Association Between Chest Compression Pause Duration and Survival After Pediatric In-Hospital Cardiac Arrest.

BACKGROUND: The association between chest compression (CC) pause duration and pediatric in-hospital cardiac arrest survival outcomes is unknown. The American Heart Association has recommended minimizing pauses in CC in children to <10 seconds, without supportive evidence. We hypothesized that longer maximum CC pause durations are associated with worse survival and neurological outcomes. METHODS: In this cohort study of index pediatric in-hospital cardiac arrests reported in pediRES-Q (Quality of Pediatric Resuscitation in a Multicenter Collaborative) from July of 2015 through December of 2021, we analyzed the association in 5-second increments of the longest CC pause duration for each event with survival and favorable neurological outcome (Pediatric Cerebral Performance Category ≤3 or no change from baseline). Secondary exposures included having any pause >10 seconds or >20 seconds and number of pauses >10 seconds and >20 seconds per 2 minutes. RESULTS: We identified 562 index in-hospital cardiac arrests (median [Q1, Q3] age 2.9 years [0.6, 10.0], 43% female, 13% shockable rhythm). Median length of the longest CC pause for each event was 29.8 seconds (11.5, 63.1). After adjustment for confounders, each 5-second increment in the longest CC pause duration was associated with a 3% lower relative risk of survival with favorable neurological outcome (adjusted risk ratio, 0.97 [95% CI, 0.95-0.99]; P=0.02). Longest CC pause duration was also associated with survival to hospital discharge (adjusted risk ratio, 0.98 [95% CI, 0.96-0.99]; P=0.01) and return of spontaneous circulation (adjusted risk ratio, 0.93 [95% CI, 0.91-0.94]; P<0.001). Secondary outcomes of any pause >10 seconds or >20 seconds and number of CC pauses >10 seconds and >20 seconds were each significantly associated with adjusted risk ratio of return of spontaneous circulation, but not survival or neurological outcomes. CONCLUSIONS: Each 5-second increment in longest CC pause duration during pediatric in-hospital cardiac arrest was associated with lower chance of survival with favorable neurological outcome, survival to hospital discharge, and return of spontaneous circulation. Any CC pause >10 seconds or >20 seconds and number of pauses >10 seconds and >20 seconds were significantly associated with lower adjusted probability of return of spontaneous circulation, but not survival or neurological outcomes.

Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation.

BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare, fatal, premature aging disease caused by a toxic protein called progerin. Circulating progerin has not been previously detected, precluding research using readily available biological samples. This study aimed to develop a plasma progerin assay to evaluate progerin's quantity, response to progerin-targeted therapy, and relationship to patient survival. METHODS: Biological samples were collected by The Progeria Research Foundation Cell and Tissue Bank from a non-HGPS cohort cross-sectionally and a HGPS cohort longitudinally. HGPS donations occurred at baseline and intermittently while treated with farnesylation inhibitors lonafarnib±pravastatin and zoledronate, within 3 sequential open-label clinical trials at Boston Children's Hospital totaling >10 years of treatment. An ultrasensitive single-molecule counting progerin immunoassay was developed with prespecified performance parameters. Intra- and interpatient group statistics were descriptive. The relationship between progerin and survival was assessed by using joint modeling with time-dependent slopes parameterization. RESULTS: The assay's dynamic detection range was 59 to 30 000 pg/mL (R2=0.9987). There was no lamin A cross-reactivity. Mean plasma progerin in non-HGPS participants (n=69; 39 male, 30 female; age, 0.2-71.3 years) was 351±251 pg/mL, and in drug-naive participants with HGPS (n=74; 37 female, 37 male; age, 2.1-17.5 years) was 33 261±12 346 pg/mL, reflecting a 95-fold increase in affected children (P<0.0001). Progerin levels did not differ by sex (P=0.99). Lonafarnib treatment resulted in an average per-visit progerin decrease from baseline of between 35% to 62% (all P<0.005); effects were not augmented by adding pravastatin and zoledronate. Progerin levels fell within 4 months of therapy and remained lower for up to 10 years. The magnitude of progerin decrease positively associated with patient survival (P<0.0001; ie, 15 000 pg/mL decrease yields a 63.9% decreased risk of death). For any given decrease in progerin, life expectancy incrementally increased with longer treatment duration. CONCLUSIONS: A sensitive, quantitative immunoassay for progerin was developed and used to demonstrate high progerin levels in HGPS plasma that decreased with lonafarnib therapy. The extent of improved survival was associated with both the magnitude of progerin decrease and duration at lower levels. Thus, plasma progerin is a biomarker for HGPS whose reduction enables short- and long-term assessment of progerin-targeted treatment efficacy. REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifiers: NCT00879034 and NCT00916747.

Characteristics and Outcomes of Cardiac Arrest in Adult Patients Admitted to Pediatric Services: A Descriptive Analysis of the American Heart Association's Get With The Guidelines-Resuscitation Data.

OBJECTIVES: Differences between adult and pediatric in-hospital cardiac arrest (IHCA) are well-described. Although most adults are cared for on adult services, pediatric services often admit adults, particularly those with chronic conditions. The objective of this study is to describe IHCA in adults admitted to pediatric services. DESIGN: Retrospective cohort analysis from the American Heart Association's Get With The Guidelines-Resuscitation registry of a subpopulation of adults with IHCA while admitted to pediatric services. Multivariable logistic regression was used to evaluate adjusted survival outcomes and compare outcomes between age groups (18-21, 22-25, and ≥26 yr old). SETTING: Hospitals contributing to the Get With The Guidelines-Resuscitation registry. PATIENTS: Adult-aged patients (≥ 18 yr) with an index pulseless IHCA while admitted to a pediatric service from 2000 to 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 491 adult IHCAs were recorded on pediatric services at 17 sites, during the 19 years of review, and these events represented 0.1% of all adult IHCAs. In total, 221 cases met inclusion criteria with 139 events excluded due to an initial rhythm of bradycardia with poor perfusion. Median patient age was 22 years (interquartile range, 19-28 yr). Ninety-eight percent of patients had at least one pre-existing condition. Return of spontaneous circulation occurred in 63% of events and 30% of the patients survived to discharge. All age groups had similar rates of survival to discharge (range 26-37%; p = 0.37), and survival did not change over the study period (range 26-37%; p = 0.23 for adjusted survival to discharge). CONCLUSIONS: In this cohort of adults with IHCA while admitted to a pediatric service, we failed to find an association between survival outcomes and age. Additional research is needed to better understand resuscitation in this population.

In-Hospital Cardiac Arrest in Adult Patients Admitted to a Quaternary Children's Center.

OBJECTIVE: This study aimed to describe baseline and event characteristics and outcomes for adult patients who experience in-hospital cardiac arrest (IHCA) in a quaternary children's hospital and compare IHCA outcomes in younger (18-24 years) versus older (≥25 years) adults. We hypothesized that the rate of survival to hospital discharge would be lower in the older adult group. METHODS: We performed a retrospective single-center cohort study of inpatient areas of a quaternary children's center. Adult patients (≥18 years of age) with an index pulseless IHCA requiring at least 1 minute of cardiopulmonary resuscitation or defibrillation were included. RESULTS: Thirty-three events met the inclusion criteria with a median patient age of 23.9 years (interquartile range, 20.2-33.3 years). Twenty-one (64%) patients had congenital heart disease, and 25 (76%) patients had comorbidities involving ≥2 organ systems. The most common prearrest interventions were invasive mechanical ventilation (76%) and vasoactive infusions (55%). Seventeen patients (52%) survived to hospital discharge.Survival to discharge was lower in patients 25 years or older compared with patients aged 18 to 24 years old (3 of 15 [20%] vs 14 of 18 [78%], respectively; P = 0.002). CONCLUSIONS: The majority of adult patients with IHCA in our pediatric hospital had preexisting multisystem comorbidities, the most common of which was congenital heart disease. Overall survival to discharge after IHCA was 52%, similar to that reported for the general pediatric population. Survival to discharge was significantly lower in the subgroup of patients 25 years or older when compared with those between the ages of 18 and 24 years.

Baseline Range of Motion, Strength, Motor Function, and Participation in Youth with Hutchinson-Gilford Progeria Syndrome.

AIMS: Limited information is available on impairments, activity limitations and participation restrictions in youth with Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic premature aging disease. The purposes were to: (1) describe range of motion (ROM), grip, pinch and quadriceps strength, functional balance, walking endurance, and gross motor limitations and participation restrictions; (2) evaluate the association between ROM impairments and age; and (3) evaluate the association between the Gross Motor Function Measure-88 (GMFM) scores and lower extremity (LE) ROM, quadriceps strength, and age. METHODS: Upper and LE ROM, grip, pinch and quadriceps strength, Timed Up and Go (TUG), Six Minute Walk Test, GMFM-88, and Canadian Occupational Performance Measure data were recorded for 38 participants with HGPS. RESULTS: All youth exhibited ROM impairments and most displayed decreased grip and pinch strength, walking endurance, and gross motor skills when compared to same-aged peers. However, the majority had good functional balance with TUG scores in the normal range. Participation restrictions included difficulty keeping up with peers when walking and difficulty completing activities of daily living. Some ROM measurements were negatively associated with age indicating that older participants had more extensive ROM limitation than younger participants. CONCLUSIONS: Physical and occupational therapists can use this information when evaluating youth with HGPS, designing a plan of care, and providing treatment interventions.

Calcium Administration During Cardiopulmonary Resuscitation for In-Hospital Cardiac Arrest in Children With Heart Disease Is Associated With Worse Survival-A Report From the American Heart Association's Get With The Guidelines-Resuscitation (GWTG-R) Registry.

OBJECTIVES: IV calcium administration during cardiopulmonary resuscitation (CPR) for pediatric in-hospital cardiac arrest (IHCA) is associated with worse survival. We evaluated survival to hospital discharge in children with heart disease (HD), where calcium is more frequently administered during CPR. DESIGN: Retrospective study of a multicenter registry database. SETTING: Data reported to the American Heart Association's (AHA) Get With The Guidelines-Resuscitation registry. PATIENTS: Children younger than 18 years with HD experiencing an index IHCA event requiring CPR between January 2000 and January 2019. Using propensity score matching (PSM), we selected matched cohorts of children receiving and not receiving IV calcium during CPR and compared the primary outcome of survival to hospital discharge. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We included 4,556 children with HD experiencing IHCA. Calcium was administered in 1,986 (44%), more frequently in children younger than 1 year old (65% vs 35%; p < 0.001) and surgical cardiac (SC) compared with medical cardiac patients (51% vs 36%; p < 0.001). Calcium administration during CPR was associated with longer duration CPR (median 27 min [interquartile range (IQR): 10-50 min] vs 5 min [IQR, 2-16 min]; p < 0.001) and more frequent extracorporeal-CPR deployment (25% vs 8%; p < 0.001). In the PSM cohort, those receiving calcium had decreased survival to hospital discharge (39% vs 46%; p = 0.02) compared with those not receiving calcium. In a subgroup analysis, decreased discharge survival was only seen in SC cohorts. CONCLUSIONS: Calcium administration during CPR for children with HD experiencing IHCA is common and is associated with worse survival. Administration of calcium during CPR in children with HD should be restricted to specific indications as recommended by the AHA CPR guidelines.

Weaning Dexmedetomidine in Non-ICU Areas: An Implementation Effort.

OBJECTIVES: To develop and implement clinical practice guidelines for safely weaning dexmedetomidine infusions in non-ICU areas. DESIGN: Development, implementation, and analysis of effectiveness of clinical practice guidelines. SETTING: Quaternary care academic free-standing pediatric hospital. PATIENTS: Children, otherwise medically ready for transfer to non-ICU areas, who were undergoing a planned wean of a dexmedetomidine infusion. INTERVENTIONS: Subject matter experts developed evidence-based guidelines for weaning dexmedetomidine in patients whose critical phase of illness had resolved. MEASUREMENTS AND MAIN RESULTS: Searches identified no prospective studies of dexmedetomidine weaning. We identified two retrospective reviews of withdrawal symptoms and one on the use of clonidine. There were case studies on withdrawal symptoms. Guidelines were piloted on a cohort of 24 patients while in the ICU. The guidelines were then implemented in non-ICU areas for patients undergoing dexmedetomidine weaning after ICU transfer. Over a 2-year period (October 1, 2018, to September 30, 2020), 63 patients (1 mo to 18 yr old) successfully weaned dexmedetomidine in non-ICU areas. The median time to discontinuation of dexmedetomidine after transfer to non-ICU areas was 5.8 days (interquartile range, 4.75-15 d). Fifty-eight percent (n = 41) of all patients were considered high risk for dexmedetomidine withdrawal based on the dose, duration of exposure, and the risk of experiencing physiologic detriment with more than mild withdrawal. Twenty-nine patients (46%) exhibited no signs or symptoms of withdrawal while weaning per guidelines. For those with signs and symptoms of withdrawal, the most common were tachycardia (n = 26, 40%), agitation (n = 9, 14%), and hypertension (n = 9, 11%). CONCLUSIONS: Weaning dexmedetomidine in non-ICU areas is feasible and can be accomplished safely even among pediatric patients at high risk for withdrawal using standardized weaning guidelines. At our institution, implementation was associated with reduced ICU length of stay for patients recovering from critical illness.

Implementation of an Analgesia-Sedation Protocol Is Associated With Reduction in Midazolam Usage in the PICU.

OBJECTIVES: Examine the association of a revised analgesia-sedation protocol with midazolam usage in the PICU. DESIGN: A single-center nonrandomized before-after study. SETTING: PICU at a quaternary pediatric hospital (Boston Children's Hospital, Boston, MA). PATIENTS: Children admitted to the PICU who were mechanically ventilated for greater than 24 hours. The preimplementation cohort included 190 eligible patients admitted between July 29, 2017, and February 28, 2018, and the postimplementation cohort included 144 patients admitted between July 29, 2019, and February 28, 2020. INTERVENTIONS: Implementation of a revised analgesia-sedation protocol. MEASUREMENTS AND MAIN RESULTS: Our primary outcome, total dose of IV midazolam administered in mechanically ventilated patients up to day 14 of ventilation, decreased by 72% (95% CI [61-80%]; p < 0.001) in the postimplementation cohort. Dexmedetomidine usage increased 230% (95% CI [145-344%]) in the postimplementation cohort. Opioid usage, our balancing metric, was not significantly different between the two cohorts. There were no significant differences in ventilator-free days, PICU length of stay, rate of unplanned extubations, failed extubations, cardiorespiratory arrest events, and 24-hour readmissions to the PICU. CONCLUSIONS: We successfully implemented an analgesia-sedation protocol that primarily uses dexmedetomidine and intermittent opioids, and it was associated with significant decrease in overall midazolam usage in mechanically ventilated patients in the PICU. The intervention was not associated with changes in opioid usage or prevalence of adverse events.

eSIMPLER: A Dynamic, Electronic Health Record-Integrated Checklist for Clinical Decision Support During PICU Daily Rounds.

OBJECTIVES: Design, implement, and evaluate a rounding checklist with deeply embedded, dynamic electronic health record integration. DESIGN: Before-after quality-improvement study. SETTING: Quaternary PICU in an academic, free-standing children's hospital. PATIENTS: All patients in the PICU during daily morning rounds. INTERVENTIONS: Implementation of an updated dynamic checklist (eSIMPLER) providing clinical decision support prompts with display of relevant data automatically pulled from the electronic health record. MEASUREMENTS AND MAIN RESULTS: The prior daily rounding checklist, eSIMPLE, was implemented for 49,709 patient-days (7,779 patients) between October 30, 2011, and October 7, 2018. eSIMPLER was implemented for 5,306 patient-days (971 patients) over 6 months. Checklist completion rates were similar (eSIMPLE: 95% [95% CI, 88-98%] vs eSIMPLER: 98% [95% CI, 92-100%] of patient-days; p = 0.40). eSIMPLER required less time per patient (28 ± 1 vs 47 ± 24 s; p < 0.001). Users reported improved satisfaction with eSIMPLER (p = 0.009). Several checklist-driven process measures-discordance between electronic health record orders for stress ulcer prophylaxis and user-recorded indication for stress ulcer prophylaxis, rate of venous thromboembolism prophylaxis prescribing, and recognition of reduced renal function-improved during the eSIMPLER phase. CONCLUSIONS: eSIMPLER, a dynamic, electronic health record-informed checklist, required less time to complete and improved certain care processes compared with a prior, static checklist with limited electronic health record data. By focusing on the "Five Rights" of clinical decision support, we created a well-accepted clinical decision support tool that was integrated efficiently into daily rounds. Generalizability of eSIMPLER's effectiveness and its impact on patient outcomes need to be examined.

The Impact of Videolaryngoscopy on Endotracheal Intubation Success by a Pediatric/Neonatal Critical Care Transport Team.

INTRODUCTION: Endotracheal intubation may be required for the transport of critically ill neonates and children. Data suggest that first pass success (FPS) is associated with lower rates of complications. Thus, understanding factors associated with FPS can have important implications for clinical outcomes. We aimed to determine the impact of videolaryngoscopy (VL) on FPS by a pediatric critical care transport team (CCTT). Methods: We performed a retrospective cross-sectional study on pediatric patients (≤ 18 years of age) requiring endotracheal intubation by a tertiary care-based pediatric CCTT between 2011 and 2019. Patients were categorized as neonatal (≤ 28 days of age, either preterm or term) or pediatric (> 28 days of age). All intubation attempts using VL were performed with the C-MAC videolaryngoscope. Our primary outcome was rate of FPS. Descriptive statistics of patient, provider, and procedure characteristics were calculated. Multivariate regression was used to test the association between FPS and type of laryngoscope (video versus direct) adjusting for significant clinical predictors. Results: Over the study period, 135 patients were intubated by the CCTT. Sixty percent of these patients were neonates, and 40% were pediatric. The overall FPS rate was 61%, with lower rates in neonates (54%) and higher rates in pediatric patients (70%). Use of videolaryngoscopy increased over the study period. First pass success rate using the C-MAC videolaryngoscope was 72% compared to 42% for direct laryngoscopy across the whole study population. In adjusted analyses, FPS using VL was significantly higher in the pediatric patient population (aOR 12.42 [95%CI 3.33, 46.29]), but not in neonates (aOR 1.08 [0.44, 2.63]). Use of VL increased significantly over the study period. Conclusion: We found use of a C-MAC videolaryngoscope by a critical care transport team was associated with improved FPS during endotracheal intubation of pediatric patients but not neonates, after controlling for other patient and provider characteristics. In addition to the impact on FPS, use of VL may offer additional educational and quality benefits.

A Stroke Alert Protocol Decreases the Time to Diagnosis of Brain Attack Symptoms in a Pediatric Emergency Department.

OBJECTIVE: To determine whether a stroke alert system decreases the time to diagnosis of children presenting to the emergency department (ED) with acute-onset focal neurologic deficits. STUDY DESIGN: We performed a retrospective comparison of clinical and demographic information for patients who presented to the ED of a tertiary children's hospital with acute-onset focal neurologic deficits during the 2.5 years before (n = 14) and after (n = 65) the implementation of a stroke alert system. The primary outcome was the median time to neuroimaging analyzed using a Wilcoxon rank-sum test. RESULTS: The median time from ED arrival to neuroimaging for patients with acute-onset focal neurologic deficits decreased significantly after implementation of a stroke alert system (196 minutes; IQR, 85-230 minutes before [n = 14] vs 82 minutes; IQR, 54-123 minutes after [n = 65]; P < .01). Potential intravenous tissue plasminogen activator candidates experienced the shortest time to neuroimaging after implementation of a stroke alert system (54 minutes; IQR, 34-66 minutes [n = 13] for intravenous tissue plasminogen activator candidates vs 89.5 minutes; IQR, 62-126.5 minutes [n = 52] for non-intravenous tissue plasminogen activator candidates; P < .01). CONCLUSIONS: A stroke alert system decreases the median time to diagnosis by neuroimaging of children presenting to the ED with acute-onset focal neurologic deficits by more than one-half. Such a protocol constitutes an important step in ensuring that a greater proportion of children with arterial ischemic stroke are diagnosed in a time frame that enables hyperacute treatment.

2017 American Heart Association Focused Update on Adult Basic Life Support and Cardiopulmonary Resuscitation Quality: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

Cardiopulmonary resuscitation is a lifesaving technique for victims of sudden cardiac arrest. Despite advances in resuscitation science, basic life support remains a critical factor in determining outcomes. The American Heart Association recommendations for adult basic life support incorporate the most recently published evidence and serve as the basis for education and training for laypeople and healthcare providers who perform cardiopulmonary resuscitation.

Out-of-Hospital Cardiac Arrest Resuscitation Systems of Care: A Scientific Statement From the American Heart Association.

The American Heart Association previously recommended implementation of cardiac resuscitation systems of care that consist of interconnected community, emergency medical services, and hospital efforts to measure and improve the process of care and outcome for patients with cardiac arrest. In addition, the American Heart Association proposed a national process to develop and implement evidence-based guidelines for cardiac resuscitation systems of care. Significant experience has been gained with implementing these systems, and new evidence has accumulated. This update describes recent advances in the science of cardiac resuscitation systems and evidence of their effectiveness, as well as recent progress in dissemination and implementation throughout the United States. Emphasis is placed on evidence published since the original recommendations (ie, including and since 2010).

ILCOR Scientific Knowledge Gaps and Clinical Research Priorities for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: A Consensus Statement.

Despite significant advances in the field of resuscitation science, important knowledge gaps persist. Current guidelines for resuscitation are based on the International Liaison Committee on Resuscitation 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations, which includes treatment recommendations supported by the available evidence. The writing group developed this consensus statement with the goal of focusing future research by addressing the knowledge gaps identified during and after the 2015 International Liaison Committee on Resuscitation evidence evaluation process. Key publications since the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations are referenced, along with known ongoing clinical trials that are likely to affect future guidelines.

Survey of plasma proteins in children with progeria pre-therapy and on-therapy with lonafarnib.

BackgroundHutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare, fatal, segmental premature aging syndrome caused by the aberrant lamin A protein, progerin. The protein farnesyltransferase inhibitor, lonafarnib, ameliorates some aspects of cardiovascular and bone disease.MethodsWe performed a prospective longitudinal survey of plasma proteins in 24 children with HGPS (an estimated 10% of the world's population at the time) at baseline and on lonafarnib therapy, compared with age- and gender-matched controls using a multi-analyte, microsphere-based immunofluorescent assay.ResultsThe mean levels for 23/66 (34.8%) proteins were significantly lower and 7/66 (10.6%) were significantly higher in HGPS samples compared with those in controls (P≤0.05). Six proteins whose concentrations were initially lower normalized with lonafarnib therapy: interleukins 1α, 7, and 13, beta-2 microglobulin, C-reactive protein, and myoglobin. Alpha-2 macroglobulin, a protease inhibitor associated with stroke, was elevated at baseline and subsequently normalized with lonafarnib therapy.ConclusionThis is the first study to employ a multi-analyte array platform in HGPS. Novel potential biomarkers identified in this study should be further validated by correlations with clinical disease status, especially proteins associated with cardiovascular disease and those that normalized with lonafarnib therapy.

Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome.

Importance: Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare fatal premature aging disease. There is no approved treatment. Objective: To evaluate the association of monotherapy using the protein farnesyltransferase inhibitor lonafarnib with mortality rate in children with HGPS. Design, Setting, and Participants: Cohort study comparing contemporaneous (birth date ≥1991) untreated patients with HGPS matched with treated patients by age, sex, and continent of residency using conditional Cox proportional hazards regression. Treatment cohorts included patients from 2 single-group, single-site clinical trials (ProLon1 [n = 27; completed] and ProLon2 [n = 36; ongoing]). Untreated patients originated from a separate natural history study (n = 103). The cutoff date for patient follow-up was January 1, 2018. Exposure: Treated patients received oral lonafarnib (150 mg/m2) twice daily. Untreated patients received no clinical trial medications. Main Outcomes and Measures: The primary outcome was mortality. The primary analysis compared treated patients from the first lonafarnib trial with matched untreated patients. A secondary analysis compared the combined cohorts from both lonafarnib trials with matched untreated patients. Results: Among untreated and treated patients (n = 258) from 6 continents, 123 (47.7%) were female; 141 (54.7%) had a known genotype, of which 125 (88.7%) were classic (c.1824C>T in LMNA). When identified (n = 73), the primary cause of death was heart failure (79.4%). The median treatment duration was 2.2 years. Median age at start of follow-up was 8.4 (interquartile range [IQR], 4.8-9.5) years in the first trial cohort and 6.5 (IQR, 3.7-9.0) years in the combined cohort. There was 1 death (3.7%) among 27 patients in the first trial group and there were 9 deaths (33.3%) among 27 patients in the matched untreated group. Treatment was associated with a lower mortality rate (hazard ratio, 0.12; 95% CI, 0.01-0.93; P = .04). In the combined cohort, there were 4 deaths (6.3%) among 63 patients in the treated group and 17 deaths (27.0%) among 63 patients in the matched untreated group (hazard ratio, 0.23; 95% CI, 0.06-0.90; P = .04). Conclusions and Relevance: Among patients with HGPS, lonafarnib monotherapy, compared with no treatment, was associated with a lower mortality rate after 2.2 years of follow-up. Study interpretation is limited by its observational design.

Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome.

BACKGROUND: Hutchinson-Gilford progeria syndrome is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA yielding the farnesylated aberrant protein progerin. Without progerin-specific treatment, death occurs at an average age of 14.6 years from an accelerated atherosclerosis. A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor lonafarnib ameliorates some aspects of cardiovascular and bone disease. This present trial sought to further improve disease by additionally inhibiting progerin prenylation. METHODS: Thirty-seven participants with Hutchinson-Gilford progeria syndrome received pravastatin, zoledronic acid, and lonafarnib. This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial. RESULTS: No participants withdrew because of side effects. Primary outcome success was predefined by improved per-patient rate of weight gain or carotid artery echodensity; 71.0% of participants succeeded (P<0.0001). Key cardiovascular and skeletal secondary variables were predefined. Secondary improvements included increased areal (P=0.001) and volumetric (P<0.001-0.006) bone mineral density and 1.5- to 1.8-fold increases in radial bone structure (P<0.001). Median carotid artery wall echodensity and carotid-femoral pulse wave velocity demonstrated no significant changes. Percentages of participants with carotid (5% to 50%; P=0.001) and femoral (0% to 12%; P=0.13) artery plaques and extraskeletal calcifications (34.4% to 65.6%; P=0.006) increased. Other than increased bone mineral density, no improvement rates exceeded those of the prior lonafarnib monotherapy treatment trial. CONCLUSIONS: Comparisons with lonafarnib monotherapy treatment reveal additional bone mineral density benefit but likely no added cardiovascular benefit with the addition of pravastatin and zoledronic acid. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00879034 and NCT00916747.

American Heart Association Response to the 2015 Institute of Medicine Report on Strategies to Improve Cardiac Arrest Survival.

The American Heart Association (AHA) commends the recently released Institute of Medicine (IOM) report, Strategies to Improve Cardiac Arrest Survival: A Time to Act (2015). The AHA recognizes the unique opportunity created by the report to meaningfully advance the objectives of improving outcomes for sudden cardiac arrest. For decades, the AHA has focused on the goal of reducing morbidity and mortality from cardiovascular disease though robust support of basic, translational, clinical, and population research. The AHA also has developed a rigorous process using the best available evidence to develop scientific, advisory, and guideline documents. These core activities of development and dissemination of scientific evidence have served as the foundation for a broad range of advocacy initiatives and programs that serve as a foundation for advancing the AHA and IOM goal of improving cardiac arrest outcomes. In response to the call to action in the IOM report, the AHA is announcing 4 new commitments to increase cardiac arrest survival: (1) The AHA will provide up to $5 million in funding over 5 years to incentivize resuscitation data interoperability; (2) the AHA will actively pursue philanthropic support for local and regional implementation opportunities to increase cardiac arrest survival by improving out-of-hospital and in-hospital systems of care; (3) the AHA will actively pursue philanthropic support to launch an AHA resuscitation research network; and (4) the AHA will cosponsor a National Cardiac Arrest Summit to facilitate the creation of a national cardiac arrest collaborative that will unify the field and identify common goals to improve survival. In addition to the AHA's historic and ongoing commitment to improving cardiac arrest care and outcomes, these new initiatives are responsive to each of the IOM recommendations and demonstrate the AHA's leadership in the field. However, successful implementation of the IOM recommendations will require a timely response by all stakeholders identified in the report and a coordinated approach to achieve our common goal of improved cardiac arrest outcomes.

Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome.

BACKGROUND: Hutchinson-Gilford progeria syndrome is an ultrarare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single-arm clinical trials administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications. METHODS AND RESULTS: We generated Kaplan-Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age- and sex-matched untreated cohorts, hazard ratio was 0.13 (95% confidence interval, 0.04-0.37; P<0.001) with median follow-up of 5.3 years from time of treatment initiation. There were 21 of 43 deaths in untreated versus 5 of 43 deaths among treated subjects. Treatment increased mean survival by 1.6 years. CONCLUSIONS: This study provides a robust untreated disease survival profile that can be used for comparisons now and in the future to assess changes in survival with treatments for Hutchinson-Gilford progeria syndrome. The current comparisons estimating increased survival with protein farnesylation inhibitors provide the first evidence of treatments influencing survival for this fatal disease. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique Indentifiers: NCT00425607, NCT00879034, and NCT00916747.