Intervention for critical aortic stenosis in Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare genetic premature aging disease that is historically fatal in teenage years, secondary to severe accelerated atherosclerosis. The only approved treatment is the farnesyltransferase inhibitor lonafarnib, which improves vascular structure and function, extending average untreated lifespan of 14.5 years by 4.3 years (30%). With this longer lifespan, calcific aortic stenosis (AS) was identified as an emerging critical risk factor for cardiac death in older patients. Intervention to relieve critical AS has the potential for immediate improvement in healthspan and lifespan. However, HGPS patient-device size mismatch, pervasive peripheral arterial disease, skin and bone abnormalities, and lifelong failure to thrive present unique challenges to intervention. An international group of experts in HGPS, pediatric and adult cardiology, cardiac surgery, and pediatric critical care convened to identify strategies for successful treatment. Candidate procedures were evaluated by in-depth examination of 4 cases that typify HGPS clinical pathology. Modified transcatheter aortic valve replacement (TAVR) and left ventricular Apico-Aortic Conduit (AAC) placement were deemed high risk but viable options. Two cases received TAVR and 2 received AAC post-summit. Three were successful and 1 patient died perioperatively due to cardiovascular disease severity, highlighting the importance of intervention timing and comparative risk stratification. These breakthrough interventions for treating critical aortic stenosis in HGPS patients could rewrite the current clinical perspective on disease course by greatly improving late-stage quality of life and increasing lifespan. Expanding worldwide medical and surgical competency for this ultra-rare disease through expert information-sharing could have high impact on treatment success.

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.

Recommendations for the Management of Initial and Refractory Pediatric Status Dystonicus.

Status dystonicus is the most severe form of dystonia with life-threatening complications if not treated promptly. We present consensus recommendations for the initial management of acutely worsening dystonia (including pre-status dystonicus and status dystonicus), as well as refractory status dystonicus in children. This guideline provides a stepwise approach to assessment, triage, interdisciplinary treatment, and monitoring of status dystonicus. The clinical pathways aim to: (1) facilitate timely recognition/triage of worsening dystonia, (2) standardize supportive and dystonia-directed therapies, (3) provide structure for interdisciplinary cooperation, (4) integrate advances in genomics and neuromodulation, (5) enable multicenter quality improvement and research, and (6) improve outcomes. © 2024 International Parkinson and Movement Disorder Society.

Prevention of postoperative stroke in pediatric moyamoya patients: a standardized perioperative care protocol.

OBJECTIVE: Perioperative stroke is a major complication of revascularization surgery in patients with moyamoya. Vomiting is common after neurosurgical procedures and may result in acute changes in intracranial pressure and cerebral blood flow. The authors instituted a standardized perioperative nausea and vomiting protocol for children with moyamoya undergoing indirect bypass surgery at their institution and analyzed its association with perioperative stroke. They hypothesized that instituting a standardized perioperative nausea and vomiting protocol would be associated with reduction in the number of perioperative strokes in children with moyamoya undergoing indirect bypass surgery. METHODS: The authors retrospectively reviewed consecutive cases of children and young adults with moyamoya who underwent indirect bypass surgery before and after implementation of a new perioperative nausea and vomiting protocol at a single institution. They compared the rate of strokes in the perioperative period (postoperative days 0 and 1) in the 31 months following implementation to 31 months prior to implementation using Fisher's exact test. RESULTS: The median ages pre- and postimplementation were 8.5 (IQR 4-12) years and 8.3 (IQR 5-15) years, respectively. There were no significant differences between the cohorts in disease severity or other potentially confounding factors. In the 31 months prior to initiation of the perioperative nausea and vomiting protocol, there were 5 strokes in 137 surgically treated hemispheres (3.6%). After initiation of the protocol, there were no strokes in 114 surgically treated hemispheres (p = 0.065). CONCLUSIONS: Instituting a standardized perioperative nausea and vomiting protocol was associated with reduction in perioperative strokes in children with moyamoya treated with indirect bypass surgery.

How do we detect and respond to clinical deterioration in hospitalized children? Results of the Pediatric Care BefOre Deterioration Events (CODE) survey.

Systems to detect and respond to deteriorating hospitalized children are common despite little evidence supporting best practices. Our objective was to describe systems to detect/respond to deteriorating hospitalized children at Pediatric Resuscitation Quality Collaborative (pediRES-Q) institutions. We performed a cross-sectional survey of pediRES-Q leaders. Questionnaire design utilized expert validation and cognitive interviews. Thirty centers (88%) responded. Most (93%) used ≥1 system to detect deterioration: most commonly, early warning scores (83%), watcher lists (55%), and proactive surveillance teams (31%). Most (90%) had a team to respond to deteriorating patients and the majority of teams could be activated by clinician or family concerns. Most institutions (90%) collect relevant data, including number of rapid responses (88%), arrests outside intensive care units (100%), and serious safety events (88%). In conclusion, most pediRES-Q institutions utilize systems to detect/respond to deteriorating hospitalized children. Heterogeneity exists among programs. Rigorous evaluation is needed to identify best practices.

Calcium during cardiac arrest: A systematic review.

Aim: To perform a systematic review of administration of calcium compared to no calcium during cardiac arrest. Methods: The search included Medline (PubMed), Embase, Cochrane, Web of Science, and CINAHL Plus and was conducted on September 30, 2022. The population included adults and children in any setting with cardiac arrest. The outcomes included return of spontaneous circulation, survival, survival with favourable neurologic outcome to hospital discharge and 30 days or longer, and quality of life outcome. Cochrane Risk of Bias 2 and ROBINS-I were performed to assess risk of bias for controlled and observational studies, respectively. Results: The systematic review identified 4 studies on 3 randomised controlled trials on 554 adult out-of-hospital cardiac arrest (OHCA) patients, 8 observational studies on 2,731 adult cardiac arrest patients, and 3 observational studies on 17,449 paediatric in-hospital cardiac arrest (IHCA) patients. The randomised controlled and observational studies showed that routine calcium administration during cardiac arrest did not improve the outcome of adult OHCA or IHCA or paediatric IHCA. The risk of bias for the adult trials was low for one recent trial and high for two earlier trials, with randomization as the primary source of bias. The risk of bias for the individual observational studies was assessed to be critical due to confounding. The certainty of evidence was assessed to be moderate for adult OHCA and low for adult and paediatric IHCA. Heterogeneity across studies precluded any meaningful meta-analyses. Conclusions: This systematic review found no evidence that routine calcium administration improves the outcomes of cardiac arrest in adults or children.PROSPERO Registration: CRD42022349641.

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.

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.

Community consultation in the pediatric intensive care unit for an exception from informed consent Trial: A survey of patient caregivers.

Aim: To explore perspectives of families in the pediatric intensive care unit (PICU) about an emergency interventional trial on peri-arrest bolus epinephrine for acute hypotension using Exception From Informed Consent (EFIC). Methods: We performed face-to-face interviews with families whose children were hospitalized in the PICU. A research team member provided an educational presentation about the planned trial and administered a survey with open- and closed-ended items. Analyses included descriptive statistics for quantitative data and thematic analysis for qualitative data. Results: Sixty-seven participants contributed to 60 survey responses (53 individuals and 7 families for whom 2 family members participated). Most participants answered favorably toward the planned trial: 55/58 (95%) reported that the trial seemed "somewhat" or "very important"; 52/57 (91%) felt the use of EFIC was "somewhat" or "completely acceptable"; and 43/58 (74%) said they would be "somewhat" or "very likely" to allow their child to participate. Five themes emerged supporting participation in the planned trial: 1) trust in the clinical team; 2) familiarity with the study intervention (epinephrine); 3) study protocol being similar to standard care; 4) informed consent during an emergency was not feasible; and 5) importance of research. Barriers to potential participation included requests for additional time to decide about participating and misconceptions about study elements, especially eligibility. Conclusions: Families of PICU patients generally supported plans for an emergency interventional trial using EFIC. Future inpatient EFIC studies may benefit from highlighting the themes identified here in their educational materials.

A Multimodal Approach to Training Coronavirus Disease (COVID-19) Processes Across Four Intensive Care Units.

Background: Coronavirus disease (COVID-19) required innovative training strategies for emergent aerosol generating procedures in intensive care units. This manuscript summarizes institutional operationalization of COVID-specific training, standardized across four intensive care units. Methods & Results: An interdisciplinary team collaborated with the Simulator Program and OpenPediatrics refining logistics using process maps, walkthroughs and simulation. A multimodal approach to information dissemination, high-volume team training in modified resuscitation practices and technical skill acquisition included instructional videos, training superusers, small-group simulation using a flipped classroom approach with rapid cycle deliberate practice, interactive webinars, and cognitive aids. Institutional data on application of this model are presented. Conclusion: Success was founded in interdisciplinary collaboration, resource availability and institutional buy in.

Clonal hematopoiesis is not prevalent in Hutchinson-Gilford progeria syndrome.

Clonal hematopoiesis of indeterminate potential (CHIP), defined as the presence of somatic mutations in cancer-related genes in blood cells in the absence of hematological cancer, has recently emerged as an important risk factor for several age-related conditions, especially cardiovascular disease. CHIP is strongly associated with normal aging, but its role in premature aging syndromes is unknown. Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare genetic condition driven by the accumulation of a truncated form of the lamin A protein called progerin. HGPS patients exhibit several features of accelerated aging and typically die from cardiovascular complications in their early teens. Previous studies have shown normal hematological parameters in HGPS patients, except for elevated platelets, and low levels of lamin A expression in hematopoietic cells relative to other cell types in solid tissues, but the prevalence of CHIP in HGPS remains unexplored. To investigate the potential role of CHIP in HGPS, we performed high-sensitivity targeted sequencing of CHIP-related genes in blood DNA samples from a cohort of 47 HGPS patients. As a control, the same sequencing strategy was applied to blood DNA samples from middle-aged and elderly individuals, expected to exhibit a biological age and cardiovascular risk profile similar to HGPS patients. We found that CHIP is not prevalent in HGPS patients, in marked contrast to our observations in individuals who age normally. Thus, our study unveils a major difference between HGPS and normal aging and provides conclusive evidence that CHIP is not frequent in HGPS and, therefore, is unlikely to contribute to the pathophysiology of this accelerated aging syndrome.

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.

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.

Guidance for Cardiopulmonary Resuscitation of Children With Suspected or Confirmed COVID-19.

This article aims to provide guidance to health care workers for the provision of basic and advanced life support to children and neonates with suspected or confirmed coronavirus disease 2019 (COVID-19). It aligns with the 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular care while providing strategies for reducing risk of transmission of severe acute respiratory syndrome coronavirus 2 to health care providers. Patients with suspected or confirmed COVID-19 and cardiac arrest should receive chest compressions and defibrillation, when indicated, as soon as possible. Because of the importance of ventilation during pediatric and neonatal resuscitation, oxygenation and ventilation should be prioritized. All CPR events should therefore be considered aerosol-generating procedures. Thus, personal protective equipment (PPE) appropriate for aerosol-generating procedures (including N95 respirators or an equivalent) should be donned before resuscitation, and high-efficiency particulate air filters should be used. Any personnel without appropriate PPE should be immediately excused by providers wearing appropriate PPE. Neonatal resuscitation guidance is unchanged from standard algorithms, except for specific attention to infection prevention and control. In summary, health care personnel should continue to reduce the risk of severe acute respiratory syndrome coronavirus 2 transmission through vaccination and use of appropriate PPE during pediatric resuscitations. Health care organizations should ensure the availability and appropriate use of PPE. Because delays or withheld CPR increases the risk to patients for poor clinical outcomes, children and neonates with suspected or confirmed COVID-19 should receive prompt, high-quality CPR in accordance with evidence-based guidelines.

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.