Do differences in emergency medical services (EMS) response time to an arrest account for the survival differences between EMS-witnessed and bystander-witnessed out of hospital cardiac arrest?

Introduction: Out-of-hospital cardiac arrests (OHCA) witnessed by Emergency Medical Services (EMS) are reported to have more favourable survival than bystander-witnessed arrests, even after adjusting for patient and arrest factors known to be associated with increased OHCA survival. This study aims to determine whether the survival advantage in EMS-witnessed arrests can be attributed to differences in the EMS response time to the arrest. Methods: Using registry data we conducted a retrospective, population-based cohort study of bystander- and EMS-witnessed OHCAs of medical aetiology who received an EMS resuscitation attempt in Western Australia between 2018-2021. EMS response time to arrest was assumed to be zero for EMS-witnessed arrests. Multivariable logistic regression was used to compare 30-day OHCA survival by witness and bystander CPR (B-CPR) status, adjusting for EMS response time to arrest, and patient and arrest characteristics. Results: Of 2,130 OHCA cases, 510 (23.9%) were EMS-witnessed and 1620 were bystander-witnessed: 1318/1620 (81.4%) with B-CPR, and 302/1620 (18.6%) with no B-CPR. The median EMS response time to bystander-witnessed arrests who received B-CPR was 9.9 [Q1,Q3: 7.4, 13.3] minutes. After adjusting for the EMS response time and patient and arrest factors, 30-day survival remained significantly lower in both the bystander-witnessed group with B-CPR (aOR 0.56; 95% CI 0.34 - 0.91) and bystander-witnessed group without B-CPR (aOR 0.23; 95% CI 0.11 - 0.46). Conclusion: An increased EMS response time does not fully account for the higher OHCA survival in EMS-witnessed arrests compared to bystander-witnessed arrests.

Emergency Medical Service Attendances for Adults with Repeat Falls in Western Australia: A State-Wide Retrospective Cohort Study.

OBJECTIVES: The risk of falls increases with age and often requires an emergency medical service (EMS) response. We compared the characteristics of patients attended by EMS in response to repeat falls within 30 days and 12 months of their first EMS-attended fall; and explored the number of days between the index fall and the subsequent fall(s). METHODS: This retrospective cohort study included all adults (> =18 years of age) who experienced their first EMS-attended fall between 1 January 2016 and 31 December 2020, followed up until 31 December 2021. Patients who experienced > =1 subsequent fall, following their first recorded fall, were defined as experiencing repeat falls. Multivariable logistic regression was used to identify the factors associated with repeat falls; and Kaplan-Meier analysis was used to estimate the time (in days) between consecutive EMS-attended falls. RESULTS: A total of 128,588 EMS-attended fall-related incidents occurred involving 77,087 individual patients. Most patients, 54,554 (71%) were attended only once for a fall-related incident (30,280 females; median age 73 years, inter-quartile range (IQR): 55-84). A total of 22,533 (29%) patients experienced repeat EMS-attended falls (13,248 females; median age 83 years, IQR: 74-89, at first call). These 22,533 patients accounted for 58% (74,034 attendances) of all EMS-attendances to fall-related incidents. Time between EMS-attended falls decreased significantly the more falls a patient sustained. Among the 22,533 patients who experienced repeat falls, 13,363 (59%) of repeat falls occurred within 12 months: 3,103 (14%) of patients sustained their second fall within 30 days of their index fall, and 10,260 (46%) between 31 days to 12 months. Patients who were transported to the hospital, via any urgency, at their first EMS-attended fall, had a reduced odds of sustaining a second EMS-attended fall within both 30 days and 31 days to 12 months, compared to non-transported patients. CONCLUSION: Nearly 30% of all patients attended by EMS for a fall, sustained repeat falls, which collectively accounted for nearly 60% of all EMS-attendances to fall-related incidents. Further exploration of the role EMS clinicians play in identifying and referring patients who sustain repeat falls into alternative pathways is needed.

Out-of-hospital cardiac arrest in residential aged care facilities is independently associated with lower survival in Perth, Australia.

Aim: To compare out-of-hospital cardiac arrest (OHCA) characteristics and outcomes between people aged ≥ 65 years who arrested in a residential aged care facility (RACF) versus a private residence in Perth, Australia. Methods: We undertook a retrospective cohort study of OHCA cases attended by emergency medical services (EMS) in Perth, January 2018-December 2021. OHCA patient and event characteristics and survival outcomes were compared via univariate analysis. Multivariable logistic regression was used to investigate the relationship between residency type and (i) return of spontaneous circulation (ROSC) at emergency department (ED) and (ii) 30-day survival. Results: A total of 435 OHCA occurred in RACFs versus 3,395 in private residences. RACF patients were significantly older (median age: 86 [IQR 79, 91] vs 78 [71, 85] years; p < 0.001), more commonly female (50.1% vs 36.8%; p < 0.001), bystander-witnessed arrests (34.9% vs 21.5%; p < 0.001), received bystander cardiopulmonary resuscitation (42.1% vs 28.6%; p < 0.001), had less shockable first monitored rhythms (4.0% vs 8.1%; p = 0.002) and more frequently had a "do not resuscitate" order identified (46.0% vs 13.6%; <0.001). Among those with EMS-attempted resuscitation or with defibrillation before EMS arrival, ROSC at ED and 30-day survival were significantly lower in the RACF group (6.2% vs 18.9%; p < 0.001 and 1.9% vs 7.7%; p < 0.001). The adjusted odds of ROSC at ED (aOR: 0.22 [95%CI: 0.10, 0.46]) and 30-day survival (aOR: 0.20 [95%CI 0.05, 0.92]) were significantly lower for RACF residents. Conclusion: RACF residency was an independent predictor of lower survival from OHCA, highlighting the importance of end-of-life planning for RACF residents.

Trends in out-of-hospital cardiac arrest incidence, patient characteristics and survival over 18 years in Perth, Western Australia.

OBJECTIVES: To investigate trends in the incidence, characteristics, and survival of out-of-hospital cardiac arrests (OHCA) in the Perth metropolitan area between 2001 and 2018. METHODS: We calculated the crude incidence rate, age-standardised incidence rate (ASIR) and age- and sex-specific incidence rates (per 100,000 population) for OHCA of presumed cardiac aetiology. ASIRs were calculated using the direct method of standardisation using the 2001 Australian Population standard. Survival was assessed at return of spontaneous circulation at emergency department arrival and at 30 days. Temporal trends in patient and arrest characteristics were assessed with logistic regression, while trends in incidence were assessed using Joinpoint regression. Survival trends were assessed using binary logistic regression. RESULTS: A total of 18,417 OHCAs of presumed cardiac aetiology were attended by emergency medical services in Perth between 2001 and 2018. Overall, there were no significant changes in the crude or ASIR of OHCA over the study period, although OHCA incidence in 15-39 year-old males increased by 12.5% annually between 2011 and 2018. Both bystander cardiopulmonary resuscitation and bystander defibrillation increased over the study period, while the proportion of shockable arrests declined. Thirty-day OHCA survival improved significantly over time, with the odds of survival (in bystander-witnessed, initial shockable rhythm arrests) improving 12% (95% CI, 9.0% to 14.0%) annually, from 8.4% in 2001 to 44.0% in 2018. CONCLUSION: Overall, there were no significant trends in OHCA incidence over the study period, although arrests in 15-39 year-old males increased significantly after 2011. There were significant improvements in 30-day survival between 2001 and 2018.

Survival to hospital discharge is equivalent to 30-day survival as a primary survival outcome for out-of-hospital cardiac arrest studies.

AIM: The 2015 Utstein guidelines stated that 30-day survival could be used as an alternative to survival to hospital discharge (STHD) as the primary survival outcome in out-of-hospital cardiac arrest (OHCA) studies. We sought to ascertain the equivalence (concordance) of these two survival outcome measures. METHODS: We conducted a population-based retrospective cohort study of OHCA patients who were attended by St John Western Australia (SJ-WA) paramedics in Perth, WA between 1999 and 2018. OHCA patients were included if they received either an attempted resuscitation by SJ-WA or bystander defibrillation; were a resident of WA; and were transported to a hospital emergency department (ED). STHD was determined through hospital record review and 30-day survival via the WA Death Registry and cemetery registration data. RESULTS: The study cohort comprised a total of 7953 OHCA patients, predominantly male (70%), with a median (IQR) age of 63 (46-77 years), a presumed cardiac arrest aetiology (78.9%), and the majority occurred in a private residence (66.8%). Survival rates were identical for STHD and 30-day survival, with both being (13.78%, 95% CI: 13.02-14.54%) (p = 0.99). The overall concordance between the two survival rates was 99.6%. There were only 30 (0.4%) discordant cases in total: 15 cases with STHD-yes but 30-day survival-no; and 15 cases with STHD-no but 30-day survival-yes. CONCLUSION: We found that STHD and 30-day survival were equivalent survival metrics in our OHCA Registry. However, given potential differences in health systems, we suggest that 30-day survival is likely to enable more reliable comparisons across jurisdictions.

Long-term survival among OHCA patients who survive to 30 days: Does initial arrest rhythm remain a prognostic determinant?

OBJECTIVE: To determine whether initial cardiac arrest rhythm remains a prognostic determinant in longer term OHCA survival. METHODS: The St John Western Australian OHCA database was used to identify adults who survived for at least 30 days after an OHCA of presumed medical aetiology, in the Perth metropolitan area between 1998 and 2017. Associations between 8-year OHCA survival and variables of interest were analysed using a Multi-Resolution Hazard (MRH) estimator model with 1-year intervals. RESULTS: Of the 871 OHCA patients who survived 30 days, 718 (82%) presented with a shockable initial arrest rhythm and 153 (18%) presented with a non-shockable rhythm. Compared to patients with initial shockable arrests, patients with non-shockable arrests experienced increased mortality in the first (HR 3.33, 95% CI 2.12-5.32), second (HR 2.58, 95% CI 1.22-5.15), third (HR 2.21, 95% CI 1.02-4.42) and fourth (HR 2.21, 95% CI 1.02-4.42) year post arrest; however, in subsequent years the initial arrest rhythm ceased to be significantly associated with survival. The overall 8-year survival estimates after adjustment for peri-arrest factors (as potential confounders) were 87% (95% CI 77-93%) for shockable arrests and 73% (95% CI 55-86%) for non-shockable arrests. CONCLUSIONS: Patients with non-shockable (as opposed to shockable) initial arrest rhythms experienced higher mortality in the first 4-years following their OHCA; however, after four years the initial arrest rhythm ceased to be associated with survival.

Relative long-term survival in out-of-hospital cardiac arrest: Is it really improving?

AIM: To describe the long-term survival of out-of-hospital cardiac arrest (OHCA) patients and to determine whether survival is improving in comparison to the general age- and sex-matched population. METHODS: We utilised the St John Western Australia (WA) OHCA database to retrospectively identify patients aged ≥16 years who experienced an OHCA within the Perth metropolitan area between 1998 and 2017 and survived for at least 30-days post arrest. Patients were excluded if their primary residence was not WA, they did not have an emergency medical services attempted resuscitation (or bystander defibrillation) or did not have an arrest of medical aetiology. Relative survival ratios stratified by decade of arrest were calculated by dividing observed survival of the study cohort by the expected survival of an age- and sex-matched cohort estimated from the Australian Bureau of Statistics life tables for WA. RESULTS: The OHCA patients who initially survived to 30-days experienced a modest reduction in long-term survival, with 84% (95% CI, 78-90) of patients surviving to 10-years relative to the age- and sex-matched general population. The 10-year relative survival increased from 76% (95% CI, 67-85) to 92% (95% CI, 84-100) between the first (1998-2007) and second (2008-2017) decade of our study. CONCLUSION: Relative long-term survival prospects for initial OHCA survivors are moderately lower than that of the general population, however these differences have reduced over time and may be approaching those of the general population.

Systematic review of the relationship between comorbidity and out-of-hospital cardiac arrest outcomes.

OBJECTIVES: To assess the current evidence on the effect pre-arrest comorbidity has on survival and neurological outcomes following out-of-hospital cardiac arrest (OHCA). DESIGN: Systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. DATA SOURCES: MEDLINE, Ovid Embase, Scopus, CINAHL, Cochrane Library and MedNar were searched from inception to 31 December 2018. ELIGIBILITY CRITERIA: Studies included if they examined the association between prearrest comorbidity and OHCA survival and neurological outcomes in adult or paediatric populations. DATA EXTRACTION AND SYNTHESIS: Data were extracted from individual studies but not pooled due to heterogeneity. Quality of included studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. RESULTS: This review included 29 observational studies. There were high levels of clinical heterogeneity between studies with regards to patient recruitment, inclusion criteria, outcome measures and statistical methods used which ultimately resulted in a high risk of bias. Comorbidities reported across the studies were diverse, with some studies reporting individual comorbidities while others reported comorbidity burden using tools like the Charlson Comorbidity Index. Generally, prearrest comorbidity was associated with both reduced survival and poorer neurological outcomes following OHCA with 79% (74/94) of all reported adjusted results across 23 studies showing effect estimates suggesting lower survival with 42% (40/94) of these being statistically significant. OHCA survival was particularly reduced in patients with a prior history of diabetes (four out of six studies). However, a prearrest history of myocardial infarction appeared to be associated with increased survival in one of four studies. CONCLUSIONS: Prearrest comorbidity is generally associated with unfavourable OHCA outcomes, however differences between individual studies makes comparisons difficult. Due to the clinical and statistical heterogeneity across the studies, no meta-analysis was conducted. Future studies should follow a more standardised approach to investigating the impact of comorbidity on OHCA outcomes. PROSPERO REGISTRATION NUMBER: CRD42018087578.

Chemotherapy broadens the range of tumor antigens seen by cytotoxic CD8(+) T cells in vivo.

Cytotoxic chemotherapies may expose the immune system to high levels of tumor antigens and expand the CD8(+) T-cell response to include weak or subdominant antigens. Here, we evaluated the in vivo CTL response to tumor antigens using a murine mesothelioma tumor cell line transfected with a neotumor antigen, ovalbumin, that contains a known hierarchy of epitopes for MHC class I molecules. We show that as tumors progress, effector CTLs are generated in vivo that focus on the dominant epitope SIINFEKL, although a weak response was seen to one (KVVRFDKL) subdominant epitope. These CTLs did not prevent tumor growth. Cisplatin treatment slowed tumor growth, slightly improved in vivo SIINFEKL presentation to T cells and reduced SIINFEKL-CTL activity. However, the CTL response to KVVRFDKL was amplified, and a response to another subdominant epitope, NAIVFKGL, was revealed. Similarly, gemcitabine cured most mice, slightly enhanced SIINFEKL presentation, reduced SIINFEKL-CTL activity yet drove a significant CTL response to NAIVFKGL, but not KVVRFDKL. These NAIVFKGL-specific CTLs secreted IFNγ and proliferated in response to in vitro NAIVFKGL stimulation. IL-2 treatment during chemotherapy refocused the response to SIINFEKL and simultaneously degraded the cisplatin-driven subdominant CTL response. These data show that chemotherapy reveals weaker tumor antigens to the immune system, a response that could be rationally targeted. Furthermore, while integrating IL-2 into the chemotherapy regimen interfered with the hierarchy of the response, IL-2 or other strategies that support CTL activity could be considered upon completion of chemotherapy.

Respiratory pattern in midline-lesioned brainstems and hemibrainstems from adult turtles.

Discrete midline lesions uncouple left and right respiratory motor output in mammals, but not in frogs and lampreys. To address this question in reptiles, isolated adult turtle brainstems were cut along the midline while recording respiratory motor output (bursts of action potentials) on left and right hypoglossal (XII) nerves. XII motor bursts were synchronized as long as a small portion of the midline was still intact. When turtle brainstems were completely cut along the midline and separated into hemibrainstems, XII motor bursts were produced that could be abolished by mu-opioid receptor (MOR) activation or exposure to high pH (7.80) solution. Also, 13/57 hemibrainstems expressed episodic discharge (>1.75bursts/episode). To test whether crossed connections were necessary to express a long-lasting increase in burst frequency (i.e., frequency plasticity), phenylbiguanide (PBG, 5-HT(3) receptor agonist, 20microM) was bath-applied to hemibrainstems. Although PBG significantly increased burst frequency by 0.43+/-0.10bursts/min after 60min, no frequency plasticity was observed because burst frequency returned to near baseline levels after a 2-h washout. Thus, crossed connections in turtle brainstems synchronize respiratory motor output and are not required for normal respiratory pattern formation, but are required for PBG-dependent frequency plasticity.

Are pacemaker properties required for respiratory rhythm generation in adult turtle brain stems in vitro?

The role of pacemaker properties in vertebrate respiratory rhythm generation is not well understood. To address this question from a comparative perspective, brain stems from adult turtles were isolated in vitro, and respiratory motor bursts were recorded on hypoglossal (XII) nerve rootlets. The goal was to test whether burst frequency could be altered by conditions known to alter respiratory pacemaker neuron activity in mammals (e.g., increased bath KCl or blockade of specific inward currents). While bathed in artificial cerebrospinal fluid (aCSF), respiratory burst frequency was not correlated with changes in bath KCl (0.5-10.0 mM). Riluzole (50 microM; persistent Na(+) channel blocker) increased burst frequency by 31 +/- 5% (P < 0.05) and decreased burst amplitude by 42 +/- 4% (P < 0.05). In contrast, flufenamic acid (FFA, 20-500 microM; Ca(2+)-activated cation channel blocker) reduced and abolished burst frequency in a dose- and time-dependent manner (P < 0.05). During synaptic inhibition blockade with bicuculline (50 microM; GABA(A) channel blocker) and strychnine (50 muM; glycine receptor blocker), rhythmic motor activity persisted, and burst frequency was directly correlated with extracellular KCl (0.5-10.0 mM; P = 0.005). During synaptic inhibition blockade, riluzole (50 microM) did not alter burst frequency, whereas FFA (100 microM) abolished burst frequency (P < 0.05). These data are most consistent with the hypothesis that turtle respiratory rhythm generation requires Ca(2+)-activated cation channels but not pacemaker neurons, which thereby favors the group-pacemaker model. During synaptic inhibition blockade, however, the rhythm generator appears to be transformed into a pacemaker-driven network that requires Ca(2+)-activated cation channels.

Evaluation of the invader assay for genotyping hepatitis C virus.

The Invader 1.0 assay (Invader HCV Genotyping Assay, version 1.0; Third Wave Technologies, Inc., Madison, WI) has been developed for the rapid differentiation of hepatitis C virus (HCV) genotypes 1 to 6 based on sequence variation within the HCV 5' noncoding (NC) region. In the present study, we evaluated the compatibility of Invader 1.0 with the COBAS MONITOR (COBAS AMPLICOR HCV MONITOR Test, version 2.0; Roche Molecular Systems, Inc., Branchburg, NJ), COBAS AMPLICOR (COBAS AMPLICOR Hepatitis C Virus Test, version 2.0; Roche Molecular Systems, Inc.), and COBAS TaqMan (COBAS TaqMan HCV Test; Roche Molecular Systems, Inc.) assays. The minimum HCV RNA titers required for successful HCV genotyping (>/=90% success rate) were 1,000 IU/ml for COBAS MONITOR, 100 IU/ml for COBAS AMPLICOR, and 10 IU/ml for COBAS TaqMan. Invader 1.0 results obtained from unpurified COBAS TaqMan amplification products of 111 retrospectively selected clinical serum specimens (genotypes 1 to 6, with virus titers ranging from 15.1 to 2.1 x 10(7) IU/ml) showed 98% concordance with results obtained from the TRUGENE HCV 5' NC Genotyping Kit (Bayer HealthCare LLC, Tarrytown, NY), used in conjunction with COBAS AMPLICOR. Although the assay is sensitive, accurate, and easy to perform, additional optimization of the Invader 1.0 interpretive software (Invader Data Analysis Worksheet) may be necessary to reduce potential misidentification of HCV genotypes in low-titer specimens. In summary, Invader 1.0 is compatible with a variety of commercially available PCR-based HCV 5' NC region amplification assays and is suitable for routine HCV genotyping in clinical laboratories.

Evaluation of the TRUGENE HCV 5'NC genotyping kit with the new GeneLibrarian module 3.1.2 for genotyping of hepatitis C virus from clinical specimens.

The TRUGENE HCV 5'NC genotyping kit (GeneLibrarian modules 3.1.1 and 3.1.2) and VERSANT HCV genotyping assay were compared by using 96 hepatitis C virus (HCV) RNA-positive patient specimens, including HCV genotypes 1, 2, 3, 4, 5, 6, and 10. The TRUGENE HCV 5'NC genotyping kit (GeneLibrarian module 3.1.2) yielded the most accurate genotyping results.

Comparison of line probe assay and DNA sequencing of 5' untranslated region for genotyping hepatitis C virus: description of novel line probe patterns.

We compared a commercial line probe assay (INNO-LiPA HCV II, Innogenetics, N.V., Ghent, Belgium, distributed by Bayer Diagnostics) to an in-house 5' untranslated region direct DNA sequencing method for genotyping hepatitis C virus (HCV). Initial evaluation demonstrated that the INNO-LiPA HCV II assay and sequencing assay assigned the same genotype for 110/132 (83.3%) patient specimens (98 subtype and 12 genotype only identifications). Following the initial evaluation, the INNO-LiPA HCV II assay was used routinely to genotype HCV from patient specimens submitted to our laboratory for genotyping (n = 1,739). During this second part of the study, novel line probe patterns have been noted and interpreted using the in-house direct sequencing assay. Reactivity at bands 1, 2, 3, 4, 5 and 8 (n = 4) or 1, 2, 3, 4, 6 and 7 (n = 2) represented HCV genotype 1. Reactivity at bands 1, 2, 5 and 9 (n = 1) represented HCV genotype 2. Reactivity at bands 1, 2, 5, 9 and 16 (n = 1) represented HCV genotype 4. Reactivity at bands 1, 2, 5, 9, 10, 11 (weak band) and 12 (n = 118) most likely represented HCV genotype 2b. This information should be of use to INNO-LiPA HCV II assay users.