± 248 dyn · s · cm-5. 136 CO-data pairs were analyzed. TPCO ranged from 5.2 to 14.3 l · min-1 (mean ± SD 8.5 ± 2.0 l · min-1) and PCCO ranged from 5.0 to 14.4 l · min-1 (mean ± SD 8.6 ± 2.0 l · min-1). Bias and limits of agreement (1.96 SD of the bias) were -0.03 ± 0.82 l · min-1 and 1.62 l · min-1, resulting in an overall percentage error of 18.8%. The precision of PCCO-measurements was 17.8%. Insufficient trending ability was indicated by concordance rates of 74% (exclusion zone of 15% (1.29 l · min-1)) and 67% (without exclusion zone), as well as by polar plot analysis. CONCLUSIONS: In neurosurgical patients requiring extensive vasoactive support, CO values obtained by calibrated PCCO showed clinically and statistically acceptable agreement with TPCO-measurements, but the results from concordance and polar plot analysis indicate an unreliable trending ability.

Comprehensive analysis and prediction of long-term durability of factor IX activity following etranacogene dezaparvovec gene therapy in the treatment of hemophilia B.

OBJECTIVE: Congenital hemophilia B is a rare bleeding disorder caused by defects in the gene encoding factor IX (FIX) leading to coagulation deficiency. Recurrent bleeds may cause chronic pain, disability, and reduced quality of life. Phase 2 b and 3 single-arm, open-label, single-dose trials assessing etranacogene dezaparvovec gene therapy for hemophilia B have demonstrated sustained FIX activity levels over observed periods, but long-term durability of the treatment effect has not been established. Using statistical modeling, we estimate long-term durability of FIX activity levels after receiving etranacogene dezaparvovec. METHODS: Participants from Phase 2 b (N = 3; NCT03489291) and 3 studies (N = 52; NCT03569891) were included. Two participants who did not respond to treatment were excluded. FIX activity was assessed by one-stage activated partial thromboplastin time assay. FIX activity levels at Month 6 post-treatment were considered baseline. Bayesian and Frequentist linear mixed models predicted FIX activity levels up to 25.5 years at an individual and population level with pre-treatment adeno-associated virus 5 (AAV5) neutralizing antibody (NAb) status as primary covariate. RESULTS: Bayesian and Frequentist linear mixed models predicted no more than 6/55 (10.91%) observed participants would have FIX activity levels <2% up to 25.5 years post-infusion. Bayesian model-based predictions of future participants suggest >80% would be free from prophylactic FIX replacement products 25.5 years post-infusion. Both models predicted FIX activity levels were not significantly influenced by pre-treatment AAV5 NAb status. CONCLUSIONS: People with hemophilia B receiving etranacogene dezaparvovec would likely achieve durable FIX activity levels and remain free of prophylactic FIX replacement products for up to 25.5 years following single administration. The long-term factor IX durability predictions are based on statistical methods and results in vivo may differ.

Hemophilia B is a rare bleeding condition where blood does not clot properly, causing excessive bleeding. It is caused by a change or mutation to a gene, leading to lower-than-normal levels of a clotting factor, called factor IX. Standard treatment involves replacing missing factor IX through lifelong, regular treatment with factor replacement products. Etranacogene dezaparvovec is a gene therapy developed to replace the faulty gene and increase factor IX activity levels in the blood, thereby reducing bleeding, after one treatment. In clinical trials of etranacogene dezaparvovec, people with severe or moderately severe hemophilia B had stable and long-lasting increases in factor IX activity levels that reached near to the normal range seen in people without hemophilia B.The purpose of this study was to predict whether these increases in factor IX activity levels will last over an extended period of time after receiving etranacogene dezaparvovec.Mathematical predictions showed less than 11% of clinical trial participants would have unacceptable factor IX activity levels (less than 2%) up to 25.5 years after receiving etranacogene dezaparvovec. Further predictions of potential future people with hemophilia B showed that over 80% would not need treatment with factor replacement products 25.5 years after receiving etranacogene dezaparvovec.The goal of treatment is to increase factor IX activity levels into the near-to-normal range in people with hemophilia B and therefore decrease or eliminate bleeding. These results suggest people with hemophilia B receiving etranacogene dezaparvovec would have long-lasting factor IX activity levels and would not need regular factor replacement products for up to 25.5 years following a single treatment of etranacogene dezaparvovec.

Combining xenon and mild therapeutic hypothermia preserves neurological function after prolonged cardiac arrest in pigs.

OBJECTIVE: Despite the introduction of mild therapeutic hypothermia into postcardiac arrest care, cerebral and myocardial injuries represent the limiting factors for survival after cardiac arrest. Administering xenon may confer an additional neuroprotective effect after successful cardiopulmonary resuscitation due to its ability to stabilize cellular calcium homeostasis via N-methyl-D-aspartate-receptor antagonism. DESIGN: In a porcine model, we evaluated effects of xenon treatment in addition to therapeutic hypothermia on neuropathologic and functional outcomes after cardiopulmonary resuscitation. SETTING: Prospective, randomized, laboratory animal study. SUBJECTS: Fifteen male pigs. INTERVENTIONS: Following 10 mins of cardiac arrest and 6 mins of cardiopulmonary resuscitation, ten pigs were randomized to receive either mild therapeutic hypothermia (33°C for 16 hrs) or mild therapeutic hypothermia 1 xenon (70% for 1 hr). Five animals served as normothermic controls. MEASUREMENTS AND MAIN RESULTS: Gross hemodynamic variables were measured using right-heart catheterization. Neurocognitive performance was evaluated for 5 days after cardiopulmonary resuscitation using a neurologic deficit score before the brains were harvested for histopathological analysis. All animals survived the observation period in the mild therapeutic hypothermia 1 xenon group while one animal in each of the other two groups died. Mild therapeutic hypothermia 1 xenon preserved cardiac output during the induction of mild therapeutic hypothermia significantly better than did mild therapeutic hypothermia alone (4.6 6 0.6 L/min vs. 3.2 6 1.6 L/min, p # .05). Both treatment groups showed significantly fewer necrotic lesions in the cerebral cortex, caudate nucleus, putamen, and in hippocampal sectors CA1 and CA3/4. However, only the combination of mild therapeutic hypothermia and xenon resulted in reduced astrogliosis in the CA1 sector and diminished microgliosis and perivascular inflammation in the putamen. Clinically, only the mild therapeutic hypothermia 1 xenon-treated animals showed significantly improved neurologic deficit scores over time (day 1 = 59.0 6 27.0 vs. day 5 = 4.0 6 5.5, p ø .05) as well as in comparison to the untreated controls on days 3 through 5 after cardiopulmonary resuscitation. CONCLUSIONS: These results demonstrate that even a short exposure to xenon during induction of mild therapeutic hypothermia results in significant improvements in functional recovery and ameliorated myocardial dysfunction.

Myocardial blood flow during general anesthesia with xenon in humans: a positron emission tomography study.

BACKGROUND: Xenon has only minimal hemodynamic side effects and induces pharmacologic preconditioning. Thus, the use of xenon could be an interesting option in patients at risk for perioperative myocardial ischemia. However, little is known about the effects of xenon anesthesia on myocardial blood flow (MBF) and coronary vascular resistance in humans. METHODS: Myocardial blood flow was noninvasively quantified by H2¹5O positron emission tomography in six healthy volunteers (age: 38 ± 8 yr). MBF was measured at baseline and during general anesthesia induced with propofol and maintained with xenon, 59 ± 0%. Absolute quantification of MBF was started after the calculated plasma concentration of propofol had decreased to less than 1.5 µg · ml⁻¹. RESULTS: Compared with baseline (MBFbaseline, 1.03 ± 0.09 ml · min⁻¹ · g⁻¹; mean ± SD), MBF was decreased insignificantly by xenon (MBFxenon, 0.80 ± 0.22 ml · min⁻¹ · g⁻¹; -21%, P = 0.11). Xenon decreased the rate-pressure product (RPP; heart rate × systolic arterial pressure), an indicator of cardiac work and myocardial oxygen consumption (-15%, P < 0.04). When correcting for the RPP, the decrease in MBF observed during xenon anesthesia was reduced to -9% (MBFcorr-xenon, 1.42 ± 0.28 ml · g⁻¹ · mmHg⁻¹ vs. MBFcorr-baseline, 1.60 ± 0.28 ml · g⁻¹ · mmHg⁻¹, P = 0.32). Xenon did not affect the dependency of MBF on the RPP. Coronary vascular resistance did not significantly change (+15 ± 23%, P = 0.18) during xenon anesthesia. CONCLUSIONS: In healthy subjects, xenon has only minimal effects on coronary flow dynamics. These effects are probably of indirect nature, reflecting the decrease in myocardial oxygen consumption induced by the effects of xenon anesthesia on cardiac work.

Aggregate Safety Assessment Planning for the Drug Development Life-Cycle.

The Program Safety Analysis Plan (PSAP) was proposed previously as a tool to proactively plan for integrated analyses of product safety data. Building on the PSAP and taking into consideration the evolving regulatory landscape, the Drug Information Association-American Statistical Association (DIA-ASA) Interdisciplinary Safety Evaluation scientific working group herein proposes the Aggregate Safety Assessment Plan (ASAP) process. The ASAP evolves over a product's life-cycle and promotes interdisciplinary, systematic safety planning as well as ongoing data review and characterization of the emerging product safety profile. Objectives include alignment on the safety topics of interest, identification of safety knowledge gaps, planning for aggregate safety evaluation of the clinical trial data and preparing for safety communications. The ASAP seeks to tailor the analyses for a drug development program while standardizing the analyses across studies within the program. The document is intended to be modular and flexible in nature, depending on the program complexity, phase of development and existing sponsor processes. Implementation of the ASAP process will facilitate early safety signal detection, improve characterization of product risks, harmonize safety messaging, and inform program decision-making.

Bispectral index monitoring during balanced xenon or sevoflurane anaesthesia in elderly patients.

BACKGROUND AND OBJECTIVE: In the elderly, monitoring depth of anaesthesia seems to be of particular importance. We evaluated the bispectral index (BIS) for monitoring depth of anaesthesia during clinically guided balanced xenon or sevoflurane anaesthesia in aged patients. METHODS: In this randomized controlled clinical trial, 40 patients (65-75 years) undergoing elective noncardiac surgery were randomly assigned to balanced anaesthesia with either 53.2 +/- 0.8% xenon (n = 19) or 1.6 +/- 0.1% sevoflurane (n = 20) in minimum 30% oxygen and remifentanil titrated to clinical needs. Depth of anaesthesia was guided by end-tidal gas concentrations and clinical signs. The attending anaesthesiologist was blinded to the BIS values, which were recorded at 1 min rates during induction, at 5 min rates during maintenance and at 20 s rates during emergence. Emergence from anaesthesia was assessed by the times to open eyes, react on demand, extubation and orientation. RESULTS: During induction and maintenance of anaesthesia, BIS values in the xenon group were comparable to sevoflurane and at the lower limit of the recommended range for deep anaesthesia. Emergence to full orientation was significantly faster from xenon than from sevoflurane. BIS values were significantly lower during emergence from xenon anaesthesia. CONCLUSION: During xenon and sevoflurane anaesthesia in the elderly, BIS-values show sufficient concordance with clinical signs of anaesthetic depth. Since during clinically guided anaesthesia values were at the lower recommended limit, additional BIS monitoring may help reduce anaesthetic consumption and costs.

Functional and structural response of arterialized femoral veins in a rodent AV fistula model.

BACKGROUND: Neointimal hyperplasia is considered to be the major cause of arteriovenous fistula (AVF) failure, resulting in vein wall thickening, stenosis and, ultimately, occlusion. Ultrasound (US) has been shown to be effective for detecting these morphological changes in patients. The aim of this study was to develop an experimental AVF model in the rat that shows typical features of fistula maturation and allows longitudinal monitoring of fistula veins by high-resolution ultrasound. METHODS: AVFs were created by a handsewn end-to-side anastomosis between the femoral vein and the femoral artery in 15 rats. A group of sham-operated animals (n = 3) served as controls. Time-related functional and morphological AVF characteristics were assessed up to 12 weeks using ultrasound (15-MHz transducer) and were correlated to histopathological changes. RESULTS: All rats survived surgery, and the patency rate was 93%. US showed a 2-fold increase in the fistula vein diameter and mean flow velocity as well as a 4-fold increase in the intima-media thickness without significant luminal loss. The afferent femoral artery exhibited no change in intima-media thickness and only minimal adaptive increases in diameter and flow velocity. Histological evaluation confirmed these observations. CONCLUSIONS: Our AVF model in the rat demonstrates maturation effects in fistula veins similar to typical clinical findings in haemodialysis patients. Noninvasive ultrasound proved to be a valuable tool for longitudinal in vivo monitoring of the fistulas in this rodent model.

Early administration of xenon or isoflurane may not improve functional outcome and cerebral alterations in a porcine model of cardiac arrest.

BACKGROUND: Xenon (Xe) is neuroprotective when given 1h after cardiopulmonary resuscitation (CPR). Here, we investigated if an earlier administration of Xe or isoflurane (Iso) would also reduce neurological dysfunction. METHODS: 10 min after CPR from 8 min of cardiac arrest 21 pigs were randomized to three groups (n=7/group) and then ventilated for 1h with gas mixtures as follows: (1) control: 30% O(2)+70% N(2); (2) Iso: 30% O(2)+69% N(2)+1% Iso; (3) Xe: 30% O(2)+70% Xe. Physiological variables were obtained before cardiac arrest and 10, 60 and 240 min post-CPR including cardiac output (CO) and mean arterial pressure (MAP). Four days after CPR we assessed functional performance using an established neurocognitive test and overall neurological status using a neurologic deficit score (NDS). On day 5, brains of the re-anaesthetized pigs were harvested for neurohistopathological analyses. RESULTS: Prior to CPR there were no differences in hemodynamics and neurological status between groups. CO and MAP were significantly reduced after starting Iso administration. Both variables were also significantly lower in comparison to Xe and control animals. Control animals presented severe neurological dysfunction as measured by the NDS and the neurocognitive tests. Although Xe and Iso animals showed slightly better functional outcome this trend was not significant. Histopathological evaluation revealed ischaemic damage of neurons predominantly in the CA1 sector of the hippocampus with no differences between groups. CONCLUSIONS: In this study early administration of Xe and Iso did not significantly reduce neurological dysfunction and histopathological alterations induced by cardiac arrest and CPR.

Changes in S-100 protein serum levels in survivors of out-of-hospital cardiac arrest treated with mild therapeutic hypothermia: a prospective, observational study.

INTRODUCTION: Knowledge about the influence of current neuroprotective interventions on prognostic markers after survival from cardiac arrest is lacking. This study aimed to investigate the effects of mild therapeutic hypothermia on the release of the astroglial protein S-100 after cardiopulmonary resuscitation (CPR) in survivors of out-of-hospital cardiac arrest. METHODS: This was a prospective, observational study performed during a two-year period, involving medical emergency services and five collaborating hospitals at the city of Aachen, Germany. Sixty-eight subjects were enrolled by the emergency physician on duty by taking blood samples after successful attempts at resuscitation with return of spontaneous circulation (ROSC), followed by samples at 6, 12, 24, 72 and 120 hours post ROSC by the appropriate intensive care unit staff. Depending on the decision of the attending physician, subjects were cooled down to 33 degrees C (n = 37) for 24 hours or were held at 37 degrees C (n = 31). Patients were tracked for estimating mortality and gross neurological outcome for 14 days. RESULTS: S-100 levels in patients not receiving mild therapeutic hypothermia (normothermia (NT)) showed equivalent numbers as compared with cooled patients (mild therapeutic hypothermia (MTH)) on baseline (NT = 1.38 mug/l versus MTH = 1.30 microg/l; P = 0.886). S-100 levels on baseline were significantly lower in patients with a good neurological outcome at 14 days after the event in comparison to their peers with adverse outcome (P = 0.014). Although the difference in S-100 levels of MTH patients with adverse or favourable neurological outcome reached statistical significance, it did not in NT patients. CONCLUSIONS: Although the predictive power of S-100 levels were best on admission but not at later time points, MTH had no influence on S-100 serum levels in survivors of non-traumatic out-of-hospital cardiac arrest in the particular setting of this investigation.