Congenital Cardiac Catheterization Risk Assessment in Infants Under 2.5kg

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O'Byrne, Nicholas S. Boscamp, Kimberlee Gauvreau, Grace R. Rahman, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5463083/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Mar, 2025 Read the published version in Pediatric Cardiology → Version 1 posted 7 You are reading this latest preprint version Abstract Background: Premature and small-for-gestational-age neonates with congenital heart disease increasingly require congenital cardiac catheterization (CCC). These patients present unique procedural and patient-specific risks that standard risk models do not fully capture. Objectives: This study aims to assess risk in infants <2.5 kg undergoing CCC, further stratifying by procedural type to better understand predictors of clinically meaningful adverse events (CMAE). Methods: Patient and Procedural data were collected on diagnostic and interventional catheterization procedures for infants <2.5 kg from the Congenital Cardiac Catheterization Project on Outcomes (C3PO) registry between 2014–2022. Cases were stratified into historical (2014–2018) and modern (2019–2022) eras and further categorized into PDA closure and ‘All Other Cases’. Multivariable logistic regression assessed associations between covariates and the risk of CMAE. Results: Analysis included 1,345 cases. In the modern era, PDA closures (n=898, 66.8%) had a lower CMAE rate at 3.6% versus 8.1% for ‘All Other Cases’ (P<0.001). Among ‘All Other Cases’ (n=447) 23% were diagnostic and 77% interventional, with CMAE rates of 7.7% and 6.4%, respectively. CMAE types varied, with PDA cases mainly experiencing respiratory events (22%) and ‘All Other Cases’ showing higher rates of access complications (27%) and arrhythmias (29%). Conclusion: Risk in infants <2.5 kg undergoing CCC is heavily dependent on procedural type and specific patient factors, highlighting the need for tailored risk assessment tools. This study, the largest to date in this population, emphasizes the importance of individualized care plans to improve outcomes. cardiac catheterization congenital heart disease small infants risk adjustment adverse events Figures Figure 1 Figure 2 Figure 3 Figure 4 Clinical Perspectives What Is Known? Infants under 2.5 kg who undergo congenital cardiac catheterization (CCC) represent a highly vulnerable population with unique procedural risks due to their low weight and physiologic vulnerability. Conventional risk models, largely developed for bigger patients and more homogenous populations, do not adequately capture the diverse risk profiles in this cohort, complicating standardized risk adjustment and outcome comparisons across institutions. As a result, clinicians face challenges in predicting and mitigating procedural risks in these patients. What Is New? This study, the largest of its kind to date for this population, provides a detailed, multicenter analysis of risk factors for CCC in infants under 2.5 kg, highlighting that procedural type, particularly PDA closure, plays a significant role in determining risk. The findings reveal that risk varies significantly across procedure types and among patients with varying degrees of physiologic vulnerability. By identifying procedure-specific risk profiles, this study lays the groundwork for tailored risk assessment strategies that accurately reflect this population’s unique needs. What Is Next? To advance clinical care in this complex cohort, further research is needed to identify additional patient- and procedure-specific predictors of risk that can inform refined, individualized risk models. Developing and validating procedure-specific guidelines and risk assessment tools will enable clinicians to make more precise, data-driven decisions. Such tailored approaches could help standardize care practices, improve outcomes, and support continuous education for clinicians committed to advancing care for this vulnerable population. Introduction As the overall survival of low-weight and premature neonates has improved over time, there has been a resultant increase in the demand for congenital cardiac catheterization (CCC) in this patient population. Furthermore, the maturation of this experience has led to numerous advancements, including the development of novel devices, procedures, and therapies to improve the survival of this patient population such as patent ductus arteriosus (PDA) closure, (1,2) PDA stenting, (3-6) and right ventricular outflow tract stenting (5,7) . However, low birthweight infants remain a highly vulnerable patient population with weight less than 2 kg associated with the highest relative risk of high severity adverse events (HSAE) (8) .Notably, there was a ten-fold increase in mortality among infants less than two kilograms when compared to the other weight groups in the study. Recent analyses assessing procedural risk in CCC highlight the importance of both low weight and young age as being independent risk factors for serious adverse events (AE) (9-11) and need for high-level post-catheterization care (12) . As demand for catheterizations in small neonates rises and novel equipment and techniques continue to evolve, there is an increasing need for a contemporary understanding of CCC risk in this vulnerable population. Unlike larger and more homogeneous groups of patients, risk assessment in infants under 2.5 kg is complex, relying heavily on procedural context and individualized patient factors. These nuances highlight the need for a tailored approach to risk stratification that aligns with the unique challenges of this population. This study represents, to our knowledge, the largest cohort to date of infants under 2.5 kg undergoing CCC, offering a comprehensive, multicenter evaluation of procedural risks specific to this highly vulnerable group. Methods Data Source and Study population Data were prospectively collected via the Congenital Cardiac Catheterization Project on Outcomes (C3PO) multicenter collaborative registry. Retrospective analysis for all catheterization cases in the C3PO-Quality Improvement (C3PO-QI) and C3PO-Registry Risk Reporting (C3PO-R3) generations of the registry in patients less than 2.5 kilograms in weight between January 1, 2014, and December 31, 2022, were eligible for inclusion in the study. Data from January 1, 2018 to December 31, 2018 were excluded, as the C3PO registry transitioned between C3PO-QI and C3PO-R3, and there was incomplete data entry during this transition. Centers with complete case entry during the study period were included in the analysis to capture a range of institutional practices, reflecting real-world procedural variability and enabling a comprehensive assessment of risk factors. Institutional review board approval for this study was obtained at the sponsor site, Boston Children’s Hospital, and sought at local institutions in accordance with institutional requirements. Because of the terms of our data use agreement, patient-level data cannot be shared. Statistical methods and code will be shared on request. Study measures: With the recent proliferation of novel procedure types in the modern era such as patent ductus arteriosus (PDA) closure, PDA stenting, and right ventricular outflow tract (RVOT) stenting, this dataset was stratified into a historical cohort (January 1, 2014 to December 31, 2017) and a modern dataset (January 1, 2019 to December 31, 2022). Given the dramatic change in procedures performed over this timeframe, along with enhancements to the C3PO dataset beginning in 2019, the modern dataset was used for detailed assessment of risk to provide modern outcome reporting in this select patient population. Predictor Variables Patient characteristics collected were age, weight, sex, single ventricle status, diagnosis of any genetic syndrome (yes/no) or an associated significant non-cardiac comorbidity active at the time of the catheterization procedure (yes/no) with further specification for coagulation disorder, chronic lung disease, renal insufficiency, or other. Definitions for genetic syndrome and non-cardiac comorbidity were available in the C3PO User Manual. If there was a recent cardiac surgery or catheterization less than 90 days prior to the index catheterization, this date and the procedure type were recorded. Patient-specific procedural hemodynamic indicator variables were collected, including saturation measurements (mixed venous saturation, systemic arterial saturation), intracardiac/vascular pressure measurements (pulmonary artery pressure, systemic ventricle end-diastolic pressure), and calculated measurements (Qp:Qs ratio, indexed pulmonary vascular resistance). Additionally, pre-procedure cardiac status (PCS) (12) and pre- and post-procedural resource requirements (2019-2022), were collected. Specifically, procedural resources included the presence of an endotracheal tube, prostaglandin infusion (PGE), essential vasoactive support, and administration of inhaled nitric oxide. Using a previously developed methodology to predict the risk of clinically meaningful adverse event (CMAE) (9 - 10) based on collected hemodynamic variables, a hemodynamic vulnerability score (HDS) was calculated for all cases in which hemodynamic data was obtained. Procedural characteristics collected included whether the procedure was diagnostic only or included an intervention. All interventions performed were recorded using the nomenclature established in The International Pediatric and Congenital Cardiac Code (IPCCC) (13,14) . These procedures were matched with established case types. (10) Case types were evaluated in isolation and stratified by PREDIC 3 T case type risk categories to evaluate the association of CMAE. Outcome The historical AE severity grading system in CCC has been recently revised to best capture clinically meaningful events to be used as a clinician-driven outcome in risk-adjusted outcome reporting. As part of this process, C3PO developed severity level 3 AE tiers (in increasing severity: 3a, 3b, and 3c) for the outcome CMAE. (10) The primary outcome variable for this study was the occurrence of a CMAE, defined as a high-severity level 3 (tiers 3b & 3c), 4, or 5 event using established definitions for reporting procedural complications, in harmony with the IPCCC and consistent with C3PO reporting practices. (9-10, 13-15) The level of severity was determined by the highest severity AE at the case level. All adverse events were independently reviewed by two fellowship-trained pediatric interventional cardiologists to ensure accuracy in AE reporting among institutions. The misapplication of AE severity definitions was appropriately adjusted to ensure standardized reporting of events based on these established definitions. Statistical Analysis Using the entire cohort of infants weighing less than 2.5 kg (historical and modern datasets combined), trends over time in the volume of cases overall and by case type were assessed using line graphs and bar charts. Institutional differences in case volume and case types were also compared graphically. In the modern cohort, patient and procedure characteristics were summarized using frequencies and percentages for categorical variables and medians with interquartile ranges (IQR, 25 th and 75 th percentiles) for continuous variables. Given the large volume of PDA closure procedures and the homogenous nature of this group compared to other diagnostic and interventional procedures, summaries were stratified by PDA closure and ‘All Other Cases’. Procedural data in the ‘All Other Cases’ cohort was further categorized into common case types performed in this weight group, such as PDA stenting, pulmonary and aortic valvotomy, RVOT stenting, and ‘other’ interventional cases. In the modern cohort, rates of CMAE were calculated for patient characteristics, procedural variables, and pre-procedural resource requirements. Comparisons across patient subgroups were performed using Fisher’s exact test. Comparisons were also performed within the PDA closure and ‘All Other Cases’ subgroups separately. To provide a comparison with older children, rates of CMAE and major life-threatening AEs were also calculated for cases weighing 2.5 to <5 kg and 5 to 10 kg, stratified by PDA closure versus ‘All Other Cases’. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC). Results Temporal Trends The annual proportion of cardiac catheterizations being performed in infants less than 2.5 kg, stratified by PDA closure vs. ‘All Other Cases’, over the study period is illustrated in Figure 1 . In the historical cohort (2014 to 2017), the annual number of cases performed in infants less than 2.5 kg ranged from a low of 52 cases in 2015 to a high of 88 total cases in 2017. This increased annually in the modern dataset to 402 cases in 2022. Some of this increase mirrors the overall increase in case volume amongst C3PO centers, as more centers were added to the C3PO registry during this timeframe. However, the percentage of cases performed in infants less than 2.5kg compared to the entire registry increased in the modern dataset from a range of 1.4% to 1.9% in 2015 and 2017, respectively, to 3.7% in 2019 and, finally, to 5.5% in 2022. There has been a substantial increase in the gross number and percentage of infants less than 2.5 kg undergoing PDA closure in this patient population with only 7% (n=4) of infants <2.5kg undergoing PDA closure in 2014, rising to 57% (n=139) in 2019 and 71% (n=287) in 2022. While PDA closure cases have made up the bulk of the overall increase in case volume in this cohort, there has also been an increase in the proportion of all other individual case types. The most common types of procedures performed were diagnostic-only catheterizations, PDA dilations and/or stent, pulmonary valvotomy, RVOT stent, and aortic valvotomy. As illustrated in Figure 2 , the proportion of annual C3PO cases performed in infants weighing less than 2.5 kg showed a fluctuating trend overall. However, there was a notable increase in PDA stenting procedures and other heterogeneous interventional procedures in the registry, while diagnostic-only, RVOT stenting, pulmonary and aortic valvotomy procedures remained relatively steady. Institutional Differences The number of total cases being performed at each individual C3PO site as a proportion of each site’s total case volume for the 2019-2022 era is illustrated in Figure 3 . Individual centers performed anywhere from 0.7% to 14% of their cases on infants less than 2.5 kg with most performing between 2.5% and 8.8% of their annual cases in this cohort. This wide range in individual center practice patterns is mirrored by differences in individual center case mix within this patient group. This is illustrated in Figure 4 . In this population of patients, it is observed that some centers perform a higher proportion of PDA closures in infants less than 2.5 kg, such as Site 1 and 2, and others have a much more varied and heterogenous mix of procedures. Demographic, Clinical, and Procedural Data Patient demographic data and pre-procedure characteristics for the modern cohort and further stratified by PDA closure and ‘All Other Cases’ are listed in Table 1 . The study cohort included 1345 total cases of infants less than 2.5 kg. PDA closure patients vs. ‘All Other Cases’ tended to be older at the time of the procedure (median age in days: 30 vs. 15) and weigh less (1.2kg vs. 2.0kg). There was a high percentage of patients with non-cardiac comorbidities (40%), with chronic lung disease being the most common (24%) and predominately affecting the PDA closure group (33%) vs. ‘All Other Cases’ (5%). Only 10% of cases were performed in patients with single ventricle physiology, with nearly all those cases belonging to the ‘All Other Cases’ grouping (125 of 129 single ventricle patients). With respect to pre-procedural resources, 54% of patients arrived intubated to the catheterization laboratory and when further stratified by PDA closure vs. ‘All Other Cases’, patients arrived intubated at a rate of 61% vs. 39%, respectively. Other resource uses, such as PGE infusions and vasoactive infusions (9% and 4%, respectively), were less common, and there were very few patients on inhaled nitric oxide therapy at the time of catheterization (1%). However, ‘All Other Case’ type patients were more likely to arrive at the laboratory utilizing more adjunct resources such as prostaglandin (26% in the ‘All Other Case’ cohort, <1% in the PDA closure cohort), vasoactive infusions (10% in the all-other case cohort, 1% in the PDA closure cohort), and inhaled nitric oxide therapy (2% in the all-other case cohort, 0% in the PDA closure cohort). There was a total of 898 PDA closure procedures (67% of the total cohort) and 447 cases recorded in the ‘All Other Cases’ grouping ( Table 2 ). In the ‘All Other Cases’ grouping the majority of cases were interventional (77%) and made up of PDA stenting procedures (22%), pulmonary valvotomy (16%), RVOT stenting (6%), and other heterogenous cases (32%). Other cases are further characterized in Supplemental Table 1 and include atrial septostomy procedures and other low volume case types. Adverse Events There was a total of 154 AEs of any severity level in 11.5% of patients ( Table 3 ). There were 68 (5.1%) cases that met the primary outcome variable of CMAE (severity level 3bc/4/5). There was a higher rate of both CMAE and major life-threatening level 4/5 AEs in the ‘All Other Cases’ grouping when compared to PDA closure cases at 8.1% and 4.9% vs. 3.6% and 1.8%, respectively. There was a total of 7 deaths, of which 6 occurred in the ‘All Other Cases’ grouping and only 1 in the PDA closure group ( Supplemental Table 2 ). When further assessing CMAE types in the PDA closure population vs. ‘All Other Cases’ there were significant differences in these clinically meaningful events ( Supplemental Table 3 ). The most common CMAE event types in the PDA closure population were device embolization (n=10), new heart valve (tricuspid) regurgitation (n=6), device malposition (n=4), and hemodynamic compromise (n=3). In the ‘All Other Cases’ population, the most common CMAE events were cardiac or vascular trauma (n=11), hemodynamic compromise (n=5), and cardiac or respiratory arrest (n=5). Predictors of Adverse Events in Less than 2.5 Kilogram Infants Through univariate analysis of the entire cohort, the most important predictor variables for CMAE were the PREDIC 3 T categories and whether the procedure was a PDA closure case or not (p<0.001) ( Table 4 ). PCS performed well for discriminating physiologic vulnerability with CMAE rates of 3.3%, 5.6%, and 10.4% for categories 1-3, respectively (p=0.008). Similarly, patients with single ventricle status had higher CMAE rates in the cohort at 10.1% vs. 4.5% (p= 0.011) but only a slight difference in the ‘All Other Cases’ grouping at 10.4% vs. 7.1% (p= 0.25). There was a trend toward higher CMAE rates in patients receiving vasoactive infusions prior to the procedure, with a CMAE rate of 10.3% vs. 4.8% (p=0.068). However, after stratifying PDA closure procedures with ‘All Other Cases’, there were no statistically significant predictor variables for the primary outcome variable. Additionally, in the ‘All Other Cases’ population there was no difference in diagnostic only vs. interventional case type (CMAE 7.7% vs. 8.2%, respectively). Outcome Comparison with Larger Weight Groups Further stratification of PDA closure vs. ‘All Other Cases’ by different weight groupings above 2.5 kg revealed notable differences and trends ( Table 5 ). Both CMAE and major life-threatening level 4/5 events were observed to be higher in the larger weight categories for the PDA closure population with the highest AE rates among infants 2.5 to <5 kg vs. infants less than 2.5 kg with CMAE rates of 8.4% and 3.6%, respectively. Conversely, both the CMAE and major life-threatening AE rate for the ‘All Other Cases’ population down-trended consistently with larger weight groupings with CMAE rates of 8.1%, 6.1%, and 4.8% for weight groupings less than 2.5 kg, 2.5 to <5 kg, and 5 to <10 kg, respectively. Discussion This study utilizes a comprehensive multicenter collaborative dataset to highlight a significant increase in the volume of CCC procedures performed on infants weighing less than 2.5 kg, while also evaluating potential risk factors associated with these procedures. From constituting merely 1.4% of all C3PO cases in 2014, this figure has risen sharply to 5.5% by 2022. Overall, procedures performed in this cohort were generally safe with a CMAE rate of 5.1%, which is favorable compared to the CMAE rates of 4.2-4.5% reported for the general population of larger pediatric patients undergoing CCC. (10) Notably, the CMAE rates were higher in non-PDA closure procedures at 8.1%, compared to just 3.6% in PDA closures, with no notable differences in diagnostic vs. interventional (non-PDA closure) cases. To our knowledge, this is the first study to evaluate this population in the modern era. Risk-adjusting outcomes for infants weighing less than 2.5 kg presents distinct challenges that complicate direct institutional comparisons. Existing models, largely developed for larger and more homogeneous populations, lack the precision needed to identify risk predictors specific to this vulnerable cohort. An important finding in this study is the considerable variability in procedural volume and types of interventions across institutions, revealing the limitations of applying a uniform risk-adjustment methodology to this diverse case mix. This diversity in case types and institutional practices supports the need to evaluate outcomes based on the specific procedures performed, rather than relying on generalized risk metrics. Moving forward, it is essential to further evaluate tailored risk models that address these specific characteristics to enable equitable comparisons across institutions and to better guide individualized patient care. Further research should focus on refining and validating procedure-specific risk models to support this goal. When further evaluating PDA closure cases vs. ‘All Other Cases’ it is important to highlight the notable differences in risk among other weight populations. For instance, when comparing PDA closure procedures in infants <2.5kg, the CMAE and major life-threatening AE (level 4/5) rates were significantly elevated in the 2.5 to <5 kg group, recorded at 8.4% and 5.3% respectively. These rates surpass those observed in both the ‘All Other Cases ’cohort across similar weight divisions, revealing a trend that merits further investigation due to its unclear implications within this specific patient group. Nevertheless, within the PDA closure group, CMAE rates stabilize at 4% in infants weighing 5 to <10 kg, aligning more closely with expectations based on larger patient sizes. These differences in AE rates among PDA closure procedures could potentially be explained by differences in PDA morphology in larger patients (2.5 to <5kg) and the increased likelihood of requiring arterial access. However, further research should be done to better understand these inherent differences noted in this study. During the pre-procedural risk assessment for infants under 2.5 kg, the type of procedure—whether PDA closure or classified as 'All Other Cases'—emerges as the primary determinant of risk. The stratification of this population by procedure type allowed for a focused analysis that identified specific predictors of risk within each group, particularly given the high volume of relatively lower-risk PDA closures. This approach revealed that, once stratified by procedure type, traditional risk predictors related to individual patient or procedural characteristics exert less influence on overall risk compared with other populations. Nonetheless, tools designed to evaluate physiological vulnerability, such as the hemodynamic vulnerability score and PCS, prove valuable in assessing individual risk. For instance, patients categorized as PCS category 3, which indicates high risk, exhibited markedly higher CMAE rates—10.4% in the overall cohort, 8.5% in the PDA closure group, and 11.2% in the ‘All Other Cases’ group. Therefore, PCS remains a valuable tool for pre-procedural risk assessment, particularly for identifying patients with significant inherent hemodynamic vulnerabilities. Stratifying patient populations based on procedural risk enables us to better anticipate complications and effectively allocate resources necessary to mitigate these risks. When evaluating specific case types, certain procedures performed in this population were associated with higher CMAE rates compared to the cohort. These included PDA and RVOT stenting procedures with CMAE rates of 12.1% and 14.8%, respectively. Given the inherent risks associated with these procedures, the development of specific care plans, comprehensive pre-procedural workups, and tailored management strategies is crucial. These measures will help mitigate risks and ensure that appropriate resources are available to achieve optimal outcomes and provide the highest standard of care. Furthermore, enhancing our understanding of AEs and employing specific tools, such as the PCS tool, will not only improve outcomes in this vulnerable population but also facilitate the creation of patient-centered care plans that are precisely tailored to individual needs. To advance our knowledge and management of risks in this population, further research is necessary. This includes exploring additional patient and procedural risk factors not captured in the current dataset. Investigating new variables could reveal insights into other predictive elements that significantly enhance our ability to assess and manage risk. Given the procedural heterogeneity and variability in institutional practices, our findings advocate for developing procedure-specific guidelines that can better address the unique risks faced by infants under 2.5 kg. The ongoing development of more sophisticated risk models will support improved decision-making in clinical practice, ensuring that interventions are both safe and effective. Limitations Certain limitations should be considered when interpreting these findings. While C3PO is open to all institutions performing CCC, the registry does not include all centers performing cases, and outcomes may differ at nonparticipating centers. C3PO is also primarily based in the United States, which may limit the interpretability in international or low-resource settings. Finally, despite C3PO data audits confirming high reliability in reporting higher severity adverse events, variations in reporting less severe events could affect outcome frequency accuracy. Additionally, the relatively small number of significant CMAEs, compared to the total number of procedures studied, may hinder the detection of subtle associations between risk factors and outcomes. Conclusion This multicenter study—the largest to date on infants under 2.5 kg undergoing CCC—offers a comprehensive, modern assessment of procedural risks in this highly vulnerable population. Our findings reveal that risk factors are not solely influenced by patient size and hemodynamic status but vary significantly by procedure type. Notably, PDA closure procedures demonstrated a relatively safer profile compared to other, often more complex and heterogeneous, CCC interventions. The variability in case mix and procedural practices across institutions further emphasizes the limitations of applying a uniform risk-adjustment approach. This diversity highlights the need for developing and validating procedure-specific risk models that can precisely capture the unique characteristics of this complex cohort. By advancing tailored risk assessment tools and guidelines, we can optimize risk stratification, enhance individualized care, and ultimately improve outcomes and survival rates for infants in this high-risk population. Abbreviations adverse events (AE) Boston Children’s Hospital (BCH) Congenital Cardiac Catheterization Project on Outcomes (C3PO) Congenital Cardiac Catheterization Project on Outcomes – Quality Improvement (C3PO-QI) Congenital Cardiac Catheterization Project on Outcomes – Registry Risk Reporting (C3PO-R3) Congenital Cardiac Catheterization (CCC) Clinically Meaningful Adverse Event (CMAE) Hemodynamic Vulnerability Score (HDS) high severity adverse events (HSAE) IPCCC (International Pediatric and Congenital Cardiac Code) Pre-procedure Cardiac Status (PCS) Patent Ductus Arteriosus (PDA) Prostaglandin Infusion (PGE) Right Ventricular Outflow Tract (RVOT) Declarations Disclosures: The authors have no conflicts of interest to disclose Tweet: Multicenter C3PO study highlights unique risks for infants<2.5 kg with #CHD undergoing #cardiaccatheterization. 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Procedure-type risk categories for pediatric and congenital cardiac catheterization. Circ. Cardiovasc. Interv. 2011;4:188–194. Tables Tables 1 to 5 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Tables.docx SmallInfantsSupplementalTables.docx smallinfantscentralfigure.pdf Cite Share Download PDF Status: Published Journal Publication published 28 Mar, 2025 Read the published version in Pediatric Cardiology → Version 1 posted Editorial decision: Revision requested 06 Feb, 2025 Reviews received at journal 06 Dec, 2024 Reviewers agreed at journal 27 Nov, 2024 Reviewers invited by journal 27 Nov, 2024 Editor assigned by journal 16 Nov, 2024 Submission checks completed at journal 16 Nov, 2024 First submitted to journal 15 Nov, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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O'Byrne","email":"","orcid":"","institution":"Children's Hospital of Philadelphia","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"L.","lastName":"O'Byrne","suffix":""},{"id":386954464,"identity":"78e2d6d7-5d4e-45d3-8d42-9e102f71f022","order_by":1,"name":"Nicholas S. Boscamp","email":"","orcid":"","institution":"Boston Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Nicholas","middleName":"S.","lastName":"Boscamp","suffix":""},{"id":386954467,"identity":"a3053958-1fa0-4e24-a134-c766fbaed7c2","order_by":2,"name":"Kimberlee Gauvreau","email":"","orcid":"","institution":"Boston Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kimberlee","middleName":"","lastName":"Gauvreau","suffix":""},{"id":386954472,"identity":"dae0dead-bca9-4e1c-9ce0-4ad174e39739","order_by":3,"name":"Grace R. 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Quinn","email":"data:image/png;base64,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","orcid":"","institution":"Boston Children's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Brian","middleName":"P.","lastName":"Quinn","suffix":""}],"badges":[],"createdAt":"2024-11-15 22:38:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5463083/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5463083/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00246-025-03821-9","type":"published","date":"2025-03-28T15:57:13+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":72298956,"identity":"b6cfdc7e-795b-4f3f-8678-b7aef0fd7fb0","added_by":"auto","created_at":"2024-12-25 00:58:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":201188,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProportion of all cases in infants \u0026lt;2.5 kg, compared to annual C3PO Case Volume\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Binder21.png","url":"https://assets-eu.researchsquare.com/files/rs-5463083/v1/9c911cd1ca6e7e19e8d3ea4b.png"},{"id":72298957,"identity":"3ee68298-6d01-445f-aaf2-a3433f7c521f","added_by":"auto","created_at":"2024-12-25 00:58:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":387137,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProcedure Types in Infants \u0026lt;2.5 kg, as Proportion of C3PO Annual Case Volume\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Binder22.png","url":"https://assets-eu.researchsquare.com/files/rs-5463083/v1/fd42a65d285be017b81e8f26.png"},{"id":72299207,"identity":"e0de7673-ff42-409e-8808-22668d04e460","added_by":"auto","created_at":"2024-12-25 01:06:26","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":310646,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProportion of Overall Cases Performed in Patients \u0026lt; 2.5 kg by C3PO Site (2019-2022)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Binder23.png","url":"https://assets-eu.researchsquare.com/files/rs-5463083/v1/bddfc0c0fa23a43ef63c4964.png"},{"id":72298961,"identity":"8336e5ce-20c1-4daf-a0f2-b1966fe7d67d","added_by":"auto","created_at":"2024-12-25 00:58:26","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":680030,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCase Mix for Procedures Performed in Infants \u0026lt;2.5kg by C3PO Site\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Binder24.png","url":"https://assets-eu.researchsquare.com/files/rs-5463083/v1/cc7d028728d24c5c9c1092aa.png"},{"id":79604811,"identity":"023a6dd5-591b-4cd2-977a-de95e62573ac","added_by":"auto","created_at":"2025-03-31 16:06:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1991303,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5463083/v1/a093a351-6144-4607-a4b7-f40f1bc5c0ca.pdf"},{"id":72299206,"identity":"a7a82703-d4d0-4d57-837e-7aacb2e657c9","added_by":"auto","created_at":"2024-12-25 01:06:26","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":50948,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5463083/v1/b9389c6537e3d2e740fdaffd.docx"},{"id":72298959,"identity":"b99c1528-3ee4-48e0-bdcf-8fa6e19b3b5d","added_by":"auto","created_at":"2024-12-25 00:58:26","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":21777,"visible":true,"origin":"","legend":"","description":"","filename":"SmallInfantsSupplementalTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5463083/v1/60d99ec54f3eb92d50de6334.docx"},{"id":72298962,"identity":"ef0857e5-6440-46dc-a4ff-4403e4108f64","added_by":"auto","created_at":"2024-12-25 00:58:27","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":204861,"visible":true,"origin":"","legend":"","description":"","filename":"smallinfantscentralfigure.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5463083/v1/2ff9c5ad4cc026e4848471e1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Congenital Cardiac Catheterization Risk Assessment in Infants Under 2.5kg","fulltext":[{"header":"Clinical Perspectives","content":"\u003cp\u003e\u003cstrong\u003eWhat Is Known?\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Infants under 2.5 kg who undergo congenital cardiac catheterization (CCC) represent a highly vulnerable population with unique procedural risks due to their low weight and physiologic vulnerability. Conventional risk models, largely developed for bigger patients and more homogenous populations, do not adequately capture the diverse risk profiles in this cohort, complicating standardized risk adjustment and outcome comparisons across institutions. As a result, clinicians face challenges in predicting and mitigating procedural risks in these patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat Is New?\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;This study, the largest of its kind to date for this population, provides a detailed, multicenter analysis of risk factors for CCC in infants under 2.5 kg, highlighting that procedural type, particularly PDA closure, plays a significant role in determining risk. The findings reveal that risk varies significantly across procedure types and among patients with varying degrees of physiologic vulnerability. By identifying procedure-specific risk profiles, this study lays the groundwork for tailored risk assessment strategies that accurately reflect this population’s unique needs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat Is Next?\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;To advance clinical care in this complex cohort, further research is needed to identify additional patient- and procedure-specific predictors of risk that can inform refined, individualized risk models. Developing and validating procedure-specific guidelines and risk assessment tools will enable clinicians to make more precise, data-driven decisions. Such tailored approaches could help standardize care practices, improve outcomes, and support continuous education for clinicians committed to advancing care for this vulnerable population.\u003c/p\u003e"},{"header":"Introduction ","content":"\u003cp\u003eAs the overall survival of low-weight and premature neonates has improved over time, there has been a resultant increase in the demand for congenital cardiac catheterization (CCC) in this patient population. Furthermore, the maturation of this experience has led to numerous advancements, including the development of novel devices, procedures, and therapies to improve the survival of this patient population such as patent ductus arteriosus (PDA) closure,\u003csup\u003e\u0026nbsp;(1,2)\u0026nbsp;\u003c/sup\u003ePDA stenting, \u003csup\u003e(3-6)\u003c/sup\u003e and right ventricular outflow tract stenting\u003csup\u003e\u0026nbsp;(5,7)\u003c/sup\u003e. However, low birthweight infants remain a highly vulnerable patient population with weight less than 2 kg associated with the highest relative risk of high severity adverse events (HSAE)\u003csup\u003e\u0026nbsp;(8)\u003c/sup\u003e.Notably, there was a ten-fold increase in mortality among infants less than two kilograms when compared to the other weight groups in the study. Recent analyses assessing procedural risk in CCC highlight the importance of both low weight and young age as being independent risk factors for serious adverse events (AE)\u003csup\u003e\u0026nbsp;(9-11)\u003c/sup\u003e and need for high-level post-catheterization care \u003csup\u003e(12)\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs demand for catheterizations in small neonates rises and novel equipment and techniques continue to evolve, there is an increasing need for a contemporary understanding of CCC risk in this vulnerable population. Unlike larger and more homogeneous groups of patients, risk assessment in infants under 2.5 kg is complex, relying heavily on procedural context and individualized patient factors. These nuances highlight the need for a tailored approach to risk stratification that aligns with the unique challenges of this population. This study represents, to our knowledge, the largest cohort to date of infants under 2.5 kg undergoing CCC, offering a comprehensive, multicenter evaluation of procedural risks specific to this highly vulnerable group.\u003c/p\u003e"},{"header":"Methods ","content":"\u003cp\u003e\u003cem\u003eData Source and Study population\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eData were prospectively collected via the Congenital Cardiac Catheterization Project on Outcomes (C3PO) multicenter collaborative registry. Retrospective analysis for all catheterization cases in the C3PO-Quality Improvement (C3PO-QI) and C3PO-Registry Risk Reporting (C3PO-R3) generations of the registry in patients less than 2.5 kilograms in weight between January 1, 2014, and December 31, 2022, were eligible for inclusion in the study. Data from January 1, 2018 to December 31, 2018 were excluded, as the C3PO registry transitioned between C3PO-QI and C3PO-R3, and there was incomplete data entry during this transition. Centers with complete case entry during the study period were included in the analysis to capture a range of institutional practices, reflecting real-world procedural variability and enabling a comprehensive assessment of risk factors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInstitutional review board approval for this study was obtained at the sponsor site, Boston Children’s Hospital, and sought at local institutions in accordance with institutional requirements. Because of the terms of our data use agreement, patient-level data cannot be shared. Statistical methods and code will be shared on request. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy measures:\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWith the recent proliferation of novel procedure types in the modern era such as patent ductus arteriosus (PDA) closure, PDA stenting, and right ventricular outflow tract (RVOT) stenting, this dataset was stratified into a historical cohort (January 1, 2014 to December 31, 2017) and a modern dataset (January 1, 2019 to December 31, 2022). Given the dramatic change in procedures performed over this timeframe, along with enhancements to the C3PO dataset beginning in 2019, the modern dataset was used for detailed assessment of risk to provide modern outcome reporting in this select patient population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePredictor Variables\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatient characteristics collected were age, weight, sex, single ventricle status, diagnosis of any genetic syndrome (yes/no) or an associated significant non-cardiac comorbidity active at the time of the catheterization procedure (yes/no) with further specification for coagulation disorder, chronic lung disease, renal insufficiency, or other. Definitions for genetic syndrome and non-cardiac comorbidity were available in the C3PO User Manual. If there was a recent cardiac surgery or catheterization less than 90 days prior to the index catheterization, this date and the procedure type were recorded. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatient-specific procedural hemodynamic indicator variables were collected, including saturation measurements (mixed venous saturation, systemic arterial saturation), intracardiac/vascular pressure measurements (pulmonary artery pressure, systemic ventricle end-diastolic pressure), and calculated measurements (Qp:Qs ratio, indexed pulmonary vascular resistance). Additionally, pre-procedure cardiac status (PCS)\u003csup\u003e\u0026nbsp;(12)\u003c/sup\u003e and pre- and post-procedural resource requirements (2019-2022), were collected. Specifically, procedural resources included the presence of an endotracheal tube, prostaglandin infusion (PGE), essential vasoactive support, and administration of inhaled nitric oxide. Using a previously developed methodology to predict the risk of clinically meaningful adverse event (CMAE)\u003csup\u003e\u0026nbsp;(9 - 10)\u0026nbsp;\u003c/sup\u003ebased on collected hemodynamic variables, a hemodynamic vulnerability score (HDS) was calculated for all cases in which hemodynamic data was obtained.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eProcedural characteristics collected included whether the procedure was diagnostic only or included an intervention. \u0026nbsp;All interventions performed were recorded using the nomenclature established in The International Pediatric and Congenital Cardiac Code (IPCCC) \u003csup\u003e(13,14)\u003c/sup\u003e. These procedures were matched with established case types.\u003csup\u003e(10)\u003c/sup\u003e Case types were evaluated in isolation and stratified by PREDIC\u003csup\u003e3\u003c/sup\u003eT case type risk categories to evaluate the association of CMAE.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eOutcome\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe historical AE severity grading system in CCC has been recently revised to best capture clinically meaningful events to be used as a clinician-driven outcome in risk-adjusted outcome reporting. As part of this process, C3PO developed severity level 3 AE tiers (in increasing severity: 3a, 3b, and 3c) for the outcome CMAE.\u003csup\u003e\u0026nbsp;(10)\u003c/sup\u003e The primary outcome variable for this study was the occurrence of a CMAE, defined as a high-severity level 3 (tiers 3b \u0026amp; 3c), 4, or 5 event using established definitions for reporting procedural complications, in harmony with the IPCCC and consistent with C3PO reporting practices.\u003csup\u003e\u0026nbsp;(9-10, 13-15)\u003c/sup\u003e The level of severity was determined by the highest severity AE at the case level.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll adverse events were independently reviewed by two fellowship-trained pediatric interventional cardiologists to ensure accuracy in AE reporting among institutions. The misapplication of AE severity definitions was appropriately adjusted to ensure standardized reporting of events based on these established definitions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical Analysis\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUsing the entire cohort of infants weighing less than 2.5 kg (historical and modern datasets combined), trends over time in the volume of cases overall and by case type were assessed using line graphs and bar charts. Institutional differences in case volume and case types were also compared graphically. \u0026nbsp;In the modern cohort, patient and procedure characteristics were summarized using frequencies and percentages for categorical variables and medians with interquartile ranges (IQR, 25\u003csup\u003eth\u003c/sup\u003e and 75\u003csup\u003eth\u003c/sup\u003e percentiles) for continuous variables. Given the large volume of PDA closure procedures and the homogenous nature of this group compared to other diagnostic and interventional procedures, summaries were stratified \u0026nbsp;by PDA closure and ‘All Other Cases’. Procedural data in the ‘All Other Cases’ cohort was further categorized into common case types performed in this weight group, such as PDA stenting, pulmonary and aortic valvotomy, RVOT stenting, and ‘other’ interventional cases. \u0026nbsp;In the modern cohort, rates of CMAE were calculated for patient characteristics, procedural variables, and pre-procedural resource requirements. Comparisons across patient subgroups were performed using Fisher’s exact test. Comparisons were also performed within the PDA closure and ‘All Other Cases’ subgroups separately. To provide a comparison with older children, rates of CMAE and major life-threatening AEs were also calculated for cases weighing 2.5 to \u0026lt;5 kg and 5 to 10 kg, stratified by PDA closure versus ‘All Other Cases’. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003eTemporal Trends\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe annual proportion of cardiac catheterizations being performed in infants less than 2.5 kg, stratified by PDA closure vs. ‘All Other Cases’, over the study period is illustrated in\u0026nbsp;\u003cstrong\u003eFigure 1\u003c/strong\u003e. In the historical cohort (2014 to 2017), the annual number of cases performed in infants less than 2.5 kg ranged from a low of 52 cases in 2015 to a high of 88 total cases in 2017. This increased annually in the modern dataset to 402 cases in 2022. Some of this increase mirrors the overall increase in case volume amongst C3PO centers, as more centers were added to the C3PO registry during this timeframe. However, the percentage of cases performed in infants less than 2.5kg compared to the entire registry increased in the modern dataset from a range of 1.4% to 1.9% in 2015 and 2017, respectively, to 3.7% in 2019 and, finally, to 5.5% in 2022.\u003c/p\u003e\n\u003cp\u003eThere has been a substantial increase in the gross number and percentage of infants less than 2.5 kg undergoing PDA closure in this patient population with only 7% (n=4) of infants \u0026lt;2.5kg undergoing PDA closure in 2014, rising to 57% (n=139) in 2019 and 71% (n=287) in 2022. While PDA closure cases have made up the bulk of the overall increase in case volume in this cohort, there has also been an increase in the proportion of all other individual case types. The most common types of procedures performed were diagnostic-only catheterizations, PDA dilations and/or stent, pulmonary valvotomy, RVOT stent, and aortic valvotomy. As illustrated in\u0026nbsp;\u003cstrong\u003eFigure 2\u003c/strong\u003e, the proportion of annual C3PO cases performed in infants weighing less than 2.5 kg showed a fluctuating trend overall. However, there was a notable increase in PDA stenting procedures and other heterogeneous interventional procedures in the registry, while diagnostic-only, RVOT stenting, pulmonary and aortic valvotomy procedures remained relatively steady.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInstitutional Differences\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe number of total cases being performed at each individual C3PO site as a proportion of each site’s total case volume for the 2019-2022 era is illustrated in\u0026nbsp;\u003cstrong\u003eFigure 3\u003c/strong\u003e. Individual centers performed anywhere from 0.7% to 14% of their cases on infants less than 2.5 kg with most performing between 2.5% and 8.8% of their annual cases in this cohort.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis wide range in individual center practice patterns is mirrored by differences in individual center case mix within this patient group. This is illustrated in\u0026nbsp;\u003cstrong\u003eFigure 4\u003c/strong\u003e. In this population of patients, it is observed that some centers perform a higher proportion of PDA closures in infants less than 2.5 kg, such as Site 1 and 2, and others have a much more varied and heterogenous mix of procedures.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDemographic, Clinical, and Procedural Data\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatient demographic data and pre-procedure characteristics for the modern cohort and further stratified by PDA closure and ‘All Other Cases’ are listed in\u0026nbsp;\u003cstrong\u003eTable 1\u003c/strong\u003e. The study cohort included 1345 total cases of infants less than 2.5 kg. PDA closure patients vs. ‘All Other Cases’ tended to be older at the time of the procedure (median age in days: 30 vs. 15) and weigh less (1.2kg vs. 2.0kg). There was a high percentage of patients with non-cardiac comorbidities (40%), with chronic lung disease being the most common (24%) and predominately affecting the PDA closure group (33%) vs. ‘All Other Cases’ (5%). Only 10% of cases were performed in patients with single ventricle physiology, with nearly all those cases belonging to the ‘All Other Cases’ grouping (125 of 129 single ventricle patients).\u003c/p\u003e\n\u003cp\u003eWith respect to pre-procedural resources, 54% of patients arrived intubated to the catheterization laboratory and when further stratified by PDA closure vs. ‘All Other Cases’, patients arrived intubated at a rate of 61% vs. 39%, respectively. Other resource uses, such as PGE infusions and vasoactive infusions (9% and 4%, respectively), were less common, and there were very few patients on inhaled nitric oxide therapy at the time of catheterization (1%). However, ‘All Other Case’ type patients were more likely to arrive at the laboratory utilizing more adjunct resources such as prostaglandin (26% in the ‘All Other Case’ cohort, \u0026lt;1% in the PDA closure cohort), vasoactive infusions (10% in the all-other case cohort, 1% in the PDA closure cohort), and inhaled nitric oxide therapy (2% in the all-other case cohort, 0% in the PDA closure cohort).\u003c/p\u003e\n\u003cp\u003eThere was a total of 898 PDA closure procedures (67% of the total cohort) and 447 cases recorded in the ‘All Other Cases’ grouping (\u003cstrong\u003eTable 2\u003c/strong\u003e). In the ‘All Other Cases’ grouping the majority of cases were interventional (77%) and made up of PDA stenting procedures (22%), pulmonary valvotomy (16%), RVOT stenting (6%), and other heterogenous cases (32%). Other cases are further characterized in\u0026nbsp;\u003cstrong\u003eSupplemental Table 1\u003c/strong\u003e and include atrial septostomy procedures and other low volume case types.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAdverse Events\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThere was a total of 154 AEs of any severity level in 11.5% of patients (\u003cstrong\u003eTable 3\u003c/strong\u003e). There were 68 (5.1%) cases that met the primary outcome variable of CMAE (severity level 3bc/4/5). There was a higher rate of both CMAE and major life-threatening level 4/5 AEs in the ‘All Other Cases’ grouping when compared to PDA closure cases at 8.1% and 4.9% vs. 3.6% and 1.8%, respectively. There was a total of 7 deaths, of which 6 occurred in the ‘All Other Cases’ grouping and only 1 in the PDA closure group (\u003cstrong\u003eSupplemental Table 2\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhen further assessing CMAE types in the PDA closure population vs. ‘All Other Cases’ there were significant differences in these clinically meaningful events (\u003cstrong\u003eSupplemental Table 3\u003c/strong\u003e). The most common CMAE event types in the PDA closure population were device embolization (n=10), new heart valve (tricuspid) regurgitation (n=6), device malposition (n=4), and hemodynamic compromise (n=3). In the ‘All Other Cases’ population, the most common CMAE events were cardiac or vascular trauma (n=11), hemodynamic compromise (n=5), and cardiac or respiratory arrest (n=5).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePredictors of Adverse Events in Less than 2.5 Kilogram Infants\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThrough univariate analysis of the entire cohort, the most important predictor variables for CMAE were the PREDIC\u003csup\u003e3\u003c/sup\u003eT categories and whether the procedure was a PDA closure case or not (p\u0026lt;0.001)\u0026nbsp;(\u003cstrong\u003eTable 4\u003c/strong\u003e). PCS performed well for discriminating physiologic vulnerability with CMAE rates of 3.3%, 5.6%, and 10.4% for categories 1-3, respectively (p=0.008). Similarly, patients with single ventricle status had higher CMAE rates in the cohort at 10.1% vs. 4.5% (p= 0.011) but only a slight difference in the ‘All Other Cases’ grouping at 10.4% vs. 7.1% (p= 0.25). There was a trend toward higher CMAE rates in patients receiving vasoactive infusions prior to the procedure, with a CMAE rate of 10.3% vs. 4.8% (p=0.068). However, after stratifying PDA closure procedures with ‘All Other Cases’, there were no statistically significant predictor variables for the primary outcome variable. Additionally, in the ‘All Other Cases’ population there was no difference in diagnostic only vs. interventional case type (CMAE 7.7% vs. 8.2%, respectively).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eOutcome Comparison with Larger Weight Groups\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFurther stratification of PDA closure vs. ‘All Other Cases’ by different weight groupings above 2.5 kg revealed notable differences and trends (\u003cstrong\u003eTable 5\u003c/strong\u003e). Both CMAE and major life-threatening level 4/5 events were observed to be higher in the larger weight categories for the PDA closure population with the highest AE rates among infants 2.5 to \u0026lt;5 kg vs. infants less than 2.5 kg with CMAE rates of 8.4% and 3.6%, respectively. Conversely, both the CMAE and major life-threatening AE rate for the ‘All Other Cases’ population down-trended consistently with larger weight groupings with CMAE rates of 8.1%, 6.1%, and 4.8% for weight groupings less than 2.5 kg, 2.5 to \u0026lt;5 kg, and 5 to \u0026lt;10 kg, respectively.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study utilizes a comprehensive multicenter collaborative dataset to highlight a significant increase in the volume of CCC procedures performed on infants weighing less than 2.5 kg, while also evaluating potential risk factors associated with these procedures. From constituting merely 1.4% of all C3PO cases in 2014, this figure has risen sharply to 5.5% by 2022. Overall, procedures performed in this cohort were generally safe with a CMAE rate of 5.1%, which is favorable compared to the CMAE rates of 4.2-4.5% reported for the general population of larger pediatric patients undergoing CCC.\u003csup\u003e(10)\u003c/sup\u003e Notably, the CMAE rates were higher in non-PDA closure procedures at 8.1%, compared to just 3.6% in PDA closures, with no notable differences in diagnostic vs. interventional (non-PDA closure) cases. To our knowledge, this is the first study to evaluate this population in the modern era.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRisk-adjusting outcomes for infants weighing less than 2.5 kg presents distinct challenges that complicate direct institutional comparisons. Existing models, largely developed for larger and more homogeneous populations, lack the precision needed to identify risk predictors specific to this vulnerable cohort. An important finding in this study is the considerable variability in procedural volume and types of interventions across institutions, revealing the limitations of applying a uniform risk-adjustment methodology to this diverse case mix. This diversity in case types and institutional practices supports the need to evaluate outcomes based on the specific procedures performed, rather than relying on generalized risk metrics. Moving forward, it is essential to further evaluate tailored risk models that address these specific characteristics to enable equitable comparisons across institutions and to better guide individualized patient care. Further research should focus on refining and validating procedure-specific risk models to support this goal.\u003c/p\u003e\n\u003cp\u003eWhen further evaluating PDA closure cases vs. \u0026lsquo;All Other Cases\u0026rsquo; it is important to highlight the notable differences in risk among other weight populations. For instance, when comparing PDA closure procedures in infants \u0026lt;2.5kg, the CMAE and major life-threatening AE (level 4/5) rates were significantly elevated in the 2.5 to \u0026lt;5 kg group, recorded at 8.4% and 5.3% respectively. These rates surpass those observed in both the \u0026lsquo;All Other Cases \u0026rsquo;cohort across similar weight divisions, revealing a trend that merits further investigation due to its unclear implications within this specific patient group. Nevertheless, within the PDA closure group, CMAE rates stabilize at 4% in infants weighing 5 to \u0026lt;10 kg, aligning more closely with expectations based on larger patient sizes. These differences in AE rates among PDA closure procedures could potentially be explained by differences in PDA morphology in larger patients (2.5 to \u0026lt;5kg) and the increased likelihood of requiring arterial access. However, further research should be done to better understand these inherent differences noted in this study.\u003c/p\u003e\n\u003cp\u003eDuring the pre-procedural risk assessment for infants under 2.5 kg, the type of procedure\u0026mdash;whether PDA closure or classified as \u0026apos;All Other Cases\u0026apos;\u0026mdash;emerges as the primary determinant of risk. The stratification of this population by procedure type allowed for a focused analysis that identified specific predictors of risk within each group, particularly given the high volume of relatively lower-risk PDA closures. This approach revealed that, once stratified by procedure type, traditional risk predictors related to individual patient or procedural characteristics exert less influence on overall risk compared with other populations. Nonetheless, tools designed to evaluate physiological vulnerability, such as the hemodynamic vulnerability score and PCS, prove valuable in assessing individual risk. For instance, patients categorized as PCS category 3, which indicates high risk, exhibited markedly higher CMAE rates\u0026mdash;10.4% in the overall cohort, 8.5% in the PDA closure group, and 11.2% in the \u0026lsquo;All Other Cases\u0026rsquo; group. Therefore, PCS remains a valuable tool for pre-procedural risk assessment, particularly for identifying patients with significant inherent hemodynamic vulnerabilities.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStratifying patient populations based on procedural risk enables us to better anticipate complications and effectively allocate resources necessary to mitigate these risks. When evaluating specific case types, certain procedures performed in this population were associated with higher CMAE rates compared to the cohort. These included PDA and RVOT stenting procedures with CMAE rates of 12.1% and 14.8%, respectively. Given the inherent risks associated with these procedures, the development of specific care plans, comprehensive pre-procedural workups, and tailored management strategies is crucial. These measures will help mitigate risks and ensure that appropriate resources are available to achieve optimal outcomes and provide the highest standard of care. Furthermore, enhancing our understanding of AEs and employing specific tools, such as the PCS tool, will not only improve outcomes in this vulnerable population but also facilitate the creation of patient-centered care plans that are precisely tailored to individual needs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo advance our knowledge and management of risks in this population, further research is necessary. This includes exploring additional patient and procedural risk factors not captured in the current dataset. Investigating new variables could reveal insights into other predictive elements that significantly enhance our ability to assess and manage risk. Given the procedural heterogeneity and variability in institutional practices, our findings advocate for developing procedure-specific guidelines that can better address the unique risks faced by infants under 2.5 kg. The ongoing development of more sophisticated risk models will support improved decision-making in clinical practice, ensuring that interventions are both safe and effective.\u003c/p\u003e\n\u003ch2\u003eLimitations\u003c/h2\u003e\n\u003cp\u003eCertain limitations should be considered when interpreting these findings. While C3PO is open to all institutions performing CCC, the registry does not include all centers performing cases, and outcomes may differ at nonparticipating centers. C3PO is also primarily based in the United States, which may limit the interpretability in international or low-resource settings.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFinally, despite C3PO data audits confirming high reliability in reporting higher severity adverse events, variations in reporting less severe events could affect outcome frequency accuracy. Additionally, the relatively small number of significant CMAEs, compared to the total number of procedures studied, may hinder the detection of subtle associations between risk factors and outcomes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis multicenter study—the largest to date on infants under 2.5 kg undergoing CCC—offers a comprehensive, modern assessment of procedural risks in this highly vulnerable population. Our findings reveal that risk factors are not solely influenced by patient size and hemodynamic status but vary significantly by procedure type. Notably, PDA closure procedures demonstrated a relatively safer profile compared to other, often more complex and heterogeneous, CCC interventions. The variability in case mix and procedural practices across institutions further emphasizes the limitations of applying a uniform risk-adjustment approach. This diversity highlights the need for developing and validating procedure-specific risk models that can precisely capture the unique characteristics of this complex cohort. By advancing tailored risk assessment tools and guidelines, we can optimize risk stratification, enhance individualized care, and ultimately improve outcomes and survival rates for infants in this high-risk population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul\u003e\n \u003cli\u003eadverse events (AE)\u003c/li\u003e\n \u003cli\u003eBoston Children\u0026rsquo;s Hospital (BCH)\u003c/li\u003e\n \u003cli\u003eCongenital Cardiac Catheterization Project on Outcomes (C3PO)\u003c/li\u003e\n \u003cli\u003eCongenital Cardiac Catheterization Project on Outcomes \u0026ndash; Quality Improvement (C3PO-QI)\u003c/li\u003e\n \u003cli\u003eCongenital Cardiac Catheterization Project on Outcomes \u0026ndash; Registry Risk Reporting (C3PO-R3)\u003c/li\u003e\n \u003cli\u003eCongenital Cardiac Catheterization (CCC)\u003c/li\u003e\n \u003cli\u003eClinically Meaningful Adverse Event (CMAE)\u003c/li\u003e\n \u003cli\u003eHemodynamic Vulnerability Score (HDS)\u003c/li\u003e\n \u003cli\u003ehigh severity adverse events (HSAE)\u003c/li\u003e\n \u003cli\u003eIPCCC (International Pediatric and Congenital Cardiac Code)\u003c/li\u003e\n \u003cli\u003ePre-procedure Cardiac Status (PCS)\u003c/li\u003e\n \u003cli\u003ePatent Ductus Arteriosus (PDA)\u003c/li\u003e\n \u003cli\u003eProstaglandin Infusion (PGE)\u003c/li\u003e\n \u003cli\u003eRight Ventricular Outflow Tract (RVOT)\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cu\u003eDisclosures:\u003c/u\u003e\u003c/strong\u003e The authors have no conflicts of interest to disclose\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eTweet:\u003c/u\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eMulticenter C3PO study highlights unique risks for infants\u0026lt;2.5 kg with #CHD undergoing #cardiaccatheterization. Data reveal procedure-specific risk \u0026amp; emphasize need for tailored care plans to improve outcomes. #Pediatriccardiology\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSathanandam SK, Gutfinger D, O\u0026rsquo;Brien L, et al. Amplatzer Piccolo Occluder clinical trial for percutaneous closure of the patent ductus arteriosus in patients \u0026ge;700 grams. Catheter. Cardiovasc. Interv. 2020;96:1266\u0026ndash;1276.\u003c/li\u003e\n \u003cli\u003eBackes CH, Cheatham SL, Deyo GM, et al. Percutaneous patent ductus arteriosus (PDA) closure in very preterm infants: Feasibility and complications. J. Am. Heart Assoc.\u0026nbsp;2016;5:1\u0026ndash;10.\u003c/li\u003e\n \u003cli\u003eSantoro G, Gaio G, Castaldi B, et al. Arterial duct stenting in low-weight newborns with duct dependent pulmonary circulation. Catheter. Cardiovasc.\u0026nbsp;Interv. 2011;78:677\u0026ndash;685.\u003c/li\u003e\n \u003cli\u003eGlatz AC, Petit CJ, Goldstein BH, et al. Comparison between Patent Ductus Arteriosus Stent and Modified Blalock-Taussig Shunt as Palliation for Infants with Ductal-Dependent Pulmonary Blood Flow: Insights from the Congenital Catheterization Research Collaborative. Circulation\u0026nbsp;2018;137:589\u0026ndash;601.\u003c/li\u003e\n \u003cli\u003eQureshi AM, Caldarone CA, Romano JC, et al. Comparison of management strategies for neonates with symptomatic tetralogy of Fallot and weight \u0026lt;2.5 kg. J. Thorac. Cardiovasc. Surg.2022;163:192-207.e3.\u003c/li\u003e\n \u003cli\u003eBentham JR,\u0026nbsp;Zava NK, Harrison WJ, et al. Duct Stenting Versus Modified Blalock-Taussig Shunt in Neonates with Duct-Dependent Pulmonary Blood Flow: Associations with Clinical Outcomes in a Multicenter National Study. Circulation 2018;137:581\u0026ndash;588.\u003c/li\u003e\n \u003cli\u003eSandoval JP, Chaturvedi RR, Benson L, et al. Right ventricular outflow tract stenting in tetralogy of fallot infants with risk factors for early primary repair. Circ. Cardiovasc. Interv. 2016;9:1\u0026ndash;10.\u003c/li\u003e\n \u003cli\u003eBackes CH, Cua C, Kreutzer J, et al. Low weight as an independent risk factor for adverse events during cardiac catheterization of infants. Catheter. Cardiovasc. Interv. 2013;82:786\u0026ndash;794.\u003c/li\u003e\n \u003cli\u003eQuinn BP, Yeh M, Gauvreau K, et al. Procedural Risk in Congenital Cardiac Catheterization (PREDIC3T). J. Am. Heart Assoc.\u0026nbsp;2022;11:1\u0026ndash;12.\u003c/li\u003e\n \u003cli\u003eQuinn, B. P., Gunnelson, L. C., Kotin, S. G., Gauvreau, K., Yeh, M. J., Hasan, B., Lozier, J., Barry, O. M., Shahanavaz, S.,\u0026nbsp;Batlivala, S. P., Salavitabar, A., Foerster, S., Goldstein, B., Divekar, A., Holzer, R., Nicholson, G. T., O\u0026apos;Byrne, M. L., Whiteside, W., \u0026amp; Bergersen, L. (2024). Catheterization for Congenital Heart Disease Adjustment for Risk Method II. Circulation. Cardiovascular interventions, 17(3), e012834.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNykanen, D. G., Forbes, T. J., Du, W., Divekar, A. A., Reeves, J. H., Hagler, D. J., Fagan, T. E., Pedra, C. A., Fleming, G. A., Khan, D. M., Javois, A. J., Gruenstein, D. H., Qureshi, S. A., Moore, P. M., Wax, D. H., \u0026amp; Congenital Cardiac Interventional Study Consortium (CCISC) (2016). CRISP: Catheterization RISk score for Pediatrics: A Report from the Congenital Cardiac Interventional Study Consortium (CCISC). \u003cem\u003eCatheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography \u0026amp; Interventions\u003c/em\u003e, \u003cem\u003e87\u003c/em\u003e(2), 302\u0026ndash;309.\u003c/li\u003e\n \u003cli\u003eQuinn BP, Shirley LC, Yeh MJ, Gauvreau K, Ibla JC, Kotin SG, Porras D, Bergersen LJ. ICU Admission Tool for Congenital Heart Catheterization (iCATCH): A Predictive Model for High Level Post-Catheterization Care and Patient Management. Pediatr Crit Care Med. 2022 Oct 1;23(10):822-830.\u003c/li\u003e\n \u003cli\u003eBergersen L, Everett AD, Giroud JM, et al. Report from the international society for\u0026nbsp;\u0026nbsp;nomenclature of paediatric and congenital heart disease: Cardiovascular catheterisation for congenital and paediatric cardiac disease (Part 1 - Procedural nomenclature). Cardiol. Young 2011;21:252\u0026ndash;259.\u003c/li\u003e\n \u003cli\u003eBergersen L, Giroud JM, Jacobs JP, et al. Report from the international society for nomenclature of\u0026nbsp;paediatric and congenital heart disease: Cardiovascular catheterisation for congenital and paediatric cardiac disease (Part 2 - Nomenclature of complications associated with interventional cardiolo. Cardiol. Young 2011;21:260\u0026ndash;265.\u003c/li\u003e\n \u003cli\u003eBergersen L, Gauvreau K, Marshall A, et al. Procedure-type risk categories for pediatric and congenital cardiac catheterization. Circ. Cardiovasc. Interv. 2011;4:188\u0026ndash;194.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 5 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-cardiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pedc","sideBox":"Learn more about [Pediatric Cardiology](http://link.springer.com/journal/246)","snPcode":"246","submissionUrl":"https://submission.nature.com/new-submission/246/3","title":"Pediatric Cardiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"cardiac catheterization, congenital heart disease, small infants, risk adjustment, adverse events","lastPublishedDoi":"10.21203/rs.3.rs-5463083/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5463083/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Premature and small-for-gestational-age neonates with congenital heart disease increasingly require congenital cardiac catheterization (CCC). These patients present unique procedural and patient-specific risks that standard risk models do not fully capture.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives:\u003c/strong\u003e This study aims to assess risk in infants \u0026lt;2.5 kg undergoing CCC, further stratifying by procedural type to better understand predictors of clinically meaningful adverse events (CMAE).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Patient and Procedural data were collected on diagnostic and interventional catheterization procedures for infants \u0026lt;2.5 kg from the Congenital Cardiac Catheterization Project on Outcomes (C3PO) registry between 2014–2022. Cases were stratified into historical (2014–2018) and modern (2019–2022) eras and further categorized into PDA closure and ‘All Other Cases’. Multivariable logistic regression assessed associations between covariates and the risk of CMAE.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Analysis included 1,345 cases. In the modern era, PDA closures (n=898, 66.8%) had a lower CMAE rate at 3.6% versus 8.1% for ‘All Other Cases’ (P\u0026lt;0.001). Among ‘All Other Cases’ (n=447) 23% were diagnostic and 77% interventional, with CMAE rates of 7.7% and 6.4%, respectively. CMAE types varied, with PDA cases mainly experiencing respiratory events (22%) and ‘All Other Cases’ showing higher rates of access complications (27%) and arrhythmias (29%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Risk in infants \u0026lt;2.5 kg undergoing CCC is heavily dependent on procedural type and specific patient factors, highlighting the need for tailored risk assessment tools. This study, the largest to date in this population, emphasizes the importance of individualized care plans to improve outcomes.\u003c/p\u003e","manuscriptTitle":"Congenital Cardiac Catheterization Risk Assessment in Infants Under 2.5kg","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-25 00:58:22","doi":"10.21203/rs.3.rs-5463083/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-02-06T15:56:50+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-06T05:34:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"128257754745486825486060622529537299879","date":"2024-11-27T21:33:30+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-27T18:16:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-16T06:11:34+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-16T06:10:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Cardiology","date":"2024-11-15T22:25:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-cardiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pedc","sideBox":"Learn more about [Pediatric Cardiology](http://link.springer.com/journal/246)","snPcode":"246","submissionUrl":"https://submission.nature.com/new-submission/246/3","title":"Pediatric Cardiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"1922db7b-faad-4796-8f17-776cf5b208dc","owner":[],"postedDate":"December 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-03-31T15:59:41+00:00","versionOfRecord":{"articleIdentity":"rs-5463083","link":"https://doi.org/10.1007/s00246-025-03821-9","journal":{"identity":"pediatric-cardiology","isVorOnly":false,"title":"Pediatric Cardiology"},"publishedOn":"2025-03-28 15:57:13","publishedOnDateReadable":"March 28th, 2025"},"versionCreatedAt":"2024-12-25 00:58:22","video":"","vorDoi":"10.1007/s00246-025-03821-9","vorDoiUrl":"https://doi.org/10.1007/s00246-025-03821-9","workflowStages":[]},"version":"v1","identity":"rs-5463083","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5463083","identity":"rs-5463083","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}