Timing and Identification of the Cause and Treatment of a Cardiac Arrest: A Potential Survival Benefit.

OBJECTIVE: The aim of this study was to evaluate how mobile medical teams (MMTs) search for the etiology of a cardiac arrest (CA) and to investigate the association between the discovery of etiology and patient outcome. SUBJECTS AND METHODS: Resuscitations of all adult patients who experienced an in- or out-of-hospital CA between 2016 and 2018 were video recorded. All video recordings were reviewed. The time to start of "cause analysis" and time to treatment by the MMT were analyzed. Also, investigations performed during etiologic evaluation were examined: heteroanamnesis, medical history-taking, clinical examinations, technical investigations, and the use of the 4Hs and 4Ts method. RESULTS: Of the 139 CA events included in this study, the MMTs performed etiologic evaluation in only 75% of the resuscitations, and in 20% of the evaluations, they did not use the recommended 4Hs and 4Ts method. Medical history-taking and heteroanamnesis were performed in the large majority, but often without clear cause. A presumptive etiology was found in 46.8% of out-of-hospital CAs and 65.2% of in-hospital CAs. A significant association was found between return of spontaneous circulation and the discovery of presumable etiology for out-of-hospital CAs (p < 0.001). The median time to treatment was 492 s (recommended: 130-250 s) for nonshockable rhythms and 422 s (recommended: 270-390 s) for shockable rhythms, up to twice the time advised according to the guidelines. CONCLUSION: The current approach for etiologic evaluation is not ideal. Further research is needed to establish a more structured and simplified approach.

Stress levels of Flemish emergency medicine residents and the implications for clinical practice and education.

BACKGROUND: mergency physicians are often confronted with challenging situations. As acute stress can adversely affect the health of physicians and the safety of patients, both could benefit from the integration of performance psychology insights in the education of physicians. A better understanding of stress is a prerequisite for the successful integration of a stress management program into residency training. METHODS: All Flemish emergency medicine residents were questioned about stressors, perceived stress, and the impact of stress on their performance. Furthermore, participants were asked to evaluate the role of training in performance under stress during residency. RESULTS: The response rate was 47.0%. Almost half of the residents indicated to be moderately to highly stressed. Half of the residents said that their performance could improve significantly if they could control their stress completely. The large majority of the residents (91.5%) indicated to see an advantage in increased training in performance enhancing techniques during residency. CONCLUSION: Although a training program could considerably contribute to reduce stress levels and its impact on performance, there is a gap between the needs of residents and the current training program. An evidence-based education program in stress reduction is urgently warranted.

The 12 -year evolution of emergency department alcohol-related admissions in a student city.

OBJECTIVE: To investigate the trends in incidence of alcohol-intoxicated patients who present at the emergency department (ED), as well as the characteristics of these patients. METHODS: Retrospective observational study based on data collected from 2008 until 2019 in two EDs in Leuven, Belgium. As a routine ED procedure, a blood alcohol concentration (BAC) test is ordered for all patients suspected of alcohol use as a primary presenting sign. Patients older than 10 years of age with a BAC ≥ 0.1 g/L were included. BAC levels, age, gender and proportion of repeat admissions were analysed. RESULTS: The absolute number of patients with a positive BAC test increased from 1260 in 2008 to 1908 in 2019 (51.4%). Male-to-female ratio remained stable (2:1). In the University Hospital Leuven , the most represented age group shifted from 20-29 and 40-49 year olds (2008) to 50-59 year olds (2019). The most common age groups in Heilig Hart Leuven were 10-19 year olds and 20-29 year olds, which remained stable over the study period. The readmission rate was 18% within the entire study period with a range of 2 to 46 times. CONCLUSION: Our study showed an annual increase in alcohol-related admissions. The highest rates of alcohol-related ED visits occurred in the age group 50-59. Patients with a repeat admission accounted for a large number of the total alcohol-related visits, placing a major burden on our healthcare system. It will be a challenge to timely detect patients at risk, regardless of their age, to prevent future ED admissions.

Early administration of Vitamin C in patients with sepsis or septic shock in emergency departments: A multicenter, double blinded, randomized controlled trial: The C-EASIE trial protocol.

BACKGROUND: Sepsis is a potentially life-threatening condition characterized by a deregulated body's response to infection causing injury to its own tissues and organs. Sepsis is the primary cause of death from infection. If not recognized and treated timely, it can evolve within minutes/hours to septic shock. Sepsis is associated with an acute deficiency of Vitamin C. Despite the proof-of-concept of the benefit of administering Vitamin C in patients with sepsis or septic shock, Vitamin C administration is not yet current practice. OBJECTIVE: To investigate the potential benefit of early administration of high doses of Vitamin C in addition to standard of care in patients with sepsis or septic shock. METHODS: This phase 3b multi-center trial is conducted in 8 hospitals throughout Belgium. In total 300 patients will be randomly assigned to one of two groups in a 1:1 allocation ratio. The intervention group will receive 1.5 g Vitamin C 4 times a day during 4 days, started within 6 hours after admission. The primary outcome is the average post-baseline patient SOFA score. CONCLUSION: This trial will determine whether the early administration of Vitamin C in patients with sepsis or septic shock can lead to a more rapid solution of shock and less deterioration from sepsis to septic shock, hereby reducing morbidity and mortality as well as the length of hospital stay in this patient population. TRIAL REGISTRATION: The C-EASIE trial has been registered on the ClinicalTrials.gov website on 10 February 2021 with registration number NCT04747795. TRIAL SPONSOR: UZ Leuven (sponsor's reference S63213).

Measuring non-technical skills during prehospital advanced cardiac life support: A pilot study.

AIM: To analyse non-technical skills of mobile medical teams during out-of-hospital cardiac arrests (OHCA) using the validated Team Emergency Assessment Measure (TEAM) tool. To research the correlation between non-technical skills and patient outcome. METHODS: Adult patients who experienced an out-of-hospital cardiac arrest between July 2016, and June 2018, and were treated by a mobile medical team from the University Hospital Leuven, were eligible for the study. Resuscitations were video recorded from the team leader's perspective. Video recordings were reviewed and scored by emergency physicians, using the TEAM evaluation form. RESULTS: In total 114 OHCAs were analysed. The mean TEAM score was 34.4/44 (SD = 5.5). The mean item score was 3.1/4 (SD = 0.8). On average, 'effective team communication' had the lowest score (2.4), while 'acting with composure and control' and 'following of approved standards/guidelines' scored the highest (3.4). The average non-technical skills theme scores were 2.9 (SD = 0.9) for 'Leadership', 3.1 (SD = 0.8) for 'Teamwork' and 3.3 (SD = 0.7) for 'Task management'. 'Leadership' was rated significantly lower than 'Teamwork' (p = 0.004) and 'Task management' (p < 0.001). No significant correlation was found between TEAM and return of spontaneous circulation (p = 0.574) or one month survival (p = 0.225). CONCLUSION: The mean overall TEAM score was categorized as good. Task management scored high, while leadership and team communication received lower scores. Future training programs should thus focus on improving leadership and communication. In this pilot study no correlation was found between non-technical skills and survival.

Assessment of chest compression interruptions during advanced cardiac life support.

AIM: To identify potentially avoidable factors responsible for chest compression interruptions and to evaluate the influence of chest compression fraction on achieving return of spontaneous circulation and survival to hospital discharge. METHODS: In this prospective observational study, each resuscitation managed by mobile medical teams from August 1st, 2016, to August 1st, 2018 was video recorded using a body-mounted GoPro camera. The duration of all chest compression interruptions was recorded and chest compression fraction was calculated. All actions causing an interruption of at least 10 s were analyzed. RESULTS: Two hundred and six resuscitations of both in- and out-of-hospital cardiac arrest patients were analysed. In total 1867 chest compression interruptions were identified. Of these, 623 were longer than 10 s in which a total of 794 actions were performed. In 4.3% of the registered pauses, cardiopulmonary resuscitation was interrupted for more than 60 s. The most performed actions during prolonged interruptions were rhythm/pulse checks (51.6%), installation/use of mechanical chest compression devices (11.1%), cardiopulmonary resuscitation provider switches (6.7%) and ETT placements (6.2%). No statistically significant relationship was found between chest compression fraction and return of spontaneous circulation or survival. CONCLUSION: The majority of chest compression interruptions during resuscitation were caused by prolonged rhythm checks, cardiopulmonary resuscitation provider switches, incorrect use of mechanical chest compression devices and ETT placement. No association was found between chest compression fraction and return of spontaneous circulation, nor an influence on survival. This was presumably caused by the high baseline chest compression fraction of >86%.

Impact of video-recording on patient outcome and data collection in out-of-hospital cardiac arrests.

BACKGROUND: Most research on out-of-hospital resuscitation relies on data collection from medical records. However, the data in medical records are often inaccurate. OBJECTIVE: To compare the data registration of the medical record with the data from the video recorded resuscitation and study the impact of video recording during resuscitation on the outcome. METHODS: Out-of-hospital cardiopulmonary resuscitation (CPR) was video recorded using a body-mounted camera. Video recordings were independently reviewed and compared with the data of the medical record. The presence of bystander CPR and witnessed arrest, the initial rhythm, total number of defibrillations, adrenaline dosage and the total duration of CPR were studied. Using the medical records, CPR outcomes were compared for the periods prior to, during and after video recording. RESULTS: In total, 129 resuscitations were analysed. Of the six parameters, only the number of defibrillations was not significantly different in the medical record compared to the video recordings. The total duration of CPR (69.0%) and the total dose of adrenaline administered (63.6%) were the most incorrectly recorded, followed by the number of defibrillations (34.0%), witnessed arrest (31.0%), bystander CPR (24.0%) and initial rhythm (7%). No statistically significant difference was found comparing the outcomes (ROSC, 24 h and 1 month survival) of the periods before, during and after video recording. CONCLUSION: We detected a high number of discrepancies between the medical record and the data from the video recorded resuscitation. No significant effect of video-recording on patient outcome was found.

The Effect of Teaching Nontechnical Skills in Advanced Life Support: A Systematic Review.

OBJECTIVES: The objective of this study was to evaluate the effect of nontechnical skills (NTS) training on performance in advanced life support (ALS) simulation. Furthermore, we aimed to determine the ideal frequency of training sessions for an optimal retention and the value of debriefing. METHODS: A systematic search was performed using PubMed, EMBASE, WoS, ERIC, CINAHL, and the Cochrane Library conducted through August 1, 2018. All primary studies mentioning NTS in ALS education were included. Three reviewers independently extracted data on study design and outcome. The MERSQI approach was used to evaluate the overall quality of evidence. RESULTS: Of the 10,723 identified articles, 40 studies were included with a combined total of 3,041 participants, ranging from students to experts. Depending on the focus of the study, articles were categorized in NTS (n = 25), retention (n = 8), and feedback (n = 10). Incorporating NTS during ALS simulation showed significant improvements in timing for performing critical first steps. Furthermore, good leadership skills had a favorable effect on overall technical performance and teamwork during simulation improved team dynamics and performance. Finally, debriefing also had a beneficial effect on team performance. One particular type of debriefing does not appear to be superior to other types of debriefing. CONCLUSION: Team simulation training resulted in improved NTS and a reduction in the time required to complete a simulated cardiac arrest. Therefore, a formal NTS program should be introduced into ALS courses. Feedback and repetitive practice are key factors to train NTS. The impact of training on team behaviors can persist for at least 3 to 6 months. In conclusion, understanding and improving NTS may help to create more effective teams. The effect on patient outcome requires further investigation.

The prognostic value of early lactate clearance for survival after out-of-hospital cardiac arrest.

BACKGROUND: Prognostication of survival after out-of-hospital cardiac arrest (OHCA) remains challenging with current guidelines recommending the prognostication no earlier than 72 h after return of spontaneous circulation (ROSC). Prognostic factors that could be used earlier after ROSC, like lactate clearance, are still being studied. OBJECTIVES: This paper aims to investigate the prognostic strength of early lactate clearance for survival after OHCA. METHODS: This retrospective observational single-center study focuses on patients for whom ROSC was achieved after OHCA. Patients ≥18 years admitted between September 2012 and January 2019, for which arterial serum lactate measurements were available immediately at and 3 h after hospital admission (T0 and T3), were included. RESULTS: 192 patients were included. Lactate clearance at T3 (p < 0.001) was identified as an independent predictor for 24 h, 48 h and 72 h survival. Witnessed arrest, bystander CPR and initial shockable rhythm were independent significant predictors for long term survival after ROSC (1 month, 3 months and 1 year; p < 0.05), but not for 24 h survival. Age (above or below 65 years) was not significant for predicting survival. Upon combination of witnessed arrest, bystander CPR and initial shockable rhythm in a multivariate logistic regression model for long term survival, the initial rhythm was the dominant factor in the combined model, making witnessed arrest and bystander CPR redundant. CONCLUSION: Lactate clearance at T3 after ROSC is associated with 24 h, 48 h and 72 h survival. Further research is needed to determine how to incorporate lactate clearance as part of a clinically useful tool to predict long term survival.

Phone CPR and barriers affecting life-saving seconds.

Objectives: Phone cardiopulmonary resuscitation (CPR) increases the rate of bystander CPR to patients suffering from an out-of-hospital cardiac arrest (OHCA). This study analyzed the effectiveness of the ALERT protocol for instructing laypeople in bystander CPR.Methods: All 244 phone CPR calls to the emergency medical communication center in Leuven during a one-year period were analyzed. Time to recognition of OHCA and to start of phone CPR was evaluated and compared to the recommendations set up by the American Heart Association (AHA). Barriers that delayed or prevented phone CPR were identified.Results: Time to recognition of OHCA and to start of chest compressions was below the benchmark set by the AHA in 37% and 32% of the calls, respectively. The most common barriers that delayed the start of phone CPR were irrelevant questioning by the dispatcher and difficulties moving the patient.In 52 calls, phone CPR was not initiated. In 54% of these calls, this was due to the bystander's inability to move the patient to the floor or to perform CPR. In 44% the bystander's lack of motivation hindered the start of CPR.Conclusions: The ALERT protocol plays a key role in bystander-CPR. Despite the increased CPR rates and reduced time to start chest compressions since its implementation, further improvement is required. Based on the barriers detected, intensive training of dispatchers is an important next step. Furthermore, adding an alternative track to the protocol for immovable patients might be worth considering.

Pulseless Electrical Activity: Detection of Underlying Causes in a Prehospital Setting.

The proportion of out-of-hospital cardiac arrests (OHCAs) with pulseless electrical activity (PEA) as initial rhythm is increasing. PEA should be managed by identifying the underlying cause of the arrest and treating it accordingly. This often poses a challenge in the chaotic prehospital environment with only limited resources available. The aim of this study was to review the diagnostic tools available in a prehospital setting, and their interpretation during cardiac arrest (CA) with PEA as initial rhythm. A systematic literature search of the PubMed database was performed. Articles were assessed for eligibility by title, abstract, and full text. Ultrasonography has become a great asset in detecting underlying causes, and a variety of protocols have been proposed. There are currently no studies comparing these protocols regarding their feasibility and their effect on patient survival. Further research concerning the relationship between electrocardiogram characteristics and underlying causes is required. Limited evidence suggests a role for point-of-care testing in detecting hyperkalemia and a role for capnography in the diagnosis of asphyxia CA. Multiple studies describe a prognostic potential. Although evidence about the prognostic potential of cerebral oximetry in OHCA is accumulating, its diagnostic potential is still unknown. In the management of OHCA, anamnestic and clinical information remains the initial source of information in search for an underlying cause. Ultrasonographic evaluation should be performed subsequently, both for detecting an underlying cause and discriminating between true PEA and pseudo PEA. Comparative studies are required to identify the best ultrasonographic protocol, which can be included in resuscitation guidelines.

Roco Proteins: GTPases with a Baroque Structure and Mechanism.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of genetically inherited Parkinson's Disease (PD). LRRK2 is a large, multi-domain protein belonging to the Roco protein family, a family of GTPases characterized by a central RocCOR (Ras of complex proteins/C-terminal of Roc) domain tandem. Despite the progress in characterizing the GTPase function of Roco proteins, there is still an ongoing debate concerning the working mechanism of Roco proteins in general, and LRRK2 in particular. This review consists of two parts. First, an overview is given of the wide evolutionary range of Roco proteins, leading to a variety of physiological functions. The second part focusses on the GTPase function of the RocCOR domain tandem central to the action of all Roco proteins, and progress in the understanding of its structure and biochemistry is discussed and reviewed. Finally, based on the recent work of our and other labs, a new working hypothesis for the mechanism of Roco proteins is proposed.

Biochemical and kinetic properties of the complex Roco G-protein cycle.

Roco proteins have come into focus after mutations in the gene coding for the human Roco protein Leucine-rich repeat kinase 2 (LRRK2) were discovered to be one of the most common genetic causes of late onset Parkinson's disease. Roco proteins are characterized by a Roc domain responsible for GTP binding and hydrolysis, followed by a COR dimerization device. The regulation and function of this RocCOR domain tandem is still not completely understood. To fully biochemically characterize Roco proteins, we performed a systematic survey of the kinetic properties of several Roco protein family members, including LRRK2. Together, our results show that Roco proteins have a unique G-protein cycle. Our results confirm that Roco proteins have a low nucleotide affinity in the micromolar range and thus do not strictly depend on G-nucleotide exchange factors. Measurement of multiple and single turnover reactions shows that neither Pi nor GDP release are rate-limiting, while this is the case for the GAP-mediated GTPase reaction of some small G-proteins like Ras and for most other high affinity Ras-like proteins, respectively. The KM values of the reactions are in the range of the physiological GTP concentration, suggesting that LRRK2 functioning might be regulated by the cellular GTP level.

Structural and biochemical analysis of the dual-specificity Trm10 enzyme from Thermococcus kodakaraensis prompts reconsideration of its catalytic mechanism.

tRNA molecules get heavily modified post-transcriptionally. The N-1 methylation of purines at position 9 of eukaryal and archaeal tRNA is catalyzed by the SPOUT methyltranferase Trm10. Remarkably, while certain Trm10 orthologs are specific for either guanosine or adenosine, others show a dual specificity. Structural and functional studies have been performed on guanosine- and adenosine-specific enzymes. Here we report the structure and biochemical analysis of the dual-specificity enzyme from Thermococcus kodakaraensis (TkTrm10). We report the first crystal structure of a construct of this enzyme, consisting of the N-terminal domain and the catalytic SPOUT domain. Moreover, crystal structures of the SPOUT domain, either in the apo form or bound to S-adenosyl-l-methionine or S-adenosyl-l-homocysteine reveal the conformational plasticity of two active site loops upon substrate binding. Kinetic analysis shows that TkTrm10 has a high affinity for its tRNA substrates, while the enzyme on its own has a very low methyltransferase activity. Mutation of either of two active site aspartate residues (Asp206 and Asp245) to Asn or Ala results in only modest effects on the N-1 methylation reaction, with a small shift toward a preference for m1G formation over m1A formation. Only a double D206A/D245A mutation severely impairs activity. These results are in line with the recent finding that the single active-site aspartate was dispensable for activity in the guanosine-specific Trm10 from yeast, and suggest that also dual-specificity Trm10 orthologs use a noncanonical tRNA methyltransferase mechanism without residues acting as general base catalysts.

A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover.

Mutations in LRRK2 are a common cause of genetic Parkinson's disease (PD). LRRK2 is a multi-domain Roco protein, harbouring kinase and GTPase activity. In analogy with a bacterial homologue, LRRK2 was proposed to act as a GTPase activated by dimerization (GAD), while recent reports suggest LRRK2 to exist under a monomeric and dimeric form in vivo. It is however unknown how LRRK2 oligomerization is regulated. Here, we show that oligomerization of a homologous bacterial Roco protein depends on the nucleotide load. The protein is mainly dimeric in the nucleotide-free and GDP-bound states, while it forms monomers upon GTP binding, leading to a monomer-dimer cycle during GTP hydrolysis. An analogue of a PD-associated mutation stabilizes the dimer and decreases the GTPase activity. This work thus provides insights into the conformational cycle of Roco proteins and suggests a link between oligomerization and disease-associated mutations in LRRK2.

Invited review: MnmE, a GTPase that drives a complex tRNA modification reaction.

MnmE is a multi-domain GTPase that is conserved from bacteria to man. Together with its partner protein MnmG it is involved in the synthesis of a tRNA wobble uridine modification. The orthologues of these proteins in eukaryotes are targeted to mitochondria and mutations in the encoding genes are associated with severe mitochondrial diseases. While classical small GTP-binding proteins are regulated via auxiliary GEFs and GAPs, the GTPase activity of MnmE is activated via potassium-dependent homodimerization of its G domains. In this review we focus on the catalytic mechanism of GTP hydrolysis by MnmE and the large scale conformational changes that are triggered throughout the GTPase cycle. We also discuss how these conformational changes might be used to drive and tune the complex tRNA modification reaction. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 568-579, 2016.

Structural and functional insights into tRNA binding and adenosine N1-methylation by an archaeal Trm10 homologue.

Purine nucleosides on position 9 of eukaryal and archaeal tRNAs are frequently modified in vivo by the post-transcriptional addition of a methyl group on their N1 atom. The methyltransferase Trm10 is responsible for this modification in both these domains of life. While certain Trm10 orthologues specifically methylate either guanosine or adenosine at position 9 of tRNA, others have a dual specificity. Until now structural information about this enzyme family was only available for the catalytic SPOUT domain of Trm10 proteins that show specificity toward guanosine. Here, we present the first crystal structure of a full length Trm10 orthologue specific for adenosine, revealing next to the catalytic SPOUT domain also N- and C-terminal domains. This structure hence provides crucial insights in the tRNA binding mechanism of this unique monomeric family of SPOUT methyltransferases. Moreover, structural comparison of this adenosine-specific Trm10 orthologue with guanosine-specific Trm10 orthologues suggests that the N1 methylation of adenosine relies on additional catalytic residues.