Rationale and design of the PRAETORIAN-COVID trial: A double-blind, placebo-controlled randomized clinical trial with valsartan for PRevention of Acute rEspiraTORy dIstress syndrome in hospitAlized patieNts with SARS-COV-2 Infection Disease.

There is much debate on the use of angiotensin receptor blockers (ARBs) in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-infected patients. Although it has been suggested that ARBs might lead to a higher susceptibility and severity of SARS-CoV-2 infection, experimental data suggest that ARBs may reduce acute lung injury via blocking angiotensin-II-mediated pulmonary permeability, inflammation, and fibrosis. However, despite these hypotheses, specific studies on ARBs in SARS-CoV-2 patients are lacking. METHODS: The PRAETORIAN-COVID trial is a multicenter, double-blind, placebo-controlled 1:1 randomized clinical trial in adult hospitalized SARS-CoV-2-infected patients (n = 651). The primary aim is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death within 14 days of randomization. The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160 mg bid, and the placebo arm will receive matching placebo. Treatment duration will be 14 days, or until the occurrence of the primary end point or until hospital discharge, if either of these occurs within 14 days. The trial is registered at clinicaltrials.gov (NCT04335786, 2020). SUMMARY: The PRAETORIAN-COVID trial is a double-blind, placebo-controlled 1:1 randomized trial to assess the effect of valsartan compared to placebo on the occurrence of ICU admission, mechanical ventilation, and death in hospitalized SARS-CoV-2-infected patients. The results of this study might impact the treatment of SARS-CoV-2 patients globally.

Proof of principle of a novel co-pulsating intra-ventricular membrane pump.

In this proof of principle study, we investigated the effectiveness and safety of hemodynamic support with the Intra-Ventricular Membrane Pump (IVMP). The IVMP was implanted into the apex of the left ventricle. Hemodynamic assessment was performed in six ex vivo beating porcine hearts (PhysioHeart platform). The cardiac output (CO), mean arterial pressure (MAP), coronary flow (CF) and pulse pressure (PP) were obtained before and during IVMP support and reported as means ± standard deviations. In two additional visualization experiments, the integrity of the mitral valve was assessed during IVMP support. We found a significant increase of the CO (+1.4 ± 0.2 L/min, P < .001), MAP (+13 ± 6 mm Hg, P = .008), CF (+0.23 ± 0.1 L/min, P = .004), and PP (+15 ± 4 mm Hg, P = .002) during IVMP support, when compared to baseline. No interference of the IVMP with mitral valve function was observed. An increase of premature ventricular complexes (PVC) was observed during support with the IVMP (mean PVC-burden 4.3% vs. 0.7% at baseline), negatively influencing hemodynamic parameters. The IVMP is able to significantly improve hemodynamic parameters in a co-pulsatile fashion, without hampering the function of the mitral valve. These findings provide a basis for future development of a catheter-based IVMP.

Central and local arterial stiffness in White Europeans compared to age-, sex-, and BMI-matched South Asians.

BACKGROUND: Ethnicity impacts cardiovascular disease (CVD) risk, and South Asians demonstrate a higher risk than White Europeans. Arterial stiffness is known to contribute to CVD, and differences in arterial stiffness between ethnicities could explain the disparity in CVD risk. We compared central and local arterial stiffness between White Europeans and South Asians and investigated which factors are associated with arterial stiffness. METHODS: Data were collected from cohorts of White Europeans (the Netherlands) and South Asians (India). We matched cohorts on individual level using age, sex, and body mass index (BMI). Arterial stiffness was measured with ARTSENS® Plus. Central stiffness was expressed as carotid-femoral pulse wave velocity (cf-PWV, m/s), and local carotid stiffness was quantified using the carotid stiffness index (Beta) and pressure-strain elastic modulus (Epsilon, kPa). We compared arterial stiffness between cohorts and used multivariable linear regression to identify factors related to stiffness. RESULTS: We included n = 121 participants per cohort (age 53±10 years, 55% male, BMI 24 kg/m2). Cf-PWV was lower in White Europeans compared to South Asians (6.8±1.9 vs. 8.2±1.8 m/s, p<0.001), but no differences were found for local stiffness parameters Beta (5.4±2.4 vs. 5.8±2.3, p = 0.17) and Epsilon (72±35 vs. 70±31 kPa, p = 0.56). Age (standardized ß, 95% confidence interval: 0.28, 0.17-0.39), systolic blood pressure (0.32, 0.21-0.43), and South Asian ethnicity (0.46, 0.35-0.57) were associated with cf-PWV; associations were similar between cohorts (p>0.05 for interaction). Systolic blood pressure was associated with carotid stiffness in both cohorts, whereas age was associated to carotid stiffness only in South Asians and BMI only in White Europeans. CONCLUSION: Ethnicity is associated with central but not local arterial stiffness. Conversely, ethnicity seems to modify associations between CVD risk factors and local but not central arterial stiffness. This suggests that ethnicity interacts with arterial stiffness measures and the association of these measures with CVD risk factors.

A novel intra-ventricular assist device enhances cardiac performance in normal and acutely failing isolated porcine hearts.

BACKGROUND: We recently demonstrated that a novel intra-ventricular membrane pump (IVMP) was able to increase the pump function of isolated beating porcine hearts. In follow-up, we now investigated the impact of the IVMP on myocardial oxygen consumption and total mechanical efficiency (TME) and assessed the effect of IVMP-support in acutely failing hearts. METHODS: In 10 ex vivo beating porcine hearts, we studied hemodynamic parameters, as well as arterial and coronary venous oxygen content. We assessed cardiac power (CP), myocardial oxygen consumption (MVO2), and TME (CP divided by MVO2) under baseline conditions and during IVMP-support. Additionally, five isolated hearts were subjected to global hypoxia to investigate the effects of IVMP-support on CP under conditions of acute heart failure. RESULTS: Under physiological conditions, baseline CP was 0.36 ± 0.10 W, which increased to 0.65 ± 0.16 W during IVMP-support (increase of 85% ± 24, p < 0.001). This was accompanied by an increase in MVO2 from 18.6 ± 6.2 ml/min at baseline, to 22.3 ± 5.0 ml/min during IVMP-support (+26 ± 31%, p = 0.005). As a result, TME (%) increased from 5.9 ± 1.2 to 8.8 ± 1.8 (50 ± 22% increase, p < 0.001). Acute hypoxia-induced cardiac pump failure reduced CP by 35 ± 6%, which was fully restored to baseline levels during IVMP-support in all hearts. CONCLUSION: IVMP-support improved mechanical efficiency under physiological conditions, as the marked increase in cardiac performance only resulted in a modest increase in oxygen consumption. Moreover, the IVMP rapidly restored cardiac performance under conditions of acute pump failure. These observations warrant further study, to evaluate the effects of IVMP-support in in vivo animal models of acute cardiac pump failure.

Long-term Effect of Face-to-Face vs Virtual Reality Cardiopulmonary Resuscitation (CPR) Training on Willingness to Perform CPR, Retention of Knowledge, and Dissemination of CPR Awareness: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Increased bystander cardiopulmonary resuscitation (CPR) is essential to improve survival after cardiac arrest. Although most studies focus on technical CPR skills, the randomized Lowlands Saves Lives trial prespecified a follow-up survey on other important aspects that affect the widespread performance of CPR. Objective: To investigate bystander willingness to perform CPR on a stranger, theoretical knowledge retention, and dissemination of CPR awareness 6 months after undergoing short face-to-face and virtual reality (VR) CPR trainings. Design, Setting, and Participants: A prespecified 6-month posttraining survey was conducted among 320 participants in the Lowlands Saves Lives trial, a randomized comparison between 20-minute face-to-face, instructor-led CPR training and VR training. Participants were recruited at the Lowlands music festival, with a designated area to conduct scientific projects (August 16-18, 2019; the Netherlands). Statistical analysis was performed from March 1, 2020, to July 31, 2021. Interventions: Two standardized 20-minute protocols on CPR and automated external defibrillator use: instructor-led face-to-face training using CPR manikins or VR training using the Resuscitation Council (UK)-endorsed Lifesaver VR smartphone application and a pillow to practice compressions. Main Outcomes and Measures: Primary outcomes were willingness to perform CPR on a stranger, theoretical knowledge retention, and dissemination of CPR awareness as reported by the entire cohort. As secondary analyses, the results of the 2 training modalities were compared. Results: Of 381 participants, 320 consented to this follow-up survey; 188 participants (115 women [61%]; median age, 26 years [IQR, 22-32 years]) completed the entire survey and were accordingly included in the secondary analysis. The overall proportion of participants willing to perform CPR on a stranger was 77% (144 of 188): 81% (79 of 97) among face-to-face participants and 71% (65 of 91) among VR participants (P = .02); 103 participants (55%) reported feeling scared to perform CPR (P = .91). Regarding theoretical knowledge retention, a median of 7 (IQR, 6-8) of 9 questions were answered correctly in both groups (P = .81). Regarding dissemination of CPR awareness, 65% of participants (123 of 188) told at least 1 to 10 family members or friends about the importance of CPR, and 15% (29 of 188) had participated in certified, instructor-led training at the time of the survey, without differences between groups. Conclusions and Relevance: In this 6-month posttraining survey, young adult participants of short CPR training modules reported high willingness (77%) to perform CPR on a stranger, with slightly higher rates for face-to-face than for VR participants. Theoretical knowledge retention was good, and the high dissemination of awareness suggests that these novel CPR training modules staged at a public event are promising sensitizers for involvement in CPR, although further challenges include mitigating the fear of performing CPR. Trial Registration: ClinicalTrials.gov Identifier: NCT04013633.

Pilot study on VF-waveform based algorithms for early detection of acute myocardial infarction during out-of-hospital cardiac arrest.

INTRODUCTION: On-scene detection of acute coronary occlusion (ACO) during ongoing ventricular fibrillation (VF) may facilitate patient-tailored triage and treatment during cardiac arrest. Experimental studies have demonstrated the diagnostic potential of the amplitude spectrum area (AMSA) of the VF-waveform to detect myocardial infarction (MI). In follow-up, we performed this clinical pilot study on VF-waveform based discriminative models to diagnose acute MI due to ACO in real-world VF-patients. METHODS: In our registry of VF-patients transported to a tertiary hospital (Nijmegen, The Netherlands), we studied patients with high-quality VF-registrations. We calculated VF-characteristics prior to the first shock, and first-to-second shock changes (Δ-characteristics). Primary aim was to assess the discriminative ability of the AMSA to detect patients with ACO. Secondarily, we investigated the discriminative value of adding ΔAMSA-measures using machine learning algorithms. Model performances were assessed using C-statistics. RESULTS: In total, there were 67 VF-patients with and 34 without an ACO, and baseline characteristics did not differ significantly. Based on the AMSA prior to the first defibrillation attempt, discrimination between ACO and non-ACO was possible, with a C-statistic of 0.66 (0.56-0.75). The discriminative model using AMSA + ΔAMSA yielded a C-statistic of 0.80 (0.69-0.88). CONCLUSION: These clinical pilot data confirm previous experimental findings that early detection of MI using VF-waveform analysis seems feasible, and add insights on the diagnostic impact of accounting for first-to-second shock changes in VF-characteristics. Confirmative studies in larger cohorts and with a variety of VF-algorithms are warranted to further investigate the potential of this innovative approach.

Optimal Combination of Chest Compression Depth and Rate in Virtual Reality Resuscitation Training: A Post Hoc Analysis of the Randomized Lowlands Saves Lives Trial.

Background Dissemination of cardiopulmonary resuscitation (CPR) skills is essential for cardiac arrest survival. Virtual reality (VR)-training methods are low cost and easily available, but to meet depth requirements adaptations are required, as confirmed in a recent randomized study on currently prevailing CPR quality criteria. Recently, the promising clinical performance of new CPR quality criteria was demonstrated, based on the optimal combination of compression depth and rate. We now study compliance with these newly proposed CPR quality criteria. Methods and Results Post hoc analysis of a randomized trial compared standardized 20-minute face-to-face CPR training with VR training using the Lifesaver VR smartphone application. During a posttraining test, compression depth and rate were measured using CPR mannequins. We assessed compliance with the newly proposed CPR criteria, that is, compression rate within ±20% of 107/minute and depth within ±20% of 47 mm. We studied 352 participants, age 26 (22-31) years, 56% female, and 15% with CPR training ≤2 years. Among VR-trained participants, there was a statistically significant difference between the proportions complying with newly proposed versus the currently prevailing quality criteria (52% versus 23%, P<0.001). The difference in proportions complying with rate requirements was statistically significant (96% for the new versus 50% for current criteria, P<0.001), whereas there was no significant difference with regard to the depth requirements (55% versus 51%, P=0.45). Conclusions Lifesaver VR training, although previously found to be inferior to face-to-face training, may lead to CPR quality compliant with recently proposed, new quality criteria. If the prognostic importance of these new criteria is confirmed in additional studies, Lifesaver VR in its current form would be an easily available vector to disseminate CPR skills.

Electrocardiographic recording direction impacts ventricular fibrillation waveform measurements: A potential pitfall for VF-waveform guided defibrillation protocols.

AIM: In cardiac arrest, ventricular fibrillation (VF) waveform analysis has identified the amplitude spectrum area (AMSA) as a key predictor of defibrillation success and favorable neurologic survival. New resuscitation protocols are under investigation, where prompt defibrillation is restricted to cases with a high AMSA. Appreciating the variability of in-field pad placement, we aimed to assess the impact of recording direction on AMSA-values, and the inherent defibrillation advice. METHODS: Prospective VF-waveform study on 12-lead surface electrocardiograms (ECGs) obtained during defibrillation testing in ICD-recipients (2010-2017). AMSA-values (mVHz) of simultaneous VF-recordings were calculated and compared between all limb leads, with lead II as reference (proxy for in-field pad position). AMSA-differences between leads I and II were quantified using Bland-Altman analysis. Moreover, we investigated differences between these adjacent leads regarding classification into high (≥15.5), intermediate (6.5-15.5) or low (≤6.5) AMSA-values. RESULTS: In this cohort (n = 243), AMSA-values in lead II (10.2 ± 4.8) differed significantly from the other limb leads (I: 8.0 ± 3.4; III: 12.9 ± 5.6, both p < 0.001). The AMSA-value in lead I was, on average, 2.24 ± 4.3 lower than in lead II. Of the subjects with high AMSA-values in lead II, only 15% were classified as high if based on assessments of lead I. For intermediate and low AMSA-values, concordances were 66% and 72% respectively. CONCLUSIONS: ECG-recording direction markedly affects the result of VF-waveform analysis, with 20-30% lower AMSA-values in lead I than in lead II. Our data suggest that electrode positioning may significantly impact shock guidance by 'smart defibrillators', especially affecting the advice for prompt defibrillation.

Computerized Analysis of the Ventricular Fibrillation Waveform Allows Identification of Myocardial Infarction: A Proof-of-Concept Study for Smart Defibrillator Applications in Cardiac Arrest.

Background In cardiac arrest, computerized analysis of the ventricular fibrillation (VF) waveform provides prognostic information, while its diagnostic potential is subject of study. Animal studies suggest that VF morphology is affected by prior myocardial infarction (MI), and even more by acute MI. This experimental in-human study reports on the discriminative value of VF waveform analysis to identify a prior MI. Outcomes may provide support for in-field studies on acute MI. Methods and Results We conducted a prospective registry of implantable cardioverter defibrillator recipients with defibrillation testing (2010-2014). From 12-lead surface ECG VF recordings, we calculated 10 VF waveform characteristics. First, we studied detection of prior MI with lead II, using one key VF characteristic (amplitude spectrum area [AMSA]). Subsequently, we constructed diagnostic machine learning models: model A, lead II, all VF characteristics; model B, 12-lead, AMSA only; and model C, 12-lead, all VF characteristics. Prior MI was present in 58% (119/206) of patients. The approach using the AMSA of lead II demonstrated a C-statistic of 0.61 (95% CI, 0.54-0.68). Model A performance was not significantly better: 0.66 (95% CI, 0.59-0.73), P=0.09 versus AMSA lead II. Model B yielded a higher C-statistic: 0.75 (95% CI, 0.68-0.81), P<0.001 versus AMSA lead II. Model C did not improve this further: 0.74 (95% CI, 0.67-0.80), P=0.66 versus model B. Conclusions This proof-of-concept study provides the first in-human evidence that MI detection seems feasible using VF waveform analysis. Information from multiple ECG leads rather than from multiple VF characteristics may improve diagnostic accuracy. These results require additional experimental studies and may serve as pilot data for in-field smart defibrillator studies, to try and identify acute MI in the earliest stages of cardiac arrest.

Effect of Face-to-Face vs Virtual Reality Training on Cardiopulmonary Resuscitation Quality: A Randomized Clinical Trial.

Importance: Bystander cardiopulmonary resuscitation (CPR) is crucial for survival after cardiac arrest but not performed in most cases. New, low-cost, and easily accessible training methods, such as virtual reality (VR), may reach broader target populations, but data on achieved CPR skills are lacking. Objective: To compare CPR quality between VR and face-to-face CPR training. Design, Setting, and Participants: Randomized noninferiority trial with a prospective randomized open blinded end point design. Participants were adult attendees from the science section of the Lowlands Music Festival (August 16 to 18, 2019) in the Netherlands. Analysis began September 2019. Interventions: Two standardized 20-minute protocols on CPR and automated external defibrillator use: instructor-led face-to-face training or VR training using a smartphone app endorsed by the Resuscitation Council (United Kingdom). Main Outcomes and Measures: During a standardized CPR scenario following the training, we assessed the primary outcome CPR quality, measured as chest compression depth and rate using CPR manikins. Overall CPR performance was assessed by examiners, blinded for study groups, using a European Resuscitation Council-endorsed checklist (maximum score, 13). Additional secondary outcomes were chest compression fraction, proportions of participants with mean depth (50 mm-60 mm) or rate (100 min-1-120 min-1) within guideline ranges, and proportions compressions with full release. Results: A total of 381 participants were randomized: 216 women (57%); median (interquartile range [IQR]) age, 26 (22-31) years. The VR app (n = 190 [49.9%]) was inferior to face-to-face training (n = 191 [50.1%]) for chest compression depth (mean [SD], VR: 49 [10] mm vs face to face: 57 [5] mm; mean [95% CI] difference, -8 [-9 to -6] mm), and noninferior for chest compression rate (mean [SD]: VR: 114 [12] min-1 vs face to face: 109 [12] min-1; mean [95% CI] difference, 6 [3 to 8] min-1). The VR group had lower overall CPR performance scores (median [IQR], 10 [8-12] vs 12 [12-13]; P < .001). Chest compression fraction (median [IQR], 61% [52%-66%] vs 67% [62%-71%]; P < .001) and proportions of participants fulfilling depth (51% [n = 89] vs 75% [n = 133], P < .001) and rate (50% [n = 87] vs 63% [n = 111], P = .01) requirements were also lower in the VR group. The proportion of compressions with full release was higher in the VR group (median [IQR], 98% [59%-100%] vs 88% [55%-99%]; P = .002). Conclusions and Relevance: In this randomized noninferiority trial, VR training resulted in comparable chest compression rate but inferior compression depth compared with face-to-face training. Given the potential of VR training to reach a larger target population, further development is needed to achieve the compression depth and overall CPR skills acquired by face-to-face training. Trial Registration: ClinicalTrials.gov identifier: NCT04013633.

Rationale and design of the Lowlands Saves Lives trial: a randomised trial to compare CPR quality and long-term attitude towards CPR performance between face-to-face and virtual reality training with the Lifesaver VR app.

INTRODUCTION: Layperson cardiopulmonary resuscitation (CPR) is a key aspect in the chain of survival after cardiac arrest. New, low-cost, easily accessible training methods such as virtual reality (VR) training with a smartphone application may reach broader populations, but data on CPR performance are scarce. METHODS AND ANALYSIS: The Lowlands Saves Lives trial is a prospective randomised open-blinded end-point evaluation study, comparing two 20 min CPR training protocols: standardised, certified instructor-led face-to-face training complying with current education guidelines (using Laerdal Little Anne manikins), and VR training, using the UK Resuscitation Council endorsed Lifesaver VR app. In the latter, chest compressions are practiced on a pillow.During VR training, participants learn to resuscitate by completing a filmed CPR scenario while wearing VR goggles and headphones. Eligible for inclusion are adult attendees of Lowlands Science, a specific section of the 3-day Lowlands music festival (50 000 attendees), dedicated exclusively to science. Following the training, all participants will perform a CPR test on a Laerdal Resusci Anne QCPR manikin. Primary outcome measures are depth and rate of chest compressions, measured using CPR manikins. The key secondary outcome is overall CPR performance, with real-time examination (blinded for study group) of all items of a European Resuscitation Council endorsed checklist, and evaluation of a sample of videotaped CPR tests by a blinded event committee.Given the unique setting of a festival, the primary additional analysis will address the impact of alcohol levels on CPR quality parameters and overall performance. Follow-up questionnaires will evaluate the attitude towards performing CPR. This unique study may provide important insights into innovative CPR training methods, factors that impact CPR performance and the impact on long-term attitude towards resuscitation. ETHICS AND DISSEMINATION: This study received approval from the research ethics committee of the Radboudumc. All participants will provide written informed consent. The results of this study will be published in peer-reviewed journals and presented at (inter)national conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov registry (NCT04013633).

Ventricular fibrillation waveform characteristics of the surface ECG: Impact of the left ventricular diameter and mass.

BACKGROUND: Despite a promising association between VF waveform characteristics and prognosis after resuscitation, studies with VF-guided treatment have so far not improved outcomes. While driven by the idea that the VF waveform reflects arrest duration, increasing evidence suggests that pre-existent disease-related changes of the myocardium affect ECG-characteristics of VF as well. In this context, we studied the impact of the left ventricular (LV) diameter and mass. METHODS: Cohort of 193 ICD-patients with defibrillation testing at the Radboudumc (2010-2014). Surface ECG-recordings (leads I,II,aVF,V1,V3,V6) were analysed to study amplitude and frequency characteristics of the induced VF. Both for LV diameter and mass, patients were categorised in two groups, using echocardiographic data (ASE-guidelines). RESULTS: In all ECG-leads, dominant and median frequencies were significantly lower in patients with (n=40) than in patients without (n=151) an increased LV diameter. The mean amplitude and amplitude spectrum area (AMSA) did not differ. In contrast, we observed no differences in frequency characteristics in relation to the LV mass, whereas mean amplitude (I,aVF,V3) and AMSA (I,V3) were significantly higher in patients with (n=57) than in patients without (n=120) an increased LV mass. CONCLUSIONS: Frequency characteristics of VF were consistently lower in case of an increased LV diameter. Whereas LV mass does not affect the frequency of the VF waveform, amplitudes seem higher with increasing mass. These findings add to the current knowledge of factors that modulate VF characteristics of the surface ECG and provide insight into factors which may be accounted for in future studies on VF-guided resuscitative interventions.

Ventricular fibrillation waveform characteristics differ according to the presence of a previous myocardial infarction: A surface ECG study in ICD-patients.

BACKGROUND: Characteristics of the ventricular fibrillation (VF) waveform reflect arrest duration and have been incorporated in studies on algorithms to guide resuscitative interventions. Findings in animals indicate that VF characteristics are also affected by the presence of a previous myocardial infarction (MI). As studies in humans are scarce, we assessed the impact of a previous MI on VF characteristics in ICD-patients. METHODS: Prospective cohort of ICD-patients (n=190) with defibrillation testing at the Radboudumc (2010-2013). VF characteristics of the 12-lead surface ECG were compared between three groups: patients without a history of MI (n=88), with a previous anterior (n=47) and a previous inferior MI (n=55). RESULTS: As compared to each of the other groups, the mean amplitude and amplitude spectrum area were lower, for an anterior MI in lead V3 and for an inferior MI in leads II and aVF. Across the three groups, the bandwidth was broader in the leads corresponding with the infarct localisation. In contrast, the dominant and median frequencies only differed between previous anterior MI and no history of MI, being lower in the former. CONCLUSIONS: The VF waveform is affected by the presence of a previous MI. Amplitude-related measures were lower and VF was less organised in the ECG-lead(s) adjacent to the area of infarction. Although VF characteristics of the surface ECG have so far primarily been considered a proxy for arrest duration and metabolic state, our findings question this paradigm and may provide additional insights into the future potential of VF-guided resuscitative interventions.