Factors Affecting the Course of Resuscitation From Cardiac Arrest With Pulseless Electrical Activity in Children and Adolescents

Background: Although in-hospital pediatric cardiac arrests and cardiopulmonary resuscitation occur >15,000/year in the US, few studies have assessed which factors affect the course of resuscitation in these patients. We investigated transitions from Pulseless Electrical Activity (PEA) to Ventricular Fibrillation/pulseless Ventricular Tachycardia (VF/pVT), Return of Spontaneous Circulation (ROSC) and recurrences from ROSC to PEA in children and adolescents with in-hospital cardiac arrest. Methods: Episodes of cardiac arrest at the Children's Hospital of Philadelphia were prospectively registered. Defibrillators that recorded chest compression depth/rate and ventilation rate were applied. CPR variables, patient characteristics and etiology, and dynamic factors (e.g. the proportion of time spent in PEA or ROSC) were entered as time-varying covariates for the transition intensities under study. Results: In 67 episodes of CPR in 59 patients (median age 15 years) with cardiac arrest, there were 52 transitions from PEA to ROSC, 22 transitions from PEA to VF/pVT, and 23 recurrences of PEA from ROSC. Except for a nearly significant effect of mean compression depth beyond a threshold of 5.7 cm, only dynamic factors that evolved during CPR favored a transition from PEA to ROSC. The latter included a lower proportion of PEA over the last 5 min and a higher proportion of ROSC over the last 5 min. Factors associated with PEA to VF/pVT development were age, weight, the proportion spent in VF/pVT or PEA the last 5 min, and the general transition intensity, while PEA recurrence from ROSC only depended on the general transition intensity. Conclusion: The clinical course during pediatric cardiac arrest was mainly influenced by dynamic factors associated with time in PEA and ROSC. Transitions from PEA to ROSC seemed to be favored by deeper compressions.publishedVersio

Training Hospital Providers in Basic CPR Skills in Botswana: Acquisition, Retention and Impact of Novel Training Techniques

Objective Globally, one third of deaths each year are from cardiovascular diseases, yet no strong evidence supports any specific method of CPR instruction in a resource-limited setting. We hypothesized that both existing and novel CPR training programs significantly impact skills of hospital-based healthcare providers (HCP) in Botswana. Methods HCP were prospectively randomized to 3 training groups: instructor led, limited instructor with manikin feedback, or self-directed learning. Data was collected prior to training, immediately after and at 3 and 6 months. Excellent CPR was prospectively defined as having at least 4 of 5 characteristics: depth, rate, release, no flow fraction, and no excessive ventilation. GEE was performed to account for within subject correlation. Results Of 214 HCP trained, 40% resuscitate ≥1/month, 28% had previous formal CPR training, and 65% required additional skills remediation to pass using AHA criteria. Excellent CPR skill acquisition was significant (infant: 32% vs. 71%, p \u3c 0.01; adult 28% vs. 48%, p \u3c 0.01). Infant CPR skill retention was significant at 3 (39% vs. 70%, p \u3c 0.01) and 6 months (38% vs. 67%, p \u3c 0.01), and adult CPR skills were retained to 3 months (34% vs. 51%, p = 0.02). On multivariable analysis, low cognitive score and need for skill remediation, but not instruction method, impacted CPR skill performance. Conclusions HCP in resource-limited settings resuscitate frequently, with little CPR training. Using existing training, HCP acquire and retain skills, yet often require remediation. Novel techniques with increased student: instructor ratio and feedback manikins were not different compared to traditional instruction

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.</p

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism

Video performance-debriefings and ventilation-refreshers improve quality of neonatal resuscitation

Aim: Providers caring for newly born infants require skills and knowledge to initiate prompt and effective positive pressure ventilation (PPV) if the newborn does not breathe spontaneously after birth. We hypothesized implementation of high frequency/short duration deliberate practice training and post event video-based debriefings would improve process of care and decreases time to effective spontaneous respiration. Methods: Pre- and post-interventional quality study performed at two Norwegian university hospitals. All newborns receiving PPV were prospectively video-recorded, and initial performance data guided the development of educational interventions. A priori primary outcome was changed from process of care using the Neonatal Resuscitation Performance Evaluation (NRPE) score to time to effective spontaneous respiration as the NRPE score could only be obtained from one site due to lack of staff resources. Results: Over 12 months, 297 PPV-Refreshers and 52 performance debriefings were completed with 227 unique providers attending a PPV-Refresher and 93 unique providers completed a debriefing. We compared 102 PPV-events pre- to 160 PPV-events post-bundle implementation. The time to effective spontaneous respiration decreased from median (95% confidence interval) 196 (140–237) to 144 (120–163) s, p = 0.010. The NRPE-score increased significantly from median 77% (75–81) pre- to 89% (86–92) post-implementation, p 100 beats/min or number of newborns transferred to intensive care. Conclusion: High frequency/short duration deliberate practice PPV psychomotor training combined with performance-focused team debriefings using video recordings of actual resuscitations may improve time to effective spontaneous breathing and adherence to guidelines during real neonatal resuscitations

Implementation and effectiveness of a video-based debriefing programme for neonatal resuscitation

Background: Approximately 5%–10% of newly born babies need intervention to assist transition from intra‐ to extrauterine life. All providers in the delivery ward are trained in neonatal resuscitation, but without clinical experience or exposure, training competency is transient with a decline in skills within a few months. The aim of this study was to evaluate whether neonatal resuscitations skills and team performance would improve after implementation of video‐assisted, performance‐focused debriefings. Methods: We installed motion‐activated video cameras in every resuscitation bay capturing consecutive compromised neonates. The videos were used in debriefings led by two experienced facilitators, focusing on guideline adherence and non‐technical skills. A modification of Neonatal Resuscitation Performance Evaluation (NRPE) was used to score team performance and procedural skills during a 7 month study period (2.5, 2.5 and 2 months pre‐, peri‐ and post‐implementation) (median score with 95% confidence interval). Results: We compared 74 resuscitation events pre‐implementation to 45 events post‐implementation. NRPE‐score improved from 77% (75, 81) to 89% (86, 93), P 100 bpm at 2 min improved from 71% pre‐ vs. 82% (P = 0.22) post‐implementation. Conclusion: Implementation of video‐assisted, performance‐focused debriefings improved adherence to best practice guidelines for neonatal resuscitation skill and team performance

Prevalence and hemodynamic effects of leaning during CPR

Cardiopulmonary resuscitation (CPR) guidelines recommend complete release between chest compressions (CC)

Poor Concordance of One‐Third Anterior–Posterior Chest Diameter Measurements With Absolute Age‐Specific Chest Compression Depth Targets in Pediatric Cardiac Arrest Patients

Background Current pediatric cardiac arrest guidelines recommend depressing the chest by one‐third anterior–posterior diameter (APD), which is presumed to equate to absolute age‐specific chest compression depth targets (4 cm for infants and 5 cm for children). However, no clinical studies during pediatric cardiac arrest have validated this presumption. We aimed to study the concordance of measured one‐third APD with absolute age‐specific chest compression depth targets in a cohort of pediatric patients with cardiac arrest. Methods and Results This was a retrospective observational study from a multicenter, pediatric resuscitation quality collaborative (pediRES‐Q [Pediatric Resuscitation Quality Collaborative]) from October 2015 to March 2022. In‐hospital patients with cardiac arrest ≤12 years old with APD measurements recorded were included for analysis. One hundred eighty‐two patients (118 infants >28 days old to <1 year old, and 64 children 1 to 12 years old) were analyzed. The mean one‐third APD of infants was 3.2 cm (SD, 0.7 cm), which was significantly smaller than the 4 cm target depth (P<0.001). Seventeen percent of the infants had one‐third APD measurements within the 4 cm ±10% target range. For children, the mean one‐third APD was 4.3 cm (SD, 1.1 cm). Thirty‐nine percent of children had one‐third APD within the 5 cm ±10% range. Except for children 8 to 12 years old and overweight children, the measured mean one‐third APD of the majority of the children was significantly smaller than the 5 cm depth target (P<0.05). Conclusions There was poor concordance between measured one‐third APD and absolute age‐specific chest compression depth targets, particularly for infants. Further study is needed to validate current pediatric chest compression depth targets and evaluate the optimal chest compression depth to improve cardiac arrest outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02708134