Effects of sex and estrous cycle on intravenous oxycodone self-administration and the reinstatement of oxycodone-seeking behavior in rats.

Introduction: The increasing misuse of both prescription and illicit opioids has culminated in a national healthcare crisis in the United States. Oxycodone is among the most widely prescribed and misused opioid pain relievers and has been associated with a high risk for transition to compulsive opioid use. Here, we sought to examine potential sex differences and estrous cycle-dependent effects on the reinforcing efficacy of oxycodone, as well as on stress-induced or cue-induced oxycodone-seeking behavior, using intravenous (IV) oxycodone self-administration and reinstatement procedures. Methods: In experiment 1, adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone according to a fixed-ratio 1 schedule of reinforcement in daily 2-h sessions, and a dose-response function was subsequently determined (0.003-0.03 mg/kg/inf). In experiment 2, a separate group of adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone for 8 sessions, followed by 0.01 mg/kg/inf oxycodone for 10 sessions. Responding was then extinguished, followed by sequential footshock-induced and cue-induced reinstatement tests. Results: In the dose-response experiment, oxycodone produced a typical inverted U-shape function with 0.01 mg/kg/inf representing the maximally effective dose in both sexes. No sex differences were detected in the reinforcing efficacy of oxycodone. In the second experiment, the reinforcing effects of 0.01-0.03 mg//kg/inf oxycodone were significantly attenuated in females during proestrus/estrus as compared to metestrus/diestrus phases of the estrous cycle. Neither males nor females displayed significant footshock-induced reinstatement of oxycodone seeking, but both sexes exhibited significant cue-induced reinstatement of oxycodone seeking at magnitudes that did not differ either by sex or by estrous cycle phase. Discussion: These results confirm and extend previous work suggesting that sex does not robustly influence the primary reinforcing effects of oxycodone nor the reinstatement of oxycodone-seeking behavior. However, our findings reveal for the first time that the reinforcing efficacy of IV oxycodone varies across the estrous cycle in female rats.

Effects of sex and estrous cycle on intravenous oxycodone self-administration and the reinstatement of oxycodone-seeking behavior in rats.

The increasing misuse of both prescription and illicit opioids has culminated in a national healthcare crisis in the United States. Oxycodone is among the most widely prescribed and misused opioid pain relievers and has been associated with a high risk for transition to compulsive opioid use. Here, we sought to examine potential sex differences and estrous cycle-dependent effects on the reinforcing efficacy of oxycodone, as well as on stress-induced or cue-induced oxycodone-seeking behavior, using intravenous (IV) oxycodone self-administration and reinstatement procedures. In experiment 1, adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone according to a fixed-ratio 1 schedule of reinforcement in daily 2-hr sessions, and a dose-response function was subsequently determined (0.003-0.03 mg/kg/inf). In experiment 2, a separate group of adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone for 8 sessions, followed by 0.01 mg/kg/inf oxycodone for 10 sessions. Responding was then extinguished, followed by sequential footshock-induced and cue-induced reinstatement tests. In the dose-response experiment, oxycodone produced a typical inverted U-shape function with 0.01 mg/kg/inf representing the maximally effective dose in both sexes. No sex differences were detected in the reinforcing efficacy of oxycodone. In the second experiment, the reinforcing effects of 0.01-0.03 mg//kg/inf oxycodone were significantly attenuated in females during proestrus/estrus as compared to metestrus/diestrus phases of the estrous cycle. Neither males nor females displayed significant footshock-induced reinstatement of oxycodone seeking, but both sexes exhibited significant cue-induced reinstatement of oxycodone seeking at magnitudes that did not differ either by sex or by estrous cycle phase. These results confirm and extend previous work suggesting that sex does not robustly influence the primary reinforcing effects of oxycodone nor the reinstatement of oxycodone-seeking behavior. However, our findings reveal for the first time that the reinforcing efficacy of IV oxycodone varies across the estrous cycle in female rats.

Cocaine Exposure Increases Excitatory Synaptic Transmission and Intrinsic Excitability in the Basolateral Amygdala in Male and Female Rats and across the Estrous Cycle.

INTRODUCTION: Sex and ovarian hormones influence cocaine seeking and relapse vulnerability, but less is known regarding the cellular and synaptic mechanisms contributing to these behavioral sex differences. One factor thought to influence cue-induced seeking behavior following withdrawal is cocaine-induced changes in the spontaneous activity of pyramidal neurons in the basolateral amygdala (BLA). However, the mechanisms underlying these changes, including potential sex or estrous cycle effects, are unknown. METHODS: Ex vivo whole-cell patch clamp electrophysiology was conducted to investigate the effects of cocaine exposure, sex, and estrous cycle fluctuations on two properties that can influence spontaneous activity of BLA pyramidal neurons: (1) frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) and (2) intrinsic excitability. Recordings of BLA pyramidal neurons were conducted in adult male and female rats and across the estrous cycle following 2-4 weeks of withdrawal from extended-access cocaine self-administration (6 h/day for 10 days) or drug-naïve conditions. RESULTS: In both sexes, cocaine exposure increased the frequency, but not amplitude, of sEPSCs and neuronal intrinsic excitability. Across the estrous cycle, sEPSC frequency and intrinsic excitability were significantly elevated only in cocaine-exposed females in the estrus stage of the cycle, a stage when cocaine-seeking behavior is known to be enhanced. CONCLUSIONS: Here, we identify potential mechanisms underlying cocaine-induced alterations in the spontaneous activity of BLA pyramidal neurons in both sexes along with changes in these properties across the estrous cycle.

mGlu5 inhibition in the basolateral amygdala prevents estrous cycle-dependent changes in cue-induced cocaine seeking.

Drug associated cues are a common relapse trigger for individuals recovering from cocaine use disorder. Sex and ovarian hormones influence patterns of cocaine use and relapse vulnerability, with studies indicating that females show increased cue-induced craving and relapse vulnerability compared to males. In a rodent model of cocaine craving and relapse vulnerability, cue-induced cocaine seeking behavior following weeks of withdrawal from extended-access cocaine self-administration is higher in females in the estrus stage of the reproductive (estrous) cycle (Estrus Females) compared to both Males and females in all other stages (Non-Estrus Females). However, the neuronal substrates and cellular mechanisms underlying these sex differences is not fully understood. One region that contributes to both sex differences in behavioral responding and cue-induced cocaine seeking is the basolateral amygdala (BLA), while one receptor known to play a critical role in mediating cocaine seeking behavior is metabotropic glutamate receptor 5 (mGlu5). Here we assessed the effects of BLA mGlu5 inhibition following prolonged withdrawal from cocaine self-administration on observed estrous cycle-dependent changes in cue-induced cocaine seeking behavior. We found that BLA microinjections of the mGlu5 antagonist MTEP selectively reduced the enhanced cue-induced cocaine seeking normally observed in Estrus Females while having no effect on cocaine seeking in Males and Non-Estrus Females. These findings identify a unique interaction between cocaine-exposure, estrous cycle fluctuations and BLA mGlu5-dependent transmission on cue-induced cocaine seeking behavior.

Age- and Sex-Dependent Changes in Locus Coeruleus Physiology and Anxiety-Like Behavior Following Acute Stressor Exposure.

Adolescence is a critical period of development with increased sensitivity toward psychological stressors. Many psychiatric conditions emerge during adolescence and animal studies have shown that that acute stress has long-term effects on hypothalamic-pituitary-adrenal axis function and behavior. We recently demonstrated that acute stress produces long-term electrophysiological changes in locus coeruleus and long-lasting anxiety-like behavior in adolescent male rats. Based on prior reports of increased stress sensitivity during adolescence and increased sensitivity of female locus coeruleus toward corticotropin releasing factor, we hypothesized that the same acute stressor would cause different behavioral and physiological responses in adolescent female and adult male and female rats one week after stressor exposure. In this study, we assessed age and sex differences in how an acute psychological stressor affects corticosterone release, anxiety-like behavior, and locus coeruleus physiology at short- and long-term intervals. All groups of animals except adult female responded to stress with elevated corticosterone levels at the acute time point. One week after stressor exposure, adolescent females showed decreased firing of locus coeruleus neurons upon current injection and increased exploratory behavior compared to controls. The results were in direct contrast to changes observed in adolescent males, which showed increased anxiety-like behavior and increased spontaneous and induced firing in locus coeruleus neurons a week after stressor exposure. Adult males and females were both behaviorally and electrophysiologically resilient to the long-term effects of acute stress. Therefore, there may be a normal developmental trajectory for locus coeruleus neurons which promotes stress resilience in adults, but stressor exposure during adolescence perturbs their function. Furthermore, while locus coeruleus neurons are more sensitive to stressor exposure during adolescence, the effect varies between adolescent males and females. These findings suggest that endocrine, behavioral, and physiological responses to stress vary among animals of different age and sex, and therefore these variables should be taken into account when selecting models and designing experiments to investigate the effects of stress. These differences in animals may also allude to age and sex differences in the prevalence of various psychiatric illnesses within the human population.

Effects of Sex and Estrous Cycle on the Time Course of Incubation of Cue-Induced Craving following Extended-Access Cocaine Self-Administration.

Cocaine addiction is a devastating public health epidemic that continues to grow. Studies focused on identifying biological factors influencing cocaine craving and relapse vulnerability are necessary to promote abstinence in recovering drug users. Sex and ovarian hormones are known to influence cocaine addiction liability and relapse vulnerability in both humans and rodents. Previous studies have investigated sex differences in the time-dependent intensification or "incubation" of cue-induced cocaine craving that occurs during withdrawal from extended-access cocaine self-administration and have identified changes across the rat reproductive cycle (estrous cycle). Female rats in the estrus stage of the cycle (Estrus Females), the phase during which ovulation occurs, show an increase in the magnitude of incubated cue-induced cocaine craving compared with females in all other phases of the estrous cycle (Non-Estrus Females). Here we extend these findings by assessing incubated craving across the estrous cycle during earlier withdrawal periods (withdrawal day 1 and 15) and later withdrawal periods (withdrawal day 48). We found that this increase in the magnitude of incubated craving during estrus (Estrus Females) is present on withdrawal day 15, but not on withdrawal day 1, and further increases by withdrawal day 48. No difference in the magnitude of incubated craving was observed between Males and Non-Estrus Females. Our data indicate that the effects of hormonal fluctuations on cue-induced cocaine craving intensify during the first month and a half of withdrawal, showing an interaction among abstinence length, estrous cycle fluctuations, and cocaine craving.

Cocaine and chronic stress exposure produce an additive increase in neuronal activity in the basolateral amygdala.

Cocaine addiction is a chronic, relapsing disorder. Stress and cues related to cocaine are two common relapse triggers. We have recently shown that exposure to repeated restraint stress during early withdrawal accelerates the time-dependent intensification or "incubation" of cue-induced cocaine craving that occurs during the first month of withdrawal, although craving ultimately plateaus at the same level observed in controls. These data indicate that chronic stress exposure during early withdrawal may result in increased vulnerability to cue-induced relapse during this period. Previous studies have shown that chronic stress exposure in drug-naïve rats increases neuronal activity in the basolateral amygdala (BLA), a region critical for behavioral responses to stress. Given that glutamatergic projections from the BLA to the nucleus accumbens are critical for the incubation of cue-induced cocaine craving, we hypothesized that cocaine withdrawal and chronic stress exposure produce separate increases that additively increase BLA neuronal activity. To assess this, we conducted in vivo extracellular single-unit recordings from the BLA of anesthetized adult male rats following cocaine or saline self-administration (6 h/day for 10 days) and repeated restraint stress or control conditions on withdrawal days (WD) 6-14. Recordings were conducted from WD15 to WD20. Interestingly, cocaine exposure alone increased the spontaneous firing rate in the BLA to levels observed following chronic stress exposure in drug-naïve rats. Chronic stress exposure during cocaine withdrawal further increased firing rate. These studies may identify a potential mechanism by which both cocaine and chronic stress exposure drive cue-induced relapse vulnerability during abstinence.

Cognition and Understanding of Neuropathy of Inpatients Admitted to a Specialized Tertiary Diabetic Foot Unit With Diabetes-Related Foot Ulcers.

This study investigated cognitive functioning and understanding of peripheral neuropathy in a cohort of individuals with diabetes-related foot ulcers requiring hospitalization. The aim was to examine the association between cognition, understanding of peripheral neuropathy, and diabetic health variables. Thirty inpatients referred to the Diabetic Foot Unit Clinical Psychology service, at the Royal Melbourne hospital, were assessed using the Montreal Cognitive Assessment (MoCA) and the Patient Interpretation of Neuropathy (PIN) questionnaire. Relevant demographic and medical information was collected. In this predominantly middle-aged, male cohort, the average MoCA score (22.37, SD = 3.65) fell below the general population age-matched mean, and a quarter of the MoCA patient scores were consistent with those seen in early dementia samples (<20). There appeared to be several misperceptions regarding peripheral neuropathy, less accurate attributions of blame to self or practitioners, and more accurate attributions of control of ulcer management to practitioners. Correlation analysis indicated that individuals with stronger MoCA scores tended to provide more accurate answers on the Acute Foot Ulcer Onset PIN scale. Individuals with diabetes-related foot ulcers requiring hospitalization demonstrate reduced cognitive functioning and this may affect their understanding of peripheral neuropathy, particularly information regarding foot ulcer onset. Routine screening of cognitive functioning in this cohort may be useful so that health education and care management can be adjusted according to individual patients' cognitive capabilities.

Association of Bystander and First-Responder Efforts and Outcomes According to Sex: Results From the North Carolina HeartRescue Statewide Quality Improvement Initiative.

Background The Institute of Medicine has called for actions to understand and target sex-related differences in care and outcomes for out-of-hospital cardiac arrest patients. We assessed changes in bystander and first-responder interventions and outcomes for males versus females after statewide efforts to improve cardiac arrest care. Methods and Results We identified out-of-hospital cardiac arrests from North Carolina (2010-2014) through the CARES (Cardiac Arrest Registry to Enhance Survival) registry. Outcomes for men versus women were examined through multivariable logistic regression analyses adjusted for (1) nonmodifiable factors (age, witnessed status, and initial heart rhythm) and (2) nonmodifiable plus modifiable factors (bystander cardiopulmonary resuscitation and defibrillation before emergency medical services), including interactions between sex and time (ie, year and year2). Of 8100 patients, 38.1% were women. From 2010 to 2014, there was an increase in bystander cardiopulmonary resuscitation (men, 40.5%-50.6%; women, 35.3%-51.8%; P for each <0.0001) and in the combination of bystander cardiopulmonary resuscitation and first-responder defibrillation (men, 15.8%-23.0%, P=0.007; women, 8.5%-23.7%, P=0.004). From 2010 to 2014, the unadjusted predicted probability of favorable neurologic outcome was higher and increased more for men (men, from 6.5% [95% confidence interval (CI), 5.1-8.0] to 9.7% [95% CI, 8.1-11.3]; women, from 6.3% [95% CI, 4.4-8.3] to 7.4% [95% CI, 5.5-9.3%]); while adjusted for nonmodifiable factors, it was slightly higher but with a nonsignificant increase for women (from 9.2% [95% CI, 6.8-11.8] to 10.2% [95% CI, 8.0-12.5]; men, from 5.8% [95% CI, 4.6-7.0] to 8.4% [95% CI, 7.1-9.7]). Adding bystander cardiopulmonary resuscitation and defibrillation before EMS (modifiable factors) did not substantially change the results. Conclusions Bystander and first-responder interventions increased for men and women, but outcomes improved significantly only for men. Additional strategies may be necessary to improve survival among female cardiac arrest patients.

Impact of Regionalization of ST-Segment-Elevation Myocardial Infarction Care on Treatment Times and Outcomes for Emergency Medical Services-Transported Patients Presenting to Hospitals With Percutaneous Coronary Intervention: Mission: Lifeline Accelerator-2.

BACKGROUND: Regional variations in reperfusion times and mortality in patients with ST-segment-elevation myocardial infarction are influenced by differences in coordinating care between emergency medical services (EMS) and hospitals. Building on the Accelerator-1 Project, we hypothesized that time to reperfusion could be further reduced with enhanced regional efforts. METHODS: Between April 2015 and March 2017, we worked with 12 metropolitan regions across the United States with 132 percutaneous coronary intervention-capable hospitals and 946 EMS agencies. Data were collected in the ACTION (Acute Coronary Treatment and Intervention Outcomes Network)-Get With The Guidelines Registry for quarterly Mission: Lifeline reports. The primary end point was the change in the proportion of EMS-transported patients with first medical contact to device time ≤90 minutes from baseline to final quarter. We also compared treatment times and mortality with patients treated in hospitals not participating in the project during the corresponding time period. RESULTS: During the study period, 10 730 patients were transported to percutaneous coronary intervention-capable hospitals, including 974 in the baseline quarter and 972 in the final quarter who met inclusion criteria. Median age was 61 years; 27% were women, 6% had cardiac arrest, and 6% had shock on admission; 10% were black, 12% were Latino, and 10% were uninsured. By the end of the intervention, all process measures reflecting coordination between EMS and hospitals had improved, including the proportion of patients with a first medical contact to device time of ≤90 minutes (67%-74%; P<0.002), a first medical contact to device time to catheterization laboratory activation of ≤20 minutes (38%-56%; P<0.0001), and emergency department dwell time of ≤20 minutes (33%-43%; P<0.0001). Of the 12 regions, 9 regions reduced first medical contact to device time, and 8 met or exceeded the national goal of 75% of patients treated in ≤90 minutes. Improvements in treatment times corresponded with a significant reduction in mortality (in-hospital death, 4.4%-2.3%; P=0.001) that was not apparent in hospitals not participating in the project during the same time period. CONCLUSIONS: Organization of care among EMS and hospitals in 12 regions was associated with significant reductions in time to reperfusion in patients with ST-segment-elevation myocardial infarction as well as in in-hospital mortality. These findings support a more intensive regional approach to emergency care for patients with ST-segment-elevation myocardial infarction.

Impact of Regional Systems of Care on Disparities in Care Among Female and Black Patients Presenting With ST-Segment-Elevation Myocardial Infarction.

BACKGROUND: The American Heart Association Mission: Lifeline STEMI (ST-segment-elevation myocardial infarction) Systems Accelerator program, conducted in 16 regions across the United States to improve key care processes, resulted in more patients being treated within national guideline goals (time from first medical contact to device: <90 minutes for direct presenters to hospitals capable of performing percutaneous coronary intervention; <120 minutes for transfers). We examined whether the effort reduced reperfusion disparities in the proportions of female versus male and black versus white patients. METHODS AND RESULTS: In total, 23 809 patients (29.3% female, 82.3% white, and 10.7% black) presented with acute STEMI between July 2012 and March 2014. Change in the proportion of patients treated within guideline goals was compared between sex and race subgroups for patients presenting directly to hospitals capable of performing percutaneous coronary intervention (n=18 267) and patients requiring transfer (n=5542). The intervention was associated with an increase in the proportion of men treated within guideline goals that presented directly (58.7-62.1%, P=0.01) or were transferred (43.3-50.7%, P<0.01). An increase was also seen among white patients who presented directly (57.7-59.9%, P=0.02) or were transferred (43.9-48.8%, P<0.01). There was no change in the proportion of female or black patients treated within guideline goals, including both those presenting directly and transferred. CONCLUSION: The STEMI Systems Accelerator project was associated with an increase in the proportion of patients meeting guideline reperfusion targets for male and white patients but not for female or black patients. Efforts to organize systems of STEMI care should implement additional processes targeting barriers to timely reperfusion among female and black patients.

Association of Public Health Initiatives With Outcomes for Out-of-Hospital Cardiac Arrest at Home and in Public Locations.

Importance: Little is known about the influence of comprehensive public health initiatives according to out-of-hospital cardiac arrest (OHCA) location, particularly at home, where resuscitation efforts and outcomes have historically been poor. Objective: To describe temporal trends in bystander cardiopulmonary resuscitation (CPR) and first-responder defibrillation for OHCAs stratified by home vs public location and their association with survival and neurological outcomes. Design, Setting, and Participants: This observational study reviewed 8269 patients with OHCAs (5602 [67.7%] at home and 2667 [32.3%] in public) for whom resuscitation was attempted using data from the Cardiac Arrest Registry to Enhance Survival (CARES) from January 1, 2010, through December 31, 2014. The setting was 16 counties in North Carolina. Exposures: Patients were stratified by home vs public OHCA. Public health initiatives to improve bystander and first-responder interventions included training members of the general population in CPR and in the use of automated external defibrillators, teaching first responders about team-based CPR (eg, automated external defibrillator use and high-performance CPR), and instructing dispatch centers on recognition of cardiac arrest. Main Outcomes and Measures: Association of resuscitation efforts with survival and neurological outcomes from 2010 through 2014. Results: Among home OHCA patients (n = 5602), the median age was 64 years, and 62.2% were male; among public OHCA patients (n = 2667), the median age was 68 years, and 61.5% were male. After comprehensive public health initiatives, the proportion of patients receiving bystander CPR increased at home (from 28.3% [275 of 973] to 41.3% [498 of 1206], P < .001) and in public (from 61.0% [275 of 451] to 70.5% [424 of 601], P = .01), while first-responder defibrillation increased at home (from 42.2% [132 of 313] to 50.8% [212 of 417], P = .02) but not significantly in public (from 33.1% [58 of 175] to 37.8% [93 of 246], P = .17). Survival to discharge improved for arrests at home (from 5.7% [60 of 1057] to 8.1% [100 of 1238], P = .047) and in public (from 10.8% [50 of 464] to 16.2% [98 of 604], P = .04). Compared with emergency medical services-initiated CPR and resuscitation, patients with home OHCA were significantly more likely to survive to hospital discharge if they received bystander-initiated CPR and first-responder defibrillation (odds ratio, 1.55; 95% CI, 1.01-2.38). Patients with arrests in public were most likely to survive if they received both bystander-initiated CPR and defibrillation (odds ratio, 4.33; 95% CI, 2.11-8.87). Conclusions and Relevance: After coordinated and comprehensive public health initiatives, more patients received bystander CPR and first-responder defibrillation at home and in public, which was associated with improved survival.

Direct Transport to a Percutaneous Cardiac Intervention Center and Outcomes in Patients With Out-of-Hospital Cardiac Arrest.

BACKGROUND: Practice guidelines recommend regional systems of care for out-of-hospital cardiac arrest. However, whether emergency medical services should bypass nonpercutaneous cardiac intervention (non-PCI) facilities and transport out-of-hospital cardiac arrest patients directly to PCI centers despite longer transport time remains unknown. METHODS AND RESULTS: Using the Cardiac Arrest Registry to Enhance Survival with geocoding of arrest location, we identified out-of-hospital cardiac arrest patients with prehospital return of spontaneous circulation and evaluated the association between direct transport to a PCI center and outcomes in North Carolina during 2012 to 2014. Destination hospital was classified according to PCI center status (catheterization laboratory immediately accessible 24/7). Inverse probability-weighted logistic regression accounting for age, sex, emergency medical services response time, clustering of county, transport time to nearest PCI center, initial heart rhythm, and prehospital ECG information was performed. Of 1507 patients with prehospital return of spontaneous circulation, 1359 (90.2%) were transported to PCI centers, of whom 873 (57.9%) bypassed the nearest non-PCI hospital and 148 (9.8%) were transported to non-PCI hospitals. Discharge survival was higher among those transported to PCI centers (33.5% versus 14.6%; adjusted odds ratio, 2.47; 95% confidence interval, 2.08-2.92). Compared with patients taken to non-PCI hospitals, odds of survival were higher for patients taken to the nearest hospital with PCI center status (odds ratio, 3.07; 95% confidence interval, 1.90-4.97) and for patients bypassing closer hospitals to PCI centers (odds ratio, 3.02; 95% confidence interval, 2.01-4.53). Adjusted survival remained significantly better across transport times of 1 to 5, 6 to 10, 11 to 20, 21 to 30, and >30 minutes. CONCLUSIONS: Direct transport to a PCI center is associated with better outcomes for out-of-hospital cardiac arrest patients, even when bypassing nearest hospital and regardless of transport time.

Association of Rapid Care Process Implementation on Reperfusion Times Across Multiple ST-Segment-Elevation Myocardial Infarction Networks.

BACKGROUND: The Mission: Lifeline STEMI Systems Accelerator program, implemented in 16 US metropolitan regions, resulted in more patients receiving timely reperfusion. We assessed whether implementing key care processes was associated with system performance improvement. METHODS AND RESULTS: Hospitals (n=167 with 23 498 ST-segment-elevation myocardial infarction patients) were surveyed before (March 2012) and after (July 2014) program intervention. Data were merged with patient-level clinical data over the same period. For reperfusion, hospitals were grouped by whether a specific process of care was implemented, preexisting, or never implemented. Uptake of 4 key care processes increased after intervention: prehospital catheterization laboratory activation (62%-91%; P<0.001), single call transfer protocol from an outside facility (45%-70%; P<0.001), and emergency department bypass for emergency medical services direct presenters (48%-59%; P=0.002) and transfers (56%-79%; P=0.001). There were significant differences in median first medical contact-to-device times among groups implementing prehospital activation (88 minutes implementers versus 89 minutes preexisting versus 98 minutes nonimplementers; P<0.001 for comparisons). Similarly, patients treated at hospitals implementing single call transfer protocols had shorter median first medical contact-to-device times (112 versus 128 versus 152 minutes; P<0.001). Emergency department bypass was also associated with shorter median first medical contact-to-device times for emergency medical services direct presenters (84 versus 88 versus 94 minutes; P<0.001) and transfers (123 versus 127 versus 167 minutes; P<0.001). CONCLUSIONS: The Accelerator program increased uptake of key care processes, which were associated with improved system performance. These findings support efforts to implement regional ST-segment-elevation myocardial infarction networks focused on prehospital catheterization laboratory activation, single call transfer protocols, and emergency department bypass.

Regional Systems of Care Demonstration Project: American Heart Association Mission: Lifeline STEMI Systems Accelerator.

BACKGROUND: Up to 50% of patients fail to meet ST-segment-elevation myocardial infarction (STEMI) guideline goals recommending a first medical contact-to-device time of <90 minutes for patients directly presenting to percutaneous coronary intervention-capable hospitals and <120 minutes for transferred patients. We sought to increase the proportion of patients treated within guideline goals by organizing coordinated regional reperfusion plans. METHODS: We established leadership teams, coordinated protocols, and provided regular feedback for 484 hospitals and 1253 emergency medical services (EMS) agencies in 16 regions across the United States. RESULTS: Between July 2012 and December 2013, 23 809 patients presented with acute STEMI (direct to percutaneous coronary intervention hospital: 11 765 EMS transported and 6502 self-transported; 5542 transferred). EMS-transported patients differed from self-transported patients in symptom onset to first medical contact time (median, 47 versus 114 minutes), incidence of cardiac arrest (10% versus 3%), shock on admission (11% versus 3%), and in-hospital mortality (8% versus 3%; P<0.001 for all comparisons). There was a significant increase in the proportion of patients meeting guideline goals of first medical contact-to-device time, including those directly presenting via EMS (50% to 55%; P<0.001) and transferred patients (44%-48%; P=0.002). Despite regional variability, the greatest gains occurred among patients in the 5 most improved regions, increasing from 45% to 57% (direct EMS; P<0.001) and 38% to 50% (transfers; P<0.001). CONCLUSIONS: This Mission: Lifeline STEMI Systems Accelerator demonstration project represents the largest national effort to organize regional STEMI care. By focusing on first medical contact-to-device time, coordinated treatment protocols, and regional data collection and reporting, we were able to increase significantly the proportion of patients treated within guideline goals.

Comparison of team-focused CPR vs standard CPR in resuscitation from out-of-hospital cardiac arrest: Results from a statewide quality improvement initiative.

BACKGROUND: Team-focused CPR (TFCPR) is a choreographed approach to cardiopulmonary resuscitation (CPR) with emphasis on minimally interrupted high-quality chest compressions, early defibrillation, discourages endotracheal intubation and encourages use of the bag-valve-mask (BVM) and/or blind-insertion airway device (BIAD) with a ventilation rate of 8-10 breaths/min to minimize hyperventilation. Widespread incorporation of TFCPR in North Carolina (NC) EMS agencies began in 2011, yet its impact on outcomes is unknown. OBJECTIVES: To determine whether TFCPR improves survival with good neurological outcome in out-of-hospital cardiac arrest (OHCA) patients compared to standard CPR. METHODS: This retrospective cohort analysis of NC EMS agencies reporting data to the Cardiac Arrest Registry for Enhanced Survival (CARES) database from January 2010 to June 2014 included adult, non-traumatic OHCA with presumed cardiac etiology where EMS performed CPR or patient received defibrillation. Exclusions were arrest terminated per EMS policy or DNR. EMS agencies self-reported the TFCPR implementation dates. Patients were categorized as receiving either TFCPR or standard CPR. The primary outcome was good neurologic outcome at time of hospital discharge defined as Pittsburgh Cerebral Performance Category (CPC) 1-2. RESULTS: Of 14,994 OHCAs, 14,129 patients were included for analysis with a mean age 65 (IQR 50-81) years, 61% male, 7.3% with good neurologic outcome, 24.3% with shockable initial rhythm, and 71.5% receiving TFCPR. Of the 3427 (24.3%) with an initial shockable rhythm, 739 (71.9%) had a good neurological outcome. Good neurologic outcome was higher with TFCPR [836 (8.3%, 95%CI 7.7-8.8%)] vs. standard CPR [193 (4.8%, 95%CI 4.2-5.5%)]. Logistic regression controlling for demographic and arrest characteristics revealed TFCPR (OR 1.5), witnessed arrest (OR 4.3), initial shockable rhythm (OR 7.1), and in-hospital hypothermia (OR 3.3) were associated with good neurologic outcome. Mechanical CPR device (OR 0.68), CPR feedback device (OR 0.47), and endotracheal intubation (OR 0.44) were associated with less likelihood for a good neurologic outcome. CONCLUSION: In our statewide OHCA cohort, TFCPR was associated with improved survival with good neurological outcome.

The role of bystanders, first responders, and emergency medical service providers in timely defibrillation and related outcomes after out-of-hospital cardiac arrest: Results from a statewide registry.

AIM: Defibrillation by bystanders and first responders has been associated with increased survival, but limited data are available from non-metropolitan areas. We examined time from 911-call to defibrillation (according to who defibrillated patients) and survival in North Carolina. METHODS: Through the Cardiac Arrest Registry to Enhance Survival, we identified 1732 defibrillated out-of-hospital cardiac arrests from counties with complete case capture (population 2.7 million) from 2010 to 2013. RESULTS: Most patients (60.9%) were defibrillated in > 10 min. A minority (8.0%) was defibrillated < 5 min; most of these patients were defibrillated by first responders (51.8%) and bystanders (33.1%), independent of location of arrest (residential or public). Bystanders initiated cardiopulmonary resuscitation (CPR) in 49.0% of cases and defibrillated 13.4% of those. Survival decreased with increasing time to defibrillation (< 2 min: 59.1%; 2 to < 5 min: 38.5%; 5-10 min: 33.1%; > 10 min: 13.2%). Odds of survival with favorable neurologic outcome adjusted for age, sex, and bystander CPR improved with faster defibrillation (<2 min: OR 7.73 [95% CI 3.19-18.73]; 2 to < 5 min: 3.78 [2.45-5.84]; 5-10 min: 3.16 [2.42-4.12]; > 10 min: reference). CONCLUSION: Bystanders and first responders were mainly responsible for defibrillation within 5 min, independent of location of arrest. Bystanders initiated CPR in half of the cardiac arrest cases but only defibrillated a minority of those. Timely defibrillation and defibrillation by bystanders and/or first responders were strongly associated with increased survival. Strategic efforts to increase bystander and first-responder defibrillation are warranted to increase survival after out-of-hospital cardiac arrest.

Bypassing the emergency department and time to reperfusion in patients with prehospital ST-segment-elevation: findings from the reperfusion in acute myocardial infarction in Carolina Emergency Departments project.

BACKGROUND: Among patients identified prehospital with ST-segment-elevation myocardial infarction, emergency medical service transport from the field directly to the catheterization laboratory, thereby bypassing the emergency department (ED), may shorten time to reperfusion. METHODS AND RESULTS: We studied 1687 patients identified prehospital with ST-segment-elevation myocardial infarction from the Reperfusion in Acute Myocardial Infarction in Carolina Emergency Departments (RACE) project, transported via emergency medical service directly to 21 North Carolina hospitals for primary percutaneous coronary intervention between July 2008 and December 2009. Treatment time intervals were compared between patients evaluated in the ED (ED evaluation) and those transported directly to the catheterization laboratory (ED bypass). Emergency medical service transported 1401 (83.0%) patients to the ED, whereas the ED was bypassed for 286 (17.0%) patients. Overall, first medical contact to device activation within 90 minutes was achieved in 913 (54.1%) patients. Among patients evaluated in the ED, median time (25th-75th percentiles) from ED arrival to catheterization laboratory arrival was 30 (20-41) minutes. First medical contact to device activation occurred faster (75 [59-93] versus 90 [76-109] minutes; P<0.001) and was more frequently achieved within 90 minutes (74.1% versus 50.1%; P<0.001) among ED bypass patients. CONCLUSIONS: Among patients identified prehospital with ST-segment-elevation myocardial infarction and transported directly to a percutaneous coronary intervention hospital, only 1 in 2 achieve device activation within 90 minutes. A median of 30 minutes is spent in the ED, contributing significantly to the failure to achieve timely reperfusion. The strategy to bypass the ED is used infrequently and represents a potential opportunity to improve reperfusion times.

Prehospital system delay in ST-segment elevation myocardial infarction care: a novel linkage of emergency medicine services and in hospital registry data.

BACKGROUND: Emergency medical services (EMS) are critical in the treatment of ST-segment elevation myocardial infarction (STEMI). Prehospital system delays are an important target for improving timely STEMI care, yet few limited data are available. METHODS: Using a deterministic approach, we merged EMS data from the North Carolina Pre-hospital Medical Information System (PreMIS) with data from the Reperfusion of Acute Myocardial Infarction in Carolina Emergency Departments-Emergency Response (RACE-ER) Project. Our sample included all patients with STEMI from June 2008 to October 2010 who arrived by EMS and who had primary percutaneous coronary intervention (PCI). Prehospital system delays were compared using both RACE-ER and PreMIS to examine agreement between the 2 data sources. RESULTS: Overall, 8,680 patients with STEMI in RACE-ER arrived at a PCI hospital by EMS; 21 RACE-ER hospitals and 178 corresponding EMS agencies across the state were represented. Of these, 6,010 (69%) patients were successfully linked with PreMIS. Linked and notlinked patients were similar. Overall, 2,696 patients were treated with PCI only and were taken directly to a PCI-capable hospital by EMS; 1,750 were transferred from a non-PCI facility. For those being transported directly to a PCI center, 53% reached the 90-minute target guideline goal. For those transferred from a non-PCI facility, 24% reached the 120-minute target goal for primary PCI. CONCLUSIONS: We successfully linked prehospital EMS data with in hospital clinical data. With this linked STEMI cohort, less than half of patients reach goals set by guidelines. Such a data source could be used for future research and quality improvement interventions.