Jane G. Wigginton

Recommended guidelines for uniform reporting of data from drowning: the “Utstein style”

This document presents the consensus of a group of international investigators who met to establish guidelines for the uniform reporting of data from studies of drowning incidents. The consensus process consisted of formal discussions at 3 international meetings as well as expert review, endorsements from multiple organizations, and invited recommendations from other interested parties. The concept of using consensus workshops to formulate guidelines is not new. Similar consensus guidelines for reporting surveillance and resuscitation research have been developed for both adult and pediatric cardiac arrest.1–3 The principal purpose of the recommendations in this advisory is to establish consistency in the reporting of drowning-related studies, both in terms of nomenclature and guidelines for reporting data. These recommendations are intended to improve the clarity of scientific communication and the comparability of scientific investigations. Improved clarity and comparability of future scientific reports will advance the clinical and epidemiological knowledge base. In turn, such studies can help identify appropriate prevention strategies as well as the best treatment for victims of drowning and can ultimately save lives. Laboratory and clinical investigators from many different specialties contribute to the multidisciplinary knowledge base of injury prevention and resuscitation science. Although diversity can be a strength, it can also be an obstacle because of the lack of a common language and communication between investigators from different backgrounds. In response to these problems, in June 1990 an international group of scientists concerned with research involving out-of-hospital cardiac arrest met at the Utstein Abbey in Stavanger, Norway. Participants discussed the lack of standardized nomenclature and definitions as a key problem in research reports. A second meeting, the Utstein Consensus Conference, was held in December 1990 in Brighton, England. Recommendations from this follow-up conference were published simultaneously in American and European journals.4,5 The report included uniform definitions, terminology, and …

Out-of-hospital cardiac arrest survival improving over time: Results from the Resuscitation Outcomes Consortium (ROC).

BACKGROUND Out-of-hospital cardiac arrest (OHCA) remains a leading cause of death and a 2010 meta-analysis concluded that outcomes have not improved over several decades. However, guidelines have changed to emphasize CPR quality, minimization of interruptions, and standardized post-resuscitation care. We sought to evaluate whether OHCA outcomes have improved over time among agencies participating in the Resuscitation Outcomes Consortium (ROC) cardiac arrest registry (Epistry) and randomized clinical trials (RCTs). METHODS Observational cohort study of 47,148 EMS-treated OHCA cases in Epistry from 139 EMS agencies at 10 ROC sites that participated in at least one RCT between 1/1/2006 and 12/31/2010. We reviewed patient, scene, event characteristics, and outcomes of EMS-treated OHCA over time, including subgroups with initial rhythm of pulseless ventricular tachycardia or ventricular fibrillation (VT/VF). RESULTS Mean response interval, median age and male proportion remained similar over time. Unadjusted survival to discharge increased between 2006 and 2010 for treated OHCA (from 8.2% to 10.4%), as well as for subgroups of VT/VF (21.4% to 29.3%) and bystander witnessed VT/VF (23.5% to 30.3%). Compared with 2006, adjusted survival to discharge was significantly higher in 2010 for treated cases (OR = 1.72; 95% CI 1.53, 1.94), VT/VF cases (OR = 1.69; 95% CI 1.45, 1.98) and bystander witnessed VT/VF cases (OR = 1.65; 95% CI 1.36, 2.00). Tests for trend in each subgroup were significant (p < 0.001). CONCLUSIONS ROC-wide survival increased significantly between 2006 and 2010. Additional research efforts are warranted to identify specific factors associated with this improvement.

Clinical and hemodynamic comparison of 15: 2 and 30:2 compression-to- ventilation ratios for cardiopulmonary resuscitation

Objective:To compare cardiopulmonary resuscitation (CPR) with a compression to ventilation (C:V) ratio of 15:2 vs. 30:2, with and without use of an impedance threshold device (ITD). Design:Prospective randomized animal and manikin study. Setting:Animal laboratory and emergency medical technician training facilities. Subjects:Twenty female pigs and 20 Basic Life Support (BLS)-certified rescuers. Interventions, Measurements, and Main Results: Animals:Acid-base status, cerebral, and cardiovascular hemodynamics were evaluated in 18 pigs in cardiac arrest randomized to a C:V ratio of 15:2 or 30:2. After 6 mins of cardiac arrest and 6 mins of CPR, an ITD was added. Compared to 15:2, 30:2 significantly increased diastolic blood pressure (20 ± 1 to 26 ± 1; p < .01); coronary perfusion pressure (18 ± 1 to 25 ± 2; p = .04); cerebral perfusion pressure (16 ± 3 to 18 ± 3; p = .07); common carotid blood flow (48 ± 5 to 82 ± 5 mL/min; p < .001); end-tidal CO2 (7.7 ± 0.9 to 15.7 ± 2.4; p < .0001); and mixed venous oxygen saturation (26 ± 5 to 36 ± 5, p < .05). Hemodynamics improved further with the ITD. Oxygenation and arterial pH were similar. Only one of nine pigs had return of spontaneous circulation with 15:2, vs. six of nine with 30:2 (p < 0.03). Humans: Fatigue and quality of CPR performance were evaluated in 20 BLS-certified rescuers randomized to perform CPR for 5 mins at 15:2 or 30:2 on a recording CPR manikin. There were no significant differences in the quality of CPR performance or measurement of fatigue. Significantly more compressions per minute were delivered with 30:2 in both the animal and human studies. Conclusions:These data strongly support the contention that a ratio of 30:2 is superior to 15:2 during manual CPR and that the ITD further enhances circulation with both C:V ratios.

Sex-related differences in the presentation and outcome of out-of-hospital cardiopulmonary arrest: a multiyear, prospective, population-based study.

Objective To examine whether previously observed sex-related differences in coronary artery disease syndromes also apply to patients with out-of-hospital sudden cardiac arrest, a probable subset of patients with coronary artery disease who are easy to recognize and are treated in a standardized fashion. Design Prospective, population-based study conducted over a 6-yr period. Setting A large urban municipality (population, 1.1 million) served by a single emergency medical services system with centralized medical direction and standardized protocols. Patients All patients with out-of-hospital, nontraumatic, primary cardiac arrest. Interventions Standardized advanced cardiac life support protocols. Measurements and Main Results During the 6 yrs of the study, 4147 consecutive patients were studied, 42% of whom were women (p < .001). Although women were significantly older than men (mean age, 68.7 ± 18 vs. 61.7 ± 17 yrs;p = .001), there were no significant differences for the percentages of witnessed and unwitnessed arrests, response intervals, and the length and type of treatment provided. Although men were more likely to have ventricular fibrillation/ventricular tachycardia on presentation (41% vs. 30%), women had more asystole (8.8% vs. 7%) and (organized) pulseless electrical activity than men (24% vs. 18%;p < .001). Nevertheless, more women were resuscitated (13.5% vs. 10.7%;p = .005), particularly women with non-ventricular fibrillation/ventricular tachycardia presentation (12.6% vs. 9.6%;p < .02). These differences were more pronounced when controlling for age (95% confidence interval, 1.44 [1.25–1.74]). Conclusions In cases of out-of-hospital sudden cardiac arrest, women have significantly better resuscitation rates than men, especially when controlling for age, particularly among women with non-ventricular fibrillation/ventricular tachycardia presentations. Additional studies are required to validate these observations, not only for long-term survival and external validity, but also for other potential genetic factors and potential discrepancies with other studies.

Resveratrol decreases inflammation in the brain of mice with mild traumatic brain injury.

BACKGROUND Following a mild traumatic brain injury (TBI) event, the secondary brain injury that persists after the initial blow to the head consists of excitotoxicity, decreased cerebral glucose levels, oxidant injury, mitochondrial dysfunction, inflammation, and neuronal cell death. To date, there are no effective interventions used at decreasing secondary brain injury after mild TBI. METHODS In this study, male mice were treated with either placebo or resveratrol (100 mg/kg) at 5 minutes and 12 hours after mild TBI. The mice were injured using the controlled cortical impact device. In this closed-head model, a midline incision was made to access the skull and the impactor tip was aligned on the sagittal suture midway between the bregma and lambda sutures. The mice were injured at a depth of 2.0 mm, velocity of 4 m/s, and a delay time of 100 milliseconds. At 72 hours following injury, the animals were intracardially perfused with 0.9% saline followed by 10% phosphate-buffered formalin. The whole brain was removed, sliced, and stained for microglial activation (Iba1). In addition, using the enzyme-linked immunosorbent assay, tissue levels of interleukin 6 (IL-6) and IL-12 were measured in the cerebral cortex and hippocampus. RESULTS In this study, we found that in the placebo treatment group, there was a significant increase in Iba1 staining in the brain. The levels of microglial activation was reduced by resveratrol in the cerebral cortex (p < 0.001), corpus callosum (p < 0.001), and dentate gyrus (p < 0.005) brain regions after mild TBI. In addition to Iba1, resveratrol decreased the brain levels of IL-6 (p < 0.0001) and IL-12 (p < 0.004), which were observed in the hippocampus of the placebo group. In our model, no increase of IL-6 or IL-12 was observed in the cerebral cortex following TBI. CONCLUSION Resveratrol given acutely after TBI results in a decrease in neuroinflammation. These results suggest that resveratrol may be beneficial in reducing secondary brain injury after experiencing a mild TBI.

Estrogen treatment following severe burn injury reduces brain inflammation and apoptotic signaling

BackgroundPatients with severe burn injury experience a rapid elevation in multiple circulating pro-inflammatory cytokines, with the levels correlating with both injury severity and outcome. Accumulations of these cytokines in animal models have been observed in remote organs, however data are lacking regarding early brain cytokine levels following burn injury, and the effects of estradiol on these levels. Using an experimental animal model, we studied the acute effects of a full-thickness third degree burn on brain levels of TNF-α, IL-1β, and IL-6 and the protective effects of acute estrogen treatment on these levels. Additionally, the acute administration of estrogen on regulation of inflammatory and apoptotic events in the brain following severe burn injury were studied through measuring the levels of phospho-ERK, phospho-Akt, active caspase-3, and PARP cleavage in the placebo and estrogen treated groups.MethodsIn this study, 149 adult Sprague-Dawley male rats received 3rd degree 40% total body surface area (TBSA) burns. Fifteen minutes following burn injury, the animals received a subcutaneous injection of either placebo (n = 72) or 17 beta-estradiol (n = 72). Brains were harvested at 0.5, 1, 2, 4, 6, 8, 12, 18, and 24 hours after injury from the control (n = 5), placebo (n = 8/time point), and estrogen treated animals (n = 8/time point). The brain cytokine levels were measured using the ELISA method. In addition, we assessed the levels of phosphorylated-ERK, phosphorylated-Akt, active caspase-3, and the levels of cleaved PARP at the 24 hour time-point using Western blot analysis.ResultsIn burned rats, 17 beta-estradiol significantly decreased the levels of brain tissue TNF-α (~25%), IL-1β (~60%), and IL-6 (~90%) when compared to the placebo group. In addition, we determined that in the estrogen-treated rats there was an increase in the levels of phospho-ERK (p < 0.01) and Akt (p < 0.05) at the 24 hour time-point, and that 17 beta-estradiol blocked the activation of caspase-3 (p < 0.01) and subsequent cleavage of PARP (p < 0.05).ConclusionFollowing severe burn injury, estrogens decrease both brain inflammation and the activation of apoptosis, represented by an increase in the levels of phospho-Akt and inhibition of caspase-3 activation and PARP cleavage. Results from these studies will help further our understanding of how estrogens protect the brain following burn injury, and may provide a novel, safe, and effective clinical treatment to combat remote secondary burn injury in the brain and to preserve cognition.

Simultaneous quantification of four native estrogen hormones at trace levels in human cerebrospinal fluid using liquid chromatography-tandem mass spectrometry

Estrogens are known to exhibit neuroprotective effects on the brain. Their importance in this regard and in others has been emphasized in many recent studies, which increases the need to develop reliable analytical methods for the measurement of estrogen hormones. A heart-cutting two-dimensional liquid chromatography separation method coupled with electrospray ionization-tandem mass spectrometry (ESI-MS/MS) has been developed for simultaneous measurement of four estrogens, including estriol (E3), estrone (E1), 17β-estradiol (17β-E2), and 17α-estradiol (17α-E2), in human cerebrospinal fluid (CSF). The method was based on liquid-liquid extraction and derivatization of estrogens with dansyl chloride to enhance the sensitivity of ESI-based detection in conjunction with tandem mass spectrometry. Dansylated estriol and estrone were separated in the first dimension by an amide-C18 column, while dansylated 17β- and 17α-estradiol were resolved on the second dimension by two C18 columns (175 mm total length) connected in series. This is the first report of a method for simultaneous quantification of all four endogenous estrogen compounds in their dansylated form. The detection limits for E1, 17α-E2, 17β-E2, and E3 were 19, 35, 26, and 61pg/mL, respectively. Due to matrix effects, validation and calibration was carried out in charcoal-stripped CSF. The precision and accuracy were more than 86% for the two E2 compounds and 79% for E1 and E3 while the extraction recovery ranged from 91% to 104%. The method was applied to measure estrogens obtained in a clinical setting, from the CSF of ischemic trauma patients. While 17β-estradiol was present at a significant level in the CSF of some samples, other estrogens were present at lower levels or were undetectable.

Specific inhibition of mitochondrial oxidative stress suppresses inflammation and improves cardiac function in a rat pneumonia-related sepsis model

Using a mitochondria-targeted vitamin E (Mito-Vit-E) in a rat pneumonia-related sepsis model, we examined the role of mitochondrial reactive oxygen species in sepsis-mediated myocardial inflammation and subsequent cardiac contractile dysfunction. Sepsis was produced in adult male Sprague-Dawley rats via intratracheal injection of S. pneumonia (4 × 10(6) colony formation units per rat). A single dose of Mito-Vit-E, vitamin E, or control vehicle, at 21.5 μmol/kg, was administered 30 min postinoculation. Blood was collected, and heart tissue was harvested at various time points. Mito-Vit-E in vivo distribution was confirmed by mass spectrometry. In cardiac mitochondria, Mito-Vit-E improved total antioxidant capacity and suppressed H(2)O(2) generation, whereas vitamin E offered little effect. In cytosol, both antioxidants decreased H(2)O(2) levels, but only vitamin E strengthened antioxidant capacity. Mito-Vit-E protected mitochondrial structure and function in the heart during sepsis, demonstrated by reduction in lipid and protein oxidation, preservation of mitochondrial membrane integrity, and recovery of respiratory function. While both Mito-Vit-E and vitamin E suppressed sepsis-induced peripheral and myocardial production of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6), Mito-Vit-E exhibited significantly higher efficacy (P < 0.05). Stronger anti-inflammatory action of Mito-Vit-E was further shown by its near-complete inhibition of sepsis-induced myeloperoxidase accumulation in myocardium, suggesting its effect on neutrophil infiltration. Echocardiography analysis indicated that Mito-Vit-E ameliorated cardiac contractility of sepsis animals, shown by improved fractional shortening and ejection fraction. Together, our data suggest that targeted scavenging of mitochondrial reactive oxygen species protects mitochondrial function, attenuates tissue-level inflammation, and improves whole organ activities in the heart during sepsis.

Mechanical devices for cardiopulmonary resuscitation

Purpose of the reviewFor over 40 years, manual chest compressions have been the foundation of cardiopulmonary resuscitation and recent studies have clearly reconfirmed the hemodynamic significance of delivering consistent, high-quality, infrequently-interrupted chest compressions. However, there remain multiple inadequacies in the actual delivery of manual chest compressions during cardiopulmonary resuscitation. One potential solution is use of adjunct mechanical devices. Recent findingsTwo different methods of accessory chest compression techniques recently have demonstrated enhanced short-term survival. The active compression-decompression device is a hand-held, manually operated suction device applied to the center of the chest wall. In tandem with an impedance threshold (airway) device, active compression-decompression has shown a 65% improvement in 24-hour survival rates (compared with standard cardiopulmonary resuscitation) in a randomized out-of-hospital clinical trial (n = 210). The second device, called Auto-Pulse CPR is an automated machine that uses a load-distributing, broad compression band that is applied across the entire anterior chest. A recent out-of-hospital retrospective case-control study (n = 162) also revealed improved short-term survival. SummaryHigh quality chest compressions during cardiopulmonary resuscitation are critical elements in effecting successful resuscitation following a cardiac arrest. Recent studies utilizing adjunct mechanical devices have not only revealed significant increases in the effectiveness of chest compressions, including improved hemodynamics in both animal models and human studies, but also improvements in short-term human survival in the clinical setting. It is hoped that these promising findings will eventually be corroborated in terms of improved neurologically intact, long-term patient survival. Clinical trials are currently underway to validate such efficacy.

Retention behavior of estrogen metabolites on hydrophilic interaction chromatography stationary phases

Estrogens and estrogen metabolites are important biological mediators of the endocrine system. They have also been implicated in detrimental carcinogenesis and beneficial neuroprotective processes. The retention behavior of estrogen metabolites was investigated on five polar stationary phases, used for hydrophilic interaction chromatography, and coupled with ESI-MS. Data were fit to partitioning and surface adsorption models. Retention of the compounds, especially estrogen glucuronides, on the amide- and diol-bonded stationary phases, could be best described by the surface adsorption model; however, mixed modes of retention were observed on most stationary phases. Retention time increased while the peak efficiency decreased proportional to the number of hydroxyl groups in the analytes. The effects of salt concentration and salt type were also investigated. The presence of solvated salt ions, which interact with the stationary phase and the analyte, enhanced retention of the analytes. This was believed to be due to two effects. The increased ionic strength reduced the contribution of secondary electrostatic interactions (mixed-mode effects). It also enhanced hydrogen-bonding and partitioning (hydrophilic interaction) between the analyte and the stationary phase, likely facilitated by the associated solvated salt ions.