Team-based care with early recognition and treatment of cardiac dysfunction for infants with CDH

Team-based care with early recognition and treatment of cardiac dysfunction for infants with CDH | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Team-based care with early recognition and treatment of cardiac dysfunction for infants with CDH Patrick Sloan, Lila Sanning, Caren Liviskie, Kristen Clark, Kylie Bushroe, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9216925/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 9 You are reading this latest preprint version Abstract Objective Identify how a core congenital diaphragmatic hernia (CDH) team coupled with early recognition and treatment of cardiac dysfunction changed outcomes for infants with CDH. Methods A retrospective chart review compared a historical cohort from 2015–2019 (n = 51) with a post-guideline cohort from 2020–2025 (n = 53). Statistical analysis was performed with Fisher’s exact, unpaired t-test, and Mann Whitney U-test. Results Survival improved from 68.6% to 88.7% ( p = 0.016) and ECMO utilization decreased, 51.0% to 26.4% ( p = 0.015). Infants with cardiac dysfunction had increased survival (47.3% vs. 81.8%, p = 0.014) and less ECMO utilization (68.4% vs. 36.3%, p = 0.043). Vasoactive choices evolved with dopamine replaced by norepinephrine, low-dose epinephrine, or calcium gluconate. Inhaled nitric oxide (iNO) use in the first 48 hours decreased significantly while prostaglandin E1 (PGE1) use increased. Discussion We implemented a core CDH team focused on a generalizable, physiology-driven approach to identify and treat cardiac dysfunction using standard neonatal echocardiography to improve outcomes. Health sciences/Health care/Paediatrics Biological sciences/Physiology/Cardiovascular biology Health sciences/Diseases/Gastrointestinal diseases Figures Figure 1 Figure 2 Figure 3 Introduction Congenital diaphragmatic hernia (CDH) is a congenital anomaly that occurs in approximately 1 in 3000 live births and carries significant cardiorespiratory morbidity and mortality. The etiology of cardiorespiratory failure in CDH is multifactorial, impacted by pulmonary hypoplasia 1 , pulmonary hypertension 2 , 3 , 4 , 5 , and cardiac dysfunction 6 , 7 , 8 , 9 . Extracorporeal membrane oxygenation (ECMO) utilization remains at nearly 30% for infants with CDH, with ECMO survival of 50% 10 . While national survival from large cohort studies has remained stable (70–75%), some individual centers have implemented comprehensive CDH care guidelines with reported improvement in survival to as high as 85% 10, 11, 12, 13, 14, 15 . Areas of controversy in the care of infants with CDH include the role of iNO 16 , timing of echocardiogram 13 , and the appropriate choice of vasoactive medications in managing systemic and pulmonary vascular resistance 17 . The benefit of conventional treatment with iNO in infants with CDH continues to be questioned. The NINOS trial, while small and with significant methodical challenges, revealed no significant benefits of iNO use and identified an increased need for ECMO in infants with CDH 18 . In the interim, many studies that have challenged the role of iNO in infants with CDH have similarly shown an increased mortality in infants who receive iNO without clear benefit 19 , 20 . Further, there is increasing recognition of post-capillary pulmonary hypertension, driven by left atrial hypertension in the setting of left ventricular (LV) dysfunction, in addition to the historically recognized pre-capillary pulmonary arterial and arteriolar hypertension in infants with CDH 2 . Most concerningly, emerging data demonstrate that isolated LV or combined right ventricular (RV) + LV dysfunction are predictive of high mortality in infants with CDH and the need for ECMO support 21 , 22 . These studies promote the use of early diagnostic imaging, limiting the use of iNO in the setting of cardiac dysfunction, and recognizing pre-capillary and post-capillary pulmonary hypertension. To improve care for infants with CDH, we first identified factors that contribute to disparity in morbidity and mortality: inter-center variability, center volume 23 , 24 , and the presence and persistence of LV or RV + LV cardiac dysfunction 6 , 7 , 21 , 22 . The success of high volume, as well as individual high-performing centers, demonstrates that experience and focus on the complex cardiorespiratory physiology of infants with CDH may optimize outcomes. Therefore, in 2020, our center formed a dedicated CDH team consisting of neonatal intensivists, neonatal nurse practitioners, and pediatric surgeons, with the addition of a dedicated cohort of CDH nurse champions in 2021. The core team developed a comprehensive physiology-driven guideline, implemented geographic co-location within the Neonatal Intensive Care Unit (NICU), and directed all care of infants with CDH. The physiologic guideline focuses on the early identification and treatment of cardiac dysfunction coupled with limitation of iNO use in the setting of LV dysfunction. This study aimed to characterize the impact of a multi-disciplinary care team in combination with revised physiology-driven resuscitation and care guidelines that concentrate on early recognition and treatment of cardiac dysfunction on our center’s clinical outcomes for infants with CDH. Our primary outcomes of interest were survival to NICU discharge, ECMO utilization, and ECMO survival. Secondary outcomes were rates of cardiac dysfunction, changes in vasoactive use, and changes in iNO utilization. We hypothesized that a core team following physiology-driven guidelines would improve outcomes in this complex population. Methods Study Cohort and Design This retrospective cohort study included all infants diagnosed with CDH at St. Louis Children’s Hospital (SLCH) Level IV NICU from 2015–2025. Data were abstracted from the electronic medical record with IRB approval through Washington University in St. Louis. Prenatal data were obtained, if available, from all infants with a prenatal diagnosis and an observed-to‐expected lung‐to‐head ratio (O/E LHR) or MRI total fetal lung volume (TFLV) were used to stratify severity. Severe CDH was defined as O/E LHR < 25 or TFLV 35–45 with liver intra-thoracic, or TFLV 25–35, and mild CDH as O/E LHR 35–45 with liver intra-abdominal, > 45 with intra-thoracic liver, or TFLV > 35 25 . Infants without prenatal data were stratified as mild if the liver was intra-abdominal and moderate if the liver was intra-thoracic. 2. Cohort Delineation and Management Infants were delineated into two treatment epochs, historical treatment and post-guideline treatment, based on year of admission. Infants admitted to our NICU with CDH from 2015–2019 were placed into the historical cohort and those treated from 2020–2025 were placed into the post-guideline cohort. Infants admitted during the historical cohort epoch were admitted to any available bedspace in the NICU, and treatment was managed by any NICU provider. Historic cohort treatment lacked focus on early recognition or treatment of cardiac dysfunction. Early use of high-frequency oscillatory ventilation (HFOV) and the use of dopamine for hypotension were standard of care during that time. The post-guideline cohort was admitted with geographic cohorting in the NICU and treatment was managed by a single NICU team comprised of a core group of physicians, nurse practitioners, and nurses that followed comprehensive, physiology-driven care guidelines. 3. Comprehensive Care Guideline and Team A comprehensive care guideline and dedicated CDH team (Fig. 1 A) aimed to improve the outcomes of our infants with CDH by mitigating systemic and cultural challenges in the NICU and bridging knowledge gaps through a three pronged approach: 1) a dedicated geographic location of all infants with CDH; 2) a core CDH-specific care team including trained neonatologists, nurse practitioners, and nurses that provide 24-hour coverage for these infants. In addition, a neonatologist on the CDH team attends all deliveries, initial stabilizations, ECMO cannulations, and surgical interventions for infants with CDH.; 3) early focus on diagnosis and treatment of cardiac dysfunction (Fig. 1 B). Care is provided collaboratively with our pediatric surgery group. To address the complex and interrelated etiologies for cardiorespiratory failure in infants with CDH and the significant role of cardiac dysfunction in extra-uterine transition and outcomes 8 , 21 , 26 , we revised our institutional guidelines to emphasize timely diagnosis of cardiac dysfunction with early targeted echocardiogram (ECHO) to support early identification and treatment. Under the revised guidelines, early LV or combined RV + LV cardiac dysfunction was managed as outlined in Fig. 1 B. The initial and all subsequent ECHOs were read and interpreted by an attending cardiologist, regardless of the time of day the ECHO was obtained. Right ventricular dysfunction was characterized by a qualitative view of the RV along with tricuspid annular plane systolic excursion (TAPSE). Left ventricular systolic dysfunction was characterized by M-mode and fractional shortening. Further, under the revised guidelines, treatment of cardiac dysfunction utilized inotropes such as low-dose epinephrine (≤ 0.05 mcg/kg/min) and maintenance of the serum ionized calcium level at 5-5.5 mg/dL, reflecting the role of calcium in supporting the function of the neonatal myocardium 27 . In the setting of RV dysfunction with systemic or supra-systemic RV pressures, we initiated prostaglandin E1 (PGE1) therapy to maintain ductal patency and systemic output 28 , 29 . The addition of milrinone could be utilized at ≥ 24 hours of life if cardiac dysfunction persisted. Blood pressure goals were based on physiologic endpoints of perfusion with avoidance of supra-systemic blood pressures. Given the potential additional benefit of reduction in pulmonary vascular resistance (PVR), hypotension was managed with norepinephrine and vasopressin as first and second line vasopressors, respectively 30 , 31 , 32 , 33 . The use of iNO was avoided in the setting of LV or combined RV + LV dysfunction, unless cardiac dysfunction resolved and pulmonary hypertension persisted. Inhaled prostacyclins (PGI2) were reserved for infants with pulmonary hypertension refractory to other interventions. Long-term management of pulmonary hypertension was preferentially treated with sildenafil with the availability of intravenous PGI2 (treprostinil) for severe cases. Our respiratory strategy utilized first-intention pressure-controlled ventilation and a PEEP of 4 cmH 2 O to limit hyperinflation during the initial lung recruitment period. Infants were transitioned to volume-targeted ventilation to maintain functional residual capacity (FRC) to limit pulmonary vasoreactivity 26 , 34 . High frequency oscillatory ventilation (HFOV) was utilized as a rescue modality for refractory hypercarbia. 4. Data Collection Demographic data were collected by retrospective chart review and included gestational age, male sex, birthweight, reported maternal race. Prenatal indices collected were O/E LHR, side of hernia, liver position, and TFLV 12 . Birth characteristics were inborn delivery, Apgar scores, mode of delivery, and initial arterial blood gas measurements. An infant was considered inborn if delivered at our primary delivery hospital, Barnes Jewish Hospital Parkview Tower, which is physically connected to our NICU by a bridge. We report length-of-stay for survivors, surgical repair approach, use of HFOV, overall survival to discharge, ECMO utilization, ECMO survival, and discharge respiratory support. Measures of cardiac dysfunction were determined by echocardiography in the first 24 hours of life, and for the post-guideline cohort we characterize the cardiac function over the first 72 hours of life. We report the use of the following vasoactive infusions in both cohorts: dopamine, norepinephrine, epinephrine, calcium gluconate infusion, and milrinone as well as pulmonary vasodilator therapy with iNO in the first 48 hours of life, iNO during the hospital stay, sildenafil, treprostinil, inhaled prostacyclins, and use of PGE1 therapy. 5. Statistical Analysis Descriptive statistics were used to characterize baseline data, demographic information, and clinical outcomes for the historical and post-guideline cohorts. Categorical data comparing outcomes between the two cohorts were analyzed with the Fisher’s exact test. Continuous data were analyzed using a Mann Whitney U test and reported as median and IQR. For TFLV and ECMO duration, which were normally distributed between the two cohorts, an unpaired t-test was used, and results were reported as mean and standard deviation. Data were analyzed using GraphPad Prism 10® (Boston, MA). Significance was defined as p < 0.05. Results 1. Baseline Characteristics A total of 117 infants were identified with 104 infants included for analysis. Eight infants were excluded from the historical cohort: 2 with Trisomy 18, 1 with CDH + giant omphalocele, 1 with Morgagni hernia, and 4 with multiple congenital anomalies where comfort care was pursued by the family. Five were excluded from the post-guideline cohort: 3 with Morgagni hernia, 1 with complex congenital heart disease where comfort care was pursued by the family, and 1 infant with CDH + giant omphalocele. After delineation into treatment epochs, the historical cohort was comprised of 51 infants, and the post-guideline cohort contained 53 infants. There were no statistical differences in infant birth weight, maternal race, mode of delivery, Apgar scores, intrathoracic liver position, or initial arterial blood gas measurements (Table 1 ). There was a higher percentage of male infants in the historical cohort with a lower gestational age (39 weeks vs 38 weeks, p = 0.034) and trend toward lower O/E LHR (49% vs. 41.7%, p = 0.053) in the post-guideline cohort. There was no difference in CDH severity between the two cohorts (Table 1 ). More infants underwent minimally invasive repair in the post-guideline cohort (9.8% vs. 26.4%, p = 0.041) (Table 2 ) reflecting a change in surgical practice with more surgeons utilizing minimally invasive approaches between the two cohorts rather than a difference in cohort severity. A similar number of infants underwent patch repair, and there was a small decrease in non-repair in the post-guideline cohort (9.8% vs. 3.8%, p = 0.265). There was no significant difference in the proportion of infants discharged home on room air, on oxygen by nasal cannula, or with a tracheostomy at time of NICU discharge in either cohort. Table 1 Cohort characteristics Variable Historical Cohort (n = 51) Post-Guideline Cohort (n = 53) p- value Gestational age, weeks, median [IQR] 39 (37–39) 38 (36–39) 0.034 Male sex, n (%) 43 (84.3) 30 (56.6) 0.003 Birthweight, grams, median [IQR] 3080 (2800–3470) 3130 (2555–3387) 0.649 Left CDH, n (%) 47 (92.2) 45 (84.9) 0.359 Intrathoracic liver, n (%) 25 (49.0) 25 (47.2) 1 O/E LHR, %, median [IQR] 46.5 (34.3–64.8) 40.0 (32.0-48.3) 0.053 TFLV, %, mean (SD) 30.41 (14.5) 35.55 (21.1) 0.249 APGAR 1 min, median [IQR] 4 (2–7) 4 (1–7) 0.778 APGAR 5 min, median [IQR] 7 (5–8) 7 (5–8) 0.961 First pH, median [IQR] 7.21 (7.09–7.31) 7.17 (7.02–7.27) 0.183 First paO2 mmHg, median [IQR] 64.0 (44.0-125.0) 55.0 (45.5–75.0) 0.268 First pCO2 mmHg, median [IQR] 62.5 (46.0–86.0) 68.0 (52.5–91.5) 0.469 Vaginal delivery, n (%) 34 (66.7) 35 (66.0) 1 Inborn, n (%) 40 (78.4) 38 (71.7) 0.500 Maternal ethnicity, n (%) White 41 (80.4) 47 (88.7) 0.285 Black 6 (11.8) 5 (9.4) 0.758 Hispanic 3 (5.9) 1 (1.9) 0.358 Asian 1 (1.9) 0 (0) 0.49 CDH severity, n (%) Mild 23 (45.1) 19 (35.8) 0.425 Moderate 12 (23.5) 19 (35.8) 0.202 Severe 16 (31.4) 15 (28.4) 0.831 Surgical repair approach, n (%) Open laparotomy 41 (80.4) 37 (69.8) 0.26 Minimally invasive 5 (9.8) 14 (26.4) 0.041 Patch repair 21 (45.6) 21 (41.2) 0.686 Non-repair 5 (9.8) 2 (3.8) 0.484 Repair on ECMO 20 (76.9) 3 (21.4) 0.002 Time of initial echo, median [IQR] 4 (2.5–11) 2 (2–3) < 0.001 Number of echos, median [IQR] 3 (1–6) 7 (3–13) < 0.001 Abbreviations: IQR = interquartile range, CDH = congenital diaphragmatic hernia, O/E LHR = observed-to‐expected lung‐to‐head ratio, SD = standard deviation, TFLV = total fetal lung volume, min = minute, ECMO = extracorporeal membrane oxygenation, echo = echocardiogram Table 2 Clinical outcomes of the infant cohort Variable Historical Cohort (n = 51) Post-Guideline Cohort (n = 53) p -value Primary outcomes Survival to discharge, n (%) 35 (68.6) 47 (88.7) 0.016 ECMO utilization, n (%) 26 (51.0) 14 (26.4) 0.015 ECMO survival, n (%) 11 (42.3) 10 (71.4) 0.104 ECMO duration, days, mean (SD) 21.42 (13.57) 12.6 (6.9) 0.040 Ventilation and nitric oxide, n (%) HFOV 30 (58.8) 18 (33.9) 0.018 iNO during hospitalization 38 (74.6) 30 (56.6) 0.065 iNO in first 48 hours 33 (62.2) 15 (28.3) < 0.001 Cardiac Dysfunction, n (%) Any cardiac dysfunction 19 (37.3) 33 (62.3) 0.018 iNO in first 48 hours 18 (94.7) 12 (36.3) < 0.001 ECMO utilization 13 (68.4) 12 (36.3) 0.043 Survival with cardiac dysfunction 9 (47.4) 27 (81.8) 0.014 Type of dysfunction (among those with dysfunction), n (%) RV dysfunction 8 (42.1) 16 (48.4) 0.775 LV dysfunction 4 (21.1) 2 (6.1) 0.175 RV + LV dysfunction 7 (36.8) 15 (45.5) 0.575 Vasoactive and vasodilator use, n (%) Dopamine 33 (64.7) 1 (1.9) < 0.001 Epinephrine 6 (11.8) 31 (58.5) < 0.001 Calcium gluconate 2 (3.9) 25 (47.2) < 0.001 Norepinephrine 14 (27.5) 30 (56.6) 0.0031 Milrinone 20 (39.2) 19 (35.9) 0.840 PGE1 2 (3.9) 23 (43.4) < 0.001 Sildenafil 27 (52.9) 23 (43.4) 0.433 Treprostinil 0 (0) 8 (15.1) 0.006 Inhaled prostacyclin 7 (13.7) 5 (9.4) 0.551 Discharge respiratory support, n (%) Room air 29 (82.8) 37 (78.7) 0.781 Nasal cannula 4 (11.4) 6 (12.8) 1 Tracheostomy 2 (5.7) 4 (8.5) 1 Room air 29 (82.8) 37 (78.7) 0.781 Length of stay, days, median [IQR] 40.0 (28.0–94.0) 54.0 (30.0-130.0) 0.196 Abbreviations: ECMO = extracorporeal membrane oxygenation, SD = standard deviation, HFOV = high-frequency oscillatory ventilation, iNO = inhaled nitric oxide, RV = right ventricular, LV = left ventricular, PGE1 = prostaglandin E1 2. Survival, ECMO Utilization and Cardiac Dysfunction Our primary outcome of overall survival to hospital discharge was significantly higher in the post-guideline cohort (68.6% vs. 88.7%, p = 0.016) (Fig. 2 A). In the post-guideline cohort, ECMO utilization decreased from 51.0% to 26.4% ( p = 0.015) and ECMO survival trended higher (42.3% vs. 71.4%, p = 0.104) (Fig. 2 A). Importantly, analysis of outcomes stratified by CDH severity based on prenatal parameters revealed an improvement in survival and decreased ECMO utilization for each severity cohort in the post-guideline cohort (Fig. 2 C). The initial postnatal echo was performed at a median time of 2 hours in the post-guideline cohort compared to a median time of 4 hours in the historical cohort ( p = < 0.001). With greater emphasis on the identification of cardiac dysfunction and post-repair monitoring of pulmonary hypertension, the post-guideline cohort received a greater total number of echocardiograms during their NICU stay (3 vs 7, p = < 0.001) (Table 2 ). Cardiac dysfunction was identified in the first 24 hours in a higher proportion of the post-guideline infants with CDH (37.3% vs 62.3%, p = 0.02) (Fig. 2 B), which may reflect increased surveillance of cardiac dysfunction as opposed to a true increase between the two cohorts. In the post-guideline cohort RV dysfunction was most common in 16 (30.2%) infants followed by RV + LV dysfunction in 15 (28.3%) infants and only 2 (3.7%) infants had isolated LV dysfunction. We next interrogated rates of survival and ECMO utilization among infants with CDH with isolated RV or LV dysfunction or RV + LV dysfunction. In the post-guideline cohort, we observed 100% survival in infants with isolated RV or LV dysfunction (Fig. 3 A). Infants with combined RV + LV dysfunction trended towards improved survival in the post-guideline cohort, though this did not meet statistical significance (28.5% vs 60.0%, p = 0.362). Overall, ECMO utilization decreased for infants with cardiac dysfunction in the post-guideline cohort (68.4% vs 36.3%, p = 0.043) (Fig. 2 B). We characterized the change in cardiac function over time in the post-guideline cohort (Fig. 3 B). 86.8% of infants in the cohort had normal cardiac function at 72 hours of life and all infants with isolated LV and all but one with RV dysfunction had resolution. There remained a component of dysfunction in 6 infants with RV + LV dysfunction, and all 6 of those infants required ECMO. 3. Change in vasoactive and pulmonary vasodilator use The physiology-driven guideline strongly recommended against dopamine use with its unfavorable effect on pulmonary vascular resistance 17 , 35 and to limit iNO use in the setting of LV or RV + LV dysfunction, so we next characterize differences in the use of vasoactive medications and pulmonary vasodilators among the two cohorts (Figs. 3 C-D). Dopamine use decreased from 64.7% to 1.9% ( p = < 0.001) whereas low-dose epinephrine administration increased from 11.8% to 58.5% ( p = < 0.001) in the historical cohort compared to the post-guideline cohort, respectively. Norepinephrine use increased from 27.5% to 56.6% ( p = 0.0031) and calcium gluconate infusions increased from 3.9% to 47.2% ( p < 0.001). There was no significant change in milrinone use. There were also no changes in sildenafil or inhaled prostacyclin use between the two cohorts. No infants received IV treprostinil in the historical cohort, compared with eight infants in the post-guideline cohort ( p = 0.006). This reflected a shift in practice with treprostinil being added as a pulmonary vasodilator in the post-guideline cohort, but not for the historical cohort. Inhaled nitric oxide use during the hospital stay showed a decreased trend from 74.6% to 56.6% ( p = 0.065) with a significant decrease in iNO use during the first 48 hours of life from 62.2% to 28.3% ( p = < 0.001) in the post-guideline cohort. In infants with cardiac dysfunction, iNO use in the first 48 hours dropped significantly from 94.7% to 36.3% ( p < 0.001) of infants. PGE1 therapy increased in the post-guideline cohort from 3.9% to 43.4% ( p < 0.001). Together, these data support recognition and treatment of cardiac dysfunction with targeted vasoactive therapy as part of comprehensive care guidelines to optimize outcomes in infants with CDH. Discussion This is the largest single-center cohort study reporting early identification and treatment of cardiac dysfunction in infants with CDH. Early identification of cardiac dysfunction, implementation of a core multidisciplinary CDH team, and physiology-driven resuscitation and care guidelines resulted in an increase in survival and decrease in ECMO requirement overall and in infants with cardiac dysfunction in our single center. Center variation in outcomes is not unique to CDH and is widely reported for many neonatal specific diseases such as the incidence of bronchopulmonary dysplasia (BPD) 36 , 37 , 38 , very low birth weight (VLBW) infants 39 , 40 , 41 , gastroschisis 42 , and congenital heart disease 43 . Prior reports have suggested high volume (> 7–10 cases per year) CDH centers have improved mortality 23 , 24 , 44 and lower recurrence rates 45 . There also exist individual high performing centers 13 , 14 , 46 , 47 whose reported outcomes are better than national datasets. This association between higher volumes of infants with CDH and improved outcomes suggests that increased exposure and expertise in complex cardiorespiratory physiology is a modifiable factor in improving outcomes. While center volume remained consistent at a median of 9 CDH infants a year, we improved expertise and exposure via creation of a focused CDH care team and geographic cohorting of infants. This approach has been described for other NICU-specific diagnoses with the creation of BPD-specific teams 37 and teams dedicated to the care of VLBW infants 48 , 49 . With this consistent care team, we have seen our primary outcome of survival to discharge improve to 88.7% and ECMO utilization decrease to 26.4%. The existence of a dedicated team, however, does not guarantee improved outcomes. The care delivered must be consistently guided by physiology coupled with current literature and a quality improvement mentality to bridge remaining gaps in evidence 47 . We hypothesized that early recognition and treatment of cardiac dysfunction is another modifiable factor to improve outcomes in infants with CDH based on several reports which identify ventricular function as a determinant in outcomes 6 , 7 , 8 , 21 , 22 , 50 . Increasing recognition of cardiac dysfunction and its interplay with pulmonary hypertension have led to the identification of specific phenotypes that can guide targeted therapy for infants with CDH 2 , 9 . These phenotypes, while imperfect, allow for identification of a mild phenotype, an RV phenotype with pulmonary hypertension and RV dysfunction, and a LV or RV + LV dysfunction phenotype with post-capillary pulmonary hypertension. We describe performing an early echocardiogram so that subsequent therapy can target the specific phenotype present (Fig. 1 B). We did not see any physiologic disturbance or intolerance during the early postnatal echo in infants with CDH. We found that two-thirds of the post-guideline cohort had some form of cardiac dysfunction. Our results mirror that of Patel et al with RV and RV + LV dysfunction being more common than isolated LV dysfunction 9 . No infants with normal cardiac function on the first postnatal echo developed dysfunction later in their course, and cardiac function was normal by 72 hours in 86.8% of the cohort (Fig. 3 B). The 6 infants with RV + LV dysfunction that did not normalize ultimately required ECMO support. This is consistent with, and reinforces, data demonstrating that infants with biventricular dysfunction are at the greatest risk for morbidity and mortality 8 , 9 , 22 . Early identification of RV + LV dysfunction may allow for targeted treatment to improve outcomes in this cohort and provides additional data for use in the decision around need for ECMO support. In addition, the new approach couples the treatment of cardiac dysfunction with guidelines to decrease inhaled nitric oxide (iNO) use in the setting of LV or RV + LV dysfunction and to discontinue the use of dopamine 17 , 35 , 51 . The historical approach to blood pressure management in the NICU was to utilize dopamine as a first line vasoactive after fluid administration. However, dopamine has a dose-dependent receptor selectivity resulting in variable physiologic effects and has an unfavorable action on PVR 17 , 35 . Instead, we implemented a more targeted vasoactive approach to complex CDH physiology. If cardiac dysfunction was identified, we intervened with low-dose epinephrine and calcium gluconate infusions. We sought to balance the treatment of cardiac dysfunction and pulmonary hypertension by utilizing a ventilator strategy that prevents hyperinflation, and subsequent elevations in PVR, and decreases in lung compliance. This was coupled with maintenance of ductal patency with PGE1 in infants with systemic or suprasystemic pulmonary hypertension 28 , 29 . Our data show that dopamine use was discontinued, targeted treatment of cardiac dysfunction was common, and that PGE1 use increased significantly in the post-guideline cohort. A complete approach to infants with CDH is necessary for success. It is not just identification of cardiac dysfunction, but a treatment strategy that focuses on concomitant pulmonary hypoplasia and pulmonary hypertension. While this is the largest single center CDH cohort reporting early identification and treatment of cardiac dysfunction, it remains limited by the single-center nature. We do not use targeted neonatal echocardiography (TNE) at our center, therefore while LV function is objective, there remains subjectivity in the identification of RV dysfunction. There was a great deal of heterogeneity in the care of infants with CDH in the historical cohort, so we cannot say with certainty which intervention has resulted in improved outcomes. However, it is clear from this data that cardiac dysfunction is prevalent and can complicate the transition to extra-uterine life in infants with CDH. The strength of this study is that we leverage a NICU team approach with existing pediatric cardiology resources to identify cardiac dysfunction. This approach does not require additional training in TNE or neonatal hemodynamics and is a generalizable approach for centers that do not have a neonatal hemodynamics program. These data add to the growing body of literature that recognition and intervention of cardiac dysfunction is equally as important as the care of pulmonary hypoplasia and pulmonary hypertension. We present our approach to the management of cardiac dysfunction, but we do not want to overshadow the role gentle ventilation, targeted use of pulmonary vasodilators, excellent surgical partnership, nutrition 52 , and high fidelity ECMO 53 play in the outcomes of infants with CDH. The ability of a multi-disciplinary team to work together to deliver high fidelity intensive care is key to improving outcomes in this population. Conclusion A dedicated care team improves expertise and consistency in the care of infants with CDH and cardiac dysfunction is prevalent in early postnatal echocardiograms of infants with CDH. A targeted postnatal echo is well tolerated and often yields clinically relevant information. We report a generalizable approach to identification and treatment of cardiac dysfunction that improved outcomes in our single-center cohort. Infants with RV + LV dysfunction have the highest ECMO utilization and highest mortality in our cohort. This phenotype remains the most refractory cohort to treatment, suggesting additional study and development of specific care strategies to decrease ECMO utilization and improve survival are needed. Declarations Conflict of Interest: All authors declare no competing financial interests. Ethics and Consent to Participate: This study was approved by the Washington University in St. Louis Institutional Review Board (#202510238) Funding: No sources of funding were received for the completion of this study. Author Contributions: Patrick E. Sloan: data collection, designed the study, statistical analysis, and drafting of the manuscript. Lila S. Sanning: review, statistical analysis and drafting of the manuscript Caren Liviskie: review and statistical analysis of the manuscript Kristen Clark: review of the manuscript Kylie Bushroe: review of the manuscript Melissa Riley: review of the manuscript Anna Lijowksa: review of the manuscript Jesse Vrecenak: designed the study and review of the manuscript Tasnim Najaf: designed the study, statistical analysis, and drafting of the manuscript. Acknowledgements: The authors thank Gina Myers, RN and Amy Distler, RN at St. Louis Children’s Hospital for their roles in maintaining the clinical database used for cohort identification and data acquisition. We also acknowledge infants with CDH, their families, and all caregivers who promote excellence in this patient population. References Montalva L, Zani A. Assessment of the nitrofen model of congenital diaphragmatic hernia and of the dysregulated factors involved in pulmonary hypoplasia. Pediatr Surg Int 2019, 35 (1) : 41-61. 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Early postnatal echocardiographic characteristics impact survival and extracorporeal life support in congenital diaphragmatic hernia. Pediatr Res 2025. Patel N, Lally PA, Kipfmueller F, Massolo AC, Luco M, Van Meurs KP , et al. Ventricular Dysfunction Is a Critical Determinant of Mortality in Congenital Diaphragmatic Hernia. Am J Respir Crit Care Med 2019, 200 (12) : 1522-1530. Patel N, Kipfmueller F. Cardiac dysfunction in congenital diaphragmatic hernia: Pathophysiology, clinical assessment, and management. Semin Pediatr Surg 2017, 26 (3) : 154-158. Gupta VS, Harting MT, Lally PA, Miller CC, Hirschl RB, Davis CF , et al. Mortality in Congenital Diaphragmatic Hernia: A Multicenter Registry Study of Over 5000 Patients Over 25 Years. Ann Surg 2023, 277 (3) : 520-527. Grover TR, Murthy K, Brozanski B, Gien J, Rintoul N, Keene S , et al. Short-term outcomes and medical and surgical interventions in infants with congenital diaphragmatic hernia. Am J Perinatol 2015, 32 (11) : 1038-1044. Perrone EE, Karmakar M, Lally PA, Chung S, Kipfmueller F, Morini F , et al. Image-based prenatal predictors correlate with postnatal survival, extracorporeal life support use, and defect size in left congenital diaphragmatic hernia. J Perinatol 2022, 42 (9) : 1195-1201. Kahan AM, Glasgow SL, Yoder BA, Yang M, Yost CC, Peterson K , et al. Less is more: ECMO utilization and outcomes in congenital diaphragmatic hernia. J Pediatr Surg 2025 : 162571. Lichtsinn K, Waltz PK, Azzuqa A, Church J, Graham J, Troutman J , et al. Impact of a standardized management guideline for infants with CDH: A single-center experience. J Pediatr Surg 2023, 58 (3) : 389-396. Kuan MTY, Yadav K, Castaldo M, Tan J, Chan NH, Traynor M , et al. The impact of a care bundle with an emphasis on hemodynamic assessment on the short-term outcomes in neonates with congenital diaphragmatic hernia. J Perinatol 2024, 44 (3) : 348-353. Putnam LR, Tsao K, Morini F, Lally PA, Miller CC, Lally KP , et al. Evaluation of Variability in Inhaled Nitric Oxide Use and Pulmonary Hypertension in Patients With Congenital Diaphragmatic Hernia. JAMA Pediatr 2016, 170 (12) : 1188-1194. McNamara PJ, Giesinger RE, Lakshminrusimha S. Dopamine and Neonatal Pulmonary Hypertension-Pressing Need for a Better Pressor? J Pediatr 2022, 246: 242-250. Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Pediatrics 1997, 99 (6) : 838-845. Sescleifer AM, Chidiac C, Hellmann ZJ, McDermott KM, Garcia AV, Rhee DS , et al. Revisiting Inhaled Nitric Oxide Utilization in Congenital Diaphragmatic Hernia: A National Cohort Study of Major Children's Hospitals in the United States. J Pediatr Surg 2025, 60 (9) : 162423. Porta NF, Naing K, Keene S, Grover TR, Hedrick H, Mahmood B , et al. Variability for Age at Successful Extubation in Infants with Congenital Diaphragmatic Hernia (CDH). J Pediatr 2022. Fraga MV, Hedrick HL, Rintoul NE, Wang Y, Ash D, Flohr SJ , et al. Congenital Diaphragmatic Hernia Patients with Left Heart Hypoplasia and Left Ventricular Dysfunction Have Highest Odds of Mortality. J Pediatr 2024, 271: 114061. Le LS, Kinsella JP, Gien J, Frank BS. Failure to Normalize Biventricular Function Is Associated with Extracorporeal Membrane Oxygenation Use in Neonates with Congenital Diaphragmatic Hernia. J Pediatr 2023, 260: 113490. Elrod J, Boettcher M, Kipfmueller F, Schaible T, Wolfram Trudo K, Mohr C , et al. Hospital Volume and Outcome in the Treatment of Congenital Diaphragmatic Hernia in Germany - Observational Study Using National Hospital Discharge Data From 2016 to 2023. J Pediatr Surg 2025, 60 (9) : 162399. Peiffer SE, Mehl SC, Powell P, Lee TC, Keswani SG, King A. Treatment Facility Case Volume and Disparities in Outcomes of Congenital Diaphragmatic Hernia Cases. J Pediatr Surg 2024, 59 (5) : 825-831. Yang MJ, Ellsworth TS, Woodward PJ, Kennedy AM, Fenton SJ, Russell KW , et al. Comparison of current to past outcomes in congenital diaphragmatic hernia using MRI observed-to-expected total fetal lung volume. J Perinatol 2024, 44 (9) : 1347-1352. Sankaran D, Lakshminrusimha S, Lim MJ. Cardiorespiratory transition in CDH. Semin Fetal Neonatal Med 2025, 30 (3) : 101649. Averin K, Villa C, Krawczeski CD, Pratt J, King E, Jefferies JL , et al. Initial Observations of the Effects of Calcium Chloride Infusions in Pediatric Patients with Low Cardiac Output. Pediatr Cardiol 2016, 37 (3) : 610-617. Le Duc K, Mur S, Sharma D, Aubry E, Recher M, Rakza T , et al. Prostaglandin E1 in infants with congenital diaphragmatic hernia (CDH) and life-threatening pulmonary hypertension. J Pediatr Surg 2020. Lawrence KM, Berger K, Herkert L, Franciscovich C, O'Dea CLH, Waqar LN , et al. Use of prostaglandin E1 to treat pulmonary hypertension in congenital diaphragmatic hernia. J Pediatr Surg 2019, 54 (1) : 55-59. Tourneux P, Rakza T, Bouissou A, Krim G, Storme L. Pulmonary circulatory effects of norepinephrine in newborn infants with persistent pulmonary hypertension. J Pediatr 2008, 153 (3) : 345-349. Jaillard S, Elbaz F, Bresson-Just S, Riou Y, Houfflin-Debarge V, Rakza T , et al. Pulmonary vasodilator effects of norepinephrine during the development of chronic pulmonary hypertension in neonatal lambs. Br J Anaesth 2004, 93 (6) : 818-824. Siehr SL, Feinstein JA, Yang W, Peng LF, Ogawa MT, Ramamoorthy C. Hemodynamic Effects of Phenylephrine, Vasopressin, and Epinephrine in Children With Pulmonary Hypertension: A Pilot Study. Pediatr Crit Care Med 2016, 17 (5) : 428-437. Acker SN, Kinsella JP, Abman SH, Gien J. Vasopressin improves hemodynamic status in infants with congenital diaphragmatic hernia. J Pediatr 2014, 165 (1) : 53-58.e51. Guevorkian D, Mur S, Cavatorta E, Pognon L, Rakza T, Storme L. Lower Distending Pressure Improves Respiratory Mechanics in Congenital Diaphragmatic Hernia Complicated by Persistent Pulmonary Hypertension. J Pediatr 2018, 200: 38-43. Hébert A, Lakshminrusimha S, Rios DR, Bhombal S, Moore SS, Ford S , et al. Physiology-guided vasoactive therapy in neonates: rethinking dopamine as first-line. J Perinatol 2025, 45 (10) : 1327-1334. Lapcharoensap W, Gage SC, Kan P, Profit J, Shaw GM, Gould JB , et al. Hospital variation and risk factors for bronchopulmonary dysplasia in a population-based cohort. JAMA Pediatr 2015, 169 (2) : e143676. Cristea AI, Tracy MC, Bauer SE, Guaman MC, Welty SE, Baker CD , et al. Approaches to Interdisciplinary Care for Infants with Severe Bronchopulmonary Dysplasia: A Survey of the Bronchopulmonary Dysplasia Collaborative. Am J Perinatol 2024, 41 (S 01) : e536-e544. House M, Lagoski M, DiGeronimo R, Eldredge LC, Manimtim W, Baker CD , et al. Interdisciplinary clinical bronchopulmonary dysplasia programs: development, evolution, and maturation. J Perinatol 2026, 46 (2) : 136-143. Hentschel R, Guenther K, Vach W, Bruder I. Risk-adjusted mortality of VLBW infants in high-volume versus low-volume NICUs. Arch Dis Child Fetal Neonatal Ed 2019, 104 (4) : F390-F395. Hyland RM, Mat HD, Boly TJ, Thomas BJ, Stanford AH, Harmon HM , et al. Outcomes of Infants Born at 21 Weeks' Gestational Age. JAMA Netw Open 2025, 8 (12) : e2548211. Edwards EM, Ehret DEY, Soll RF, Horbar JD. Survival of Infants Born at 22 to 25 Weeks' Gestation Receiving Care in the NICU: 2020-2022. Pediatrics 2024, 154 (4). Apfeld JC, Kastenberg ZJ, Sylvester KG, Lee HC. The Effect of Level of Care on Gastroschisis Outcomes. J Pediatr 2017, 190: 79-84.e71. Pasquali SK, Gaies MG, Jacobs JP, William Gaynor J, Jacobs ML. Centre variation in cost and outcomes for congenital heart surgery. Cardiol Young 2012, 22 (6) : 796-799. Bucher BT, Guth RM, Saito JM, Najaf T, Warner BW. Impact of hospital volume on in-hospital mortality of infants undergoing repair of congenital diaphragmatic hernia. Ann Surg 2010, 252 (4) : 635-642. Tamura R, O'Connor E, Jaffray B. Surgeon level variation in outcome of repair of congenital diaphragmatic hernia with particular reference to the management of recurrence. J Pediatr Surg 2021, 56 (12) : 2207-2214. Kays DW, Talbert JL, Islam S, Larson SD, Taylor JA, Perkins J. Improved Survival in Left Liver-Up Congenital Diaphragmatic Hernia by Early Repair Before Extracorporeal Membrane Oxygenation: Optimization of Patient Selection by Multivariate Risk Modeling. J Am Coll Surg 2016, 222 (4) : 459-470. Wild KT, Hedrick HL, Rintoul NE, Ades AM, Gebb JS, Mathew L , et al. Golden hour management of infants with congenital diaphragmatic hernia: 15 year experience at a high-volume center. J Perinatol 2025, 45 (9) : 1247-1254. Liska S, Schmidt G, Brunquist S. Developing a Small Baby Program for the Extremely Low Birth Weight: The Wee CARE Team. Neonatal Netw 2021, 40 (4) : 233-241. Phillips R, Solomon J, Dixon L, Altimier L. Neuroprotective Infant and Family-Centered Developmental Care for the Tiniest Babies: Perspectives from Key Members of the Neonatal Intensive Care Unit Small Baby Team. Crit Care Nurs Clin North Am 2024, 36 (2) : 167-184. Patel N, Massolo AC, Kipfmueller F. Congenital diaphragmatic hernia-associated cardiac dysfunction. Semin Perinatol 2020, 44 (1) : 151168. Seri I. Cardiovascular, renal, and endocrine actions of dopamine in neonates and children. J Pediatr 1995, 126 (3) : 333-344. Sloan P, Johng S, Daniel JM, Rhee CJ, Mahmood B, Gravari E , et al. A clinical consensus guideline for nutrition in infants with congenital diaphragmatic hernia from birth through discharge. J Perinatol 2024, 44 (5) : 694-701. Kays DW. ECMO in CDH: Is there a role? Semin Pediatr Surg 2017, 26 (3) : 166-170. Additional Declarations There is NO conflict of interest to disclose. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: revise 05 May, 2026 Review # 1 received at journal 01 May, 2026 Review # 2 received at journal 27 Apr, 2026 Reviewer # 2 agreed at journal 08 Apr, 2026 Reviewer # 1 agreed at journal 02 Apr, 2026 Reviewers invited by journal 26 Mar, 2026 Submission checks completed at journal 26 Mar, 2026 Editor assigned by journal 24 Mar, 2026 First submitted to journal 24 Mar, 2026 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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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9216925","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":612942429,"identity":"29c15df7-475d-4275-a656-11ac7509ff80","order_by":0,"name":"Patrick Sloan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIiWNgGAWjYDACdjiLsYGxoQLEYG5gYGDDo4UZSvOAtZwBstgYidYCtKexjQgt8s3MBz8XMNyRt5c+3Phx5rzDifPnNzYwfCg7jFOLwWG2ZOkZDM8Me/gSmyU3bjucuOEY0IUzzuHRwsxjIM3DcJixh4exjfHhttuJG4AOY+Ztw61FvpnH+DdQiz1Ey5zbifPbgFr+4tHCcJjHDGRLIljLxobbiQ1AhzEz4tEC9EuaNY/Bs+SeM4zNkjOO/TfecCyx4WDPuXTcDmtvPnybp+KObXsP+8OPPTVpsvObDx988KPMGrfDIHYdQOUfwKYIDRCjZhSMglEwCkYsAAAyxVcP80DYcAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-6546-5069","institution":"Washington University in St. Louis","correspondingAuthor":true,"prefix":"","firstName":"Patrick","middleName":"","lastName":"Sloan","suffix":""},{"id":612942430,"identity":"9ab7f6c4-5df1-4ac9-9a6b-013677d022d2","order_by":1,"name":"Lila Sanning","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Lila","middleName":"","lastName":"Sanning","suffix":""},{"id":612942431,"identity":"6b3d6b88-a99e-466b-bf53-a84ea0a24778","order_by":2,"name":"Caren Liviskie","email":"","orcid":"https://orcid.org/0000-0002-2007-6577","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Caren","middleName":"","lastName":"Liviskie","suffix":""},{"id":612942432,"identity":"95e2baa2-56ee-4b3d-a201-774d73ec17c1","order_by":3,"name":"Kristen Clark","email":"","orcid":"","institution":"BJC Healthcare","correspondingAuthor":false,"prefix":"","firstName":"Kristen","middleName":"","lastName":"Clark","suffix":""},{"id":612942433,"identity":"344c7c5a-a36a-4508-8fbc-a8a1ff8d8b07","order_by":4,"name":"Kylie Bushroe","email":"","orcid":"https://orcid.org/0000-0003-0652-8220","institution":"Washington University in St. Louis","correspondingAuthor":false,"prefix":"","firstName":"Kylie","middleName":"","lastName":"Bushroe","suffix":""},{"id":612942434,"identity":"ba9faeba-41e5-4e26-93aa-451a65b06943","order_by":5,"name":"Melissa Riley","email":"","orcid":"https://orcid.org/0000-0002-3339-8639","institution":"Washington University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Melissa","middleName":"","lastName":"Riley","suffix":""},{"id":612942435,"identity":"d23c4ab5-89e2-4d82-a13e-1c9be508bc2b","order_by":6,"name":"Anna Lijowska","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Lijowska","suffix":""},{"id":612942436,"identity":"59213f56-5992-45ee-8367-5c61639bb98c","order_by":7,"name":"Jesse Vrecenak","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jesse","middleName":"","lastName":"Vrecenak","suffix":""},{"id":612942437,"identity":"c7b3fa5d-8740-4126-8c71-53759ee43357","order_by":8,"name":"Tasnim Najaf","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Tasnim","middleName":"","lastName":"Najaf","suffix":""}],"badges":[],"createdAt":"2026-03-25 01:50:57","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9216925/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9216925/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105787916,"identity":"bc093ef0-e542-4086-8547-b2993ea981d0","added_by":"auto","created_at":"2026-03-31 06:57:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":108436,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA multi-disciplinary care team and early recognition of cardiac dysfunction support improved care of CDH infants. A.\u003c/strong\u003e A comprehensive and multi-disciplinary approach to the care of CDH infants spans from antenatal counseling, a dedicated delivery team, and guideline-based postnatal management. \u003cstrong\u003eB.\u003c/strong\u003e Echocardiographic algorithm for the diagnosis and intervention of cardiac dysfunction in CDH. \u003cem\u003eAbbreviations: HFOV: high frequency oscillatory ventilation, iNO: inhaled nitric oxide, LV: left ventricular, PDA: patent ductus arteriosus, PGE: prostaglandin E1, RV: right ventricular.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9216925/v1/5808d10938dee85a16559887.png"},{"id":105787914,"identity":"693303e8-12ba-4264-bef0-667be0e3036f","added_by":"auto","created_at":"2026-03-31 06:57:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":49141,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival to discharge, ECMO survival and ECMO utilization. A.\u003c/strong\u003e Comparison of primary outcomes in the historical and post-guideline cohort. \u003cstrong\u003eB. \u003c/strong\u003eComparison of rates of cardiac dysfunction and outcomes for patients with cardiac dysfunction between the historical and post-guideline cohort. \u003cstrong\u003eC.\u003c/strong\u003e Comparison of survival and ECMO utilization in the two cohorts of infants with mild, moderate, or severe CDH. \u003cem\u003eAbbreviation: ECMO: extracorporeal membrane oxygenation.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9216925/v1/f7e5c6aba3a0b9359ae896eb.png"},{"id":105787837,"identity":"9360417b-051b-4db0-85a1-d23fd09af21e","added_by":"auto","created_at":"2026-03-31 06:57:00","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":69787,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOutcomes stratified by type of cardiac dysfunction and changes in vasoactive use with guideline implementation A.\u003c/strong\u003e Comparison of survival and ECMO utilization in the historical and post-guideline cohorts of infants with CDH with either RV, LV, or RV+LV dysfunction. \u003cstrong\u003eB. \u003c/strong\u003eChanges in cardiac function over the first 72 hours in the post-guideline cohort.\u003cstrong\u003e C-D.\u003c/strong\u003e Changes in vasoactive and vasodilator use between the two cohorts. ***p\u0026lt;0.001, **p\u0026lt;0.01, ns: not significant \u003cem\u003eAbbreviations: ECMO: Extracorporeal membrane oxygenation, iNO: inhaled nitric oxide, IN: inhaled, IV: intravenous, LV: left ventricular, PGE1: prostaglandin E1, RV: right ventricular.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9216925/v1/cb41e3937e148133d55e85bc.png"},{"id":105904522,"identity":"6729428e-ba2e-4093-8fad-2aeaaf60e090","added_by":"auto","created_at":"2026-04-01 10:09:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1590566,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9216925/v1/0353287f-4228-4854-9019-b50d24c5ea14.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Team-based care with early recognition and treatment of cardiac dysfunction for infants with CDH","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCongenital diaphragmatic hernia (CDH) is a congenital anomaly that occurs in approximately 1 in 3000 live births and carries significant cardiorespiratory morbidity and mortality. The etiology of cardiorespiratory failure in CDH is multifactorial, impacted by pulmonary hypoplasia \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e, pulmonary hypertension \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, and cardiac dysfunction \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Extracorporeal membrane oxygenation (ECMO) utilization remains at nearly 30% for infants with CDH, with ECMO survival of 50% \u003csup\u003e10\u003c/sup\u003e. While national survival from large cohort studies has remained stable (70–75%), some individual centers have implemented comprehensive CDH care guidelines with reported improvement in survival to as high as 85% \u003csup\u003e10, 11, 12, 13, 14, 15\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAreas of controversy in the care of infants with CDH include the role of iNO \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, timing of echocardiogram \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, and the appropriate choice of vasoactive medications in managing systemic and pulmonary vascular resistance \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. The benefit of conventional treatment with iNO in infants with CDH continues to be questioned. The NINOS trial, while small and with significant methodical challenges, revealed no significant benefits of iNO use and identified an increased need for ECMO in infants with CDH \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. In the interim, many studies that have challenged the role of iNO in infants with CDH have similarly shown an increased mortality in infants who receive iNO without clear benefit \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Further, there is increasing recognition of post-capillary pulmonary hypertension, driven by left atrial hypertension in the setting of left ventricular (LV) dysfunction, in addition to the historically recognized pre-capillary pulmonary arterial and arteriolar hypertension in infants with CDH \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Most concerningly, emerging data demonstrate that isolated LV or combined right ventricular (RV) + LV dysfunction are predictive of high mortality in infants with CDH and the need for ECMO support \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. These studies promote the use of early diagnostic imaging, limiting the use of iNO in the setting of cardiac dysfunction, and recognizing pre-capillary and post-capillary pulmonary hypertension.\u003c/p\u003e \u003cp\u003eTo improve care for infants with CDH, we first identified factors that contribute to disparity in morbidity and mortality: inter-center variability, center volume \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, and the presence and persistence of LV or RV + LV cardiac dysfunction \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. The success of high volume, as well as individual high-performing centers, demonstrates that experience and focus on the complex cardiorespiratory physiology of infants with CDH may optimize outcomes. Therefore, in 2020, our center formed a dedicated CDH team consisting of neonatal intensivists, neonatal nurse practitioners, and pediatric surgeons, with the addition of a dedicated cohort of CDH nurse champions in 2021. The core team developed a comprehensive physiology-driven guideline, implemented geographic co-location within the Neonatal Intensive Care Unit (NICU), and directed all care of infants with CDH. The physiologic guideline focuses on the early identification and treatment of cardiac dysfunction coupled with limitation of iNO use in the setting of LV dysfunction.\u003c/p\u003e \u003cp\u003e This study aimed to characterize the impact of a multi-disciplinary care team in combination with revised physiology-driven resuscitation and care guidelines that concentrate on early recognition and treatment of cardiac dysfunction on our center’s clinical outcomes for infants with CDH. Our primary outcomes of interest were survival to NICU discharge, ECMO utilization, and ECMO survival. Secondary outcomes were rates of cardiac dysfunction, changes in vasoactive use, and changes in iNO utilization. We hypothesized that a core team following physiology-driven guidelines would improve outcomes in this complex population.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e\u003c/p\u003e \n\n\n\n \u003cp\u003e \u003c/p\u003e \n\n \n\n"},{"header":"Methods","content":"\u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eStudy Cohort and Design\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e\u003cp\u003eThis retrospective cohort study included all infants diagnosed with CDH at St. Louis Children’s Hospital (SLCH) Level IV NICU from 2015–2025. Data were abstracted from the electronic medical record with IRB approval through Washington University in St. Louis. Prenatal data were obtained, if available, from all infants with a prenatal diagnosis and an observed-to‐expected lung‐to‐head ratio (O/E LHR) or MRI total fetal lung volume (TFLV) were used to stratify severity. Severe CDH was defined as O/E LHR \u0026lt; 25 or TFLV \u0026lt; 25, moderate CDH as O/E LHR 25–35 regardless of liver position,\u0026gt;35–45 with liver intra-thoracic, or TFLV 25–35, and mild CDH as O/E LHR 35–45 with liver intra-abdominal, \u0026gt; 45 with intra-thoracic liver, or TFLV \u0026gt; 35 \u003csup\u003e25\u003c/sup\u003e. Infants without prenatal data were stratified as mild if the liver was intra-abdominal and moderate if the liver was intra-thoracic.\u003c/p\u003e\u003ch3\u003e2. Cohort Delineation and Management\u003c/h3\u003e\u003cp\u003e Infants were delineated into two treatment epochs, historical treatment and post-guideline treatment, based on year of admission. Infants admitted to our NICU with CDH from 2015–2019 were placed into the historical cohort and those treated from 2020–2025 were placed into the post-guideline cohort. Infants admitted during the historical cohort epoch were admitted to any available bedspace in the NICU, and treatment was managed by any NICU provider. Historic cohort treatment lacked focus on early recognition or treatment of cardiac dysfunction. Early use of high-frequency oscillatory ventilation (HFOV) and the use of dopamine for hypotension were standard of care during that time. The post-guideline cohort was admitted with geographic cohorting in the NICU and treatment was managed by a single NICU team comprised of a core group of physicians, nurse practitioners, and nurses that followed comprehensive, physiology-driven care guidelines.\u003c/p\u003e\u003ch3\u003e3. Comprehensive Care Guideline and Team\u003c/h3\u003e\u003cp\u003e A comprehensive care guideline and dedicated CDH team (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA) aimed to improve the outcomes of our infants with CDH by mitigating systemic and cultural challenges in the NICU and bridging knowledge gaps through a three pronged approach: 1) a dedicated geographic location of all infants with CDH; 2) a core CDH-specific care team including trained neonatologists, nurse practitioners, and nurses that provide 24-hour coverage for these infants. In addition, a neonatologist on the CDH team attends all deliveries, initial stabilizations, ECMO cannulations, and surgical interventions for infants with CDH.; 3) early focus on diagnosis and treatment of cardiac dysfunction (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB). Care is provided collaboratively with our pediatric surgery group.\u003c/p\u003e\u003cp\u003eTo address the complex and interrelated etiologies for cardiorespiratory failure in infants with CDH and the significant role of cardiac dysfunction in extra-uterine transition and outcomes \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, we revised our institutional guidelines to emphasize timely diagnosis of cardiac dysfunction with early targeted echocardiogram (ECHO) to support early identification and treatment. Under the revised guidelines, early LV or combined RV + LV cardiac dysfunction was managed as outlined in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB. The initial and all subsequent ECHOs were read and interpreted by an attending cardiologist, regardless of the time of day the ECHO was obtained. Right ventricular dysfunction was characterized by a qualitative view of the RV along with tricuspid annular plane systolic excursion (TAPSE). Left ventricular systolic dysfunction was characterized by M-mode and fractional shortening.\u003c/p\u003e\u003cp\u003eFurther, under the revised guidelines, treatment of cardiac dysfunction utilized inotropes such as low-dose epinephrine (≤ 0.05 mcg/kg/min) and maintenance of the serum ionized calcium level at 5-5.5 mg/dL, reflecting the role of calcium in supporting the function of the neonatal myocardium \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. In the setting of RV dysfunction with systemic or supra-systemic RV pressures, we initiated prostaglandin E1 (PGE1) therapy to maintain ductal patency and systemic output \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. The addition of milrinone could be utilized at ≥ 24 hours of life if cardiac dysfunction persisted. Blood pressure goals were based on physiologic endpoints of perfusion with avoidance of supra-systemic blood pressures. Given the potential additional benefit of reduction in pulmonary vascular resistance (PVR), hypotension was managed with norepinephrine and vasopressin as first and second line vasopressors, respectively \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. The use of iNO was avoided in the setting of LV or combined RV + LV dysfunction, unless cardiac dysfunction resolved and pulmonary hypertension persisted. Inhaled prostacyclins (PGI2) were reserved for infants with pulmonary hypertension refractory to other interventions. Long-term management of pulmonary hypertension was preferentially treated with sildenafil with the availability of intravenous PGI2 (treprostinil) for severe cases. Our respiratory strategy utilized first-intention pressure-controlled ventilation and a PEEP of 4 cmH\u003csub\u003e2\u003c/sub\u003eO to limit hyperinflation during the initial lung recruitment period. Infants were transitioned to volume-targeted ventilation to maintain functional residual capacity (FRC) to limit pulmonary vasoreactivity \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. High frequency oscillatory ventilation (HFOV) was utilized as a rescue modality for refractory hypercarbia.\u003c/p\u003e\u003ch3\u003e4. Data Collection\u003c/h3\u003e\u003cp\u003eDemographic data were collected by retrospective chart review and included gestational age, male sex, birthweight, reported maternal race. Prenatal indices collected were O/E LHR, side of hernia, liver position, and TFLV\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Birth characteristics were inborn delivery, Apgar scores, mode of delivery, and initial arterial blood gas measurements. An infant was considered inborn if delivered at our primary delivery hospital, Barnes Jewish Hospital Parkview Tower, which is physically connected to our NICU by a bridge.\u003c/p\u003e\u003cp\u003eWe report length-of-stay for survivors, surgical repair approach, use of HFOV, overall survival to discharge, ECMO utilization, ECMO survival, and discharge respiratory support. Measures of cardiac dysfunction were determined by echocardiography in the first 24 hours of life, and for the post-guideline cohort we characterize the cardiac function over the first 72 hours of life. We report the use of the following vasoactive infusions in both cohorts: dopamine, norepinephrine, epinephrine, calcium gluconate infusion, and milrinone as well as pulmonary vasodilator therapy with iNO in the first 48 hours of life, iNO during the hospital stay, sildenafil, treprostinil, inhaled prostacyclins, and use of PGE1 therapy.\u003c/p\u003e\u003ch3\u003e5. Statistical Analysis\u003c/h3\u003e\u003cp\u003e Descriptive statistics were used to characterize baseline data, demographic information, and clinical outcomes for the historical and post-guideline cohorts. Categorical data comparing outcomes between the two cohorts were analyzed with the Fisher’s exact test. Continuous data were analyzed using a Mann Whitney U test and reported as median and IQR. For TFLV and ECMO duration, which were normally distributed between the two cohorts, an unpaired t-test was used, and results were reported as mean and standard deviation. Data were analyzed using GraphPad Prism 10® (Boston, MA). Significance was defined as \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05.\u003c/p\u003e"},{"header":"Results","content":"\n\u003ch3\u003e1. Baseline Characteristics\u003c/h3\u003e\n\u003cp\u003eA total of 117 infants were identified with 104 infants included for analysis. Eight infants were excluded from the historical cohort: 2 with Trisomy 18, 1 with CDH\u0026thinsp;+\u0026thinsp;giant omphalocele, 1 with Morgagni hernia, and 4 with multiple congenital anomalies where comfort care was pursued by the family. Five were excluded from the post-guideline cohort: 3 with Morgagni hernia, 1 with complex congenital heart disease where comfort care was pursued by the family, and 1 infant with CDH\u0026thinsp;+\u0026thinsp;giant omphalocele. After delineation into treatment epochs, the historical cohort was comprised of 51 infants, and the post-guideline cohort contained 53 infants.\u003c/p\u003e \u003cp\u003eThere were no statistical differences in infant birth weight, maternal race, mode of delivery, Apgar scores, intrathoracic liver position, or initial arterial blood gas measurements (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). There was a higher percentage of male infants in the historical cohort with a lower gestational age (39 weeks vs 38 weeks, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.034) and trend toward lower O/E LHR (49% vs. 41.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.053) in the post-guideline cohort. There was no difference in CDH severity between the two cohorts (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). More infants underwent minimally invasive repair in the post-guideline cohort (9.8% vs. 26.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) reflecting a change in surgical practice with more surgeons utilizing minimally invasive approaches between the two cohorts rather than a difference in cohort severity. A similar number of infants underwent patch repair, and there was a small decrease in non-repair in the post-guideline cohort (9.8% vs. 3.8%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.265). There was no significant difference in the proportion of infants discharged home on room air, on oxygen by nasal cannula, or with a tracheostomy at time of NICU discharge in either cohort.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCohort characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHistorical\u0026nbsp;Cohort\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;51)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePost-Guideline\u0026nbsp;Cohort\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;53)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep-\u003c/em\u003evalue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eGestational\u0026nbsp;age, weeks, median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (37\u0026ndash;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (36\u0026ndash;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.034\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMale sex, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43 (84.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (56.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBirthweight, grams, median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3080 (2800\u0026ndash;3470)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3130 (2555\u0026ndash;3387)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.649\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLeft CDH, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47 (92.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45 (84.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.359\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eIntrathoracic\u0026nbsp;liver, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (49.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (47.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eO/E LHR, %, median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46.5\u0026nbsp;(34.3\u0026ndash;64.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40.0 (32.0-48.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eTFLV, %, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.41 (14.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35.55 (21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.249\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAPGAR 1 min, median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (2\u0026ndash;7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (1\u0026ndash;7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.778\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAPGAR 5 min, median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (5\u0026ndash;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (5\u0026ndash;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.961\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eFirst pH, median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.21 (7.09\u0026ndash;7.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.17 (7.02\u0026ndash;7.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.183\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eFirst paO2 mmHg, median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.0 (44.0-125.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e55.0 (45.5\u0026ndash;75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.268\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eFirst pCO2 mmHg, median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.5 (46.0\u0026ndash;86.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68.0 (52.5\u0026ndash;91.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.469\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eVaginal delivery, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 (66.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eInborn, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (78.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (71.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.500\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaternal ethnicity, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eWhite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (80.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47 (88.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.285\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBlack\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (11.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (9.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.758\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHispanic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.358\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAsian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCDH severity, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (45.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (35.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.425\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (23.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (35.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.202\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (31.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (28.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e0.831\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSurgical\u0026nbsp;repair\u0026nbsp;approach, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eOpen\u0026nbsp;laparotomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (80.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e37 (69.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMinimally invasive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e14 (26.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.041\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePatch repair\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (45.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e21 (41.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.686\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNon-repair\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e2 (3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.484\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eRepair on ECMO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (76.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e3 (21.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eTime of\u0026nbsp;initial\u0026nbsp;echo, median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (2.5\u0026ndash;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e2 (2\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNumber of\u0026nbsp;echos, median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (1\u0026ndash;6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e7 (3\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviations: IQR\u0026thinsp;=\u0026thinsp;interquartile range, CDH\u0026thinsp;=\u0026thinsp;congenital diaphragmatic hernia, O/E LHR\u0026thinsp;=\u0026thinsp;observed-to‐expected lung‐to‐head ratio, SD\u0026thinsp;=\u0026thinsp;standard deviation, TFLV\u0026thinsp;=\u0026thinsp;total fetal lung volume, min\u0026thinsp;=\u0026thinsp;minute, ECMO\u0026thinsp;=\u0026thinsp;extracorporeal membrane oxygenation, echo\u0026thinsp;=\u0026thinsp;echocardiogram\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical outcomes of the infant cohort\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHistorical\u0026nbsp;Cohort\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;51)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003ePost-Guideline\u0026nbsp;Cohort\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;53)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003ePrimary outcomes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSurvival to discharge, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (68.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e47 (88.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.016\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eECMO utilization, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (51.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e14 (26.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.015\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eECMO survival, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (42.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e10\u0026nbsp;(71.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eECMO duration, days, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.42 (13.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e12.6 (6.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.040\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVentilation and nitric oxide, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHFOV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (58.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e18 (33.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.018\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eiNO\u0026nbsp;during hospitalization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (74.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e30 (56.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e0.065\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eiNO\u0026nbsp;in first\u0026nbsp;48 hours\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (62.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e15 (28.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCardiac Dysfunction, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAny cardiac dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (37.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e33 (62.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.018\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eiNO\u0026nbsp;in first\u0026nbsp;48 hours\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (94.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e12 (36.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eECMO utilization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (68.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e12 (36.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.043\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSurvival with cardiac dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (47.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e27 (81.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.014\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eType of dysfunction (among those with dysfunction), n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eRV dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (42.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e16 (48.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e0.775\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLV dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e2 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e0.175\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eRV\u0026thinsp;+\u0026thinsp;LV dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (36.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e15 (45.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e0.575\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVasoactive and vasodilator\u0026nbsp;use,\u0026nbsp;n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDopamine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (64.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e1 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eEpinephrine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (11.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e31 (58.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCalcium gluconate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e25 (47.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNorepinephrine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (27.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e30 (56.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.0031\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMilrinone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (39.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e19 (35.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.840\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePGE1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e23 (43.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSildenafil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (52.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e23 (43.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.433\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eTreprostinil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e8 (15.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.006\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eInhaled prostacyclin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (13.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e5 (9.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.551\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDischarge respiratory support, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eRoom air\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (82.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e37 (78.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.781\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNasal cannula\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (11.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e6 (12.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eTracheostomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e4 (8.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eRoom air\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (82.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e37 (78.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.781\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLength of stay, days, median [IQR]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.0 (28.0\u0026ndash;94.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e54.0\u0026nbsp;(30.0-130.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c9\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eAbbreviations: ECMO\u0026thinsp;=\u0026thinsp;extracorporeal membrane oxygenation, SD\u0026thinsp;=\u0026thinsp;standard deviation, HFOV\u0026thinsp;=\u0026thinsp;high-frequency oscillatory ventilation, iNO\u0026thinsp;=\u0026thinsp;inhaled nitric oxide, RV\u0026thinsp;=\u0026thinsp;right ventricular, LV\u0026thinsp;=\u0026thinsp;left ventricular, PGE1\u0026thinsp;=\u0026thinsp;prostaglandin E1\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003e2. Survival, ECMO Utilization and Cardiac Dysfunction\u003c/h3\u003e\n\u003cp\u003eOur primary outcome of overall survival to hospital discharge was significantly higher in the post-guideline cohort (68.6% vs. 88.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). In the post-guideline cohort, ECMO utilization decreased from 51.0% to 26.4% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015) and ECMO survival trended higher (42.3% vs. 71.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.104) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Importantly, analysis of outcomes stratified by CDH severity based on prenatal parameters revealed an improvement in survival and decreased ECMO utilization for each severity cohort in the post-guideline cohort (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe initial postnatal echo was performed at a median time of 2 hours in the post-guideline cohort compared to a median time of 4 hours in the historical cohort (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001). With greater emphasis on the identification of cardiac dysfunction and post-repair monitoring of pulmonary hypertension, the post-guideline cohort received a greater total number of echocardiograms during their NICU stay (3 vs 7, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Cardiac dysfunction was identified in the first 24 hours in a higher proportion of the post-guideline infants with CDH (37.3% vs 62.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), which may reflect increased surveillance of cardiac dysfunction as opposed to a true increase between the two cohorts. In the post-guideline cohort RV dysfunction was most common in 16 (30.2%) infants followed by RV\u0026thinsp;+\u0026thinsp;LV dysfunction in 15 (28.3%) infants and only 2 (3.7%) infants had isolated LV dysfunction.\u003c/p\u003e \u003cp\u003eWe next interrogated rates of survival and ECMO utilization among infants with CDH with isolated RV or LV dysfunction or RV\u0026thinsp;+\u0026thinsp;LV dysfunction. In the post-guideline cohort, we observed 100% survival in infants with isolated RV or LV dysfunction (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Infants with combined RV\u0026thinsp;+\u0026thinsp;LV dysfunction trended towards improved survival in the post-guideline cohort, though this did not meet statistical significance (28.5% vs 60.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.362). Overall, ECMO utilization decreased for infants with cardiac dysfunction in the post-guideline cohort (68.4% vs 36.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.043) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e We characterized the change in cardiac function over time in the post-guideline cohort (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). 86.8% of infants in the cohort had normal cardiac function at 72 hours of life and all infants with isolated LV and all but one with RV dysfunction had resolution. There remained a component of dysfunction in 6 infants with RV\u0026thinsp;+\u0026thinsp;LV dysfunction, and all 6 of those infants required ECMO.\u003c/p\u003e\n\u003ch3\u003e3. Change in vasoactive and pulmonary vasodilator use\u003c/h3\u003e\n\u003cp\u003eThe physiology-driven guideline strongly recommended against dopamine use with its unfavorable effect on pulmonary vascular resistance \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e and to limit iNO use in the setting of LV or RV\u0026thinsp;+\u0026thinsp;LV dysfunction, so we next characterize differences in the use of vasoactive medications and pulmonary vasodilators among the two cohorts (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC-D). Dopamine use decreased from 64.7% to 1.9% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001) whereas low-dose epinephrine administration increased from 11.8% to 58.5% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in the historical cohort compared to the post-guideline cohort, respectively. Norepinephrine use increased from 27.5% to 56.6% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0031) and calcium gluconate infusions increased from 3.9% to 47.2% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). There was no significant change in milrinone use.\u003c/p\u003e \u003cp\u003eThere were also no changes in sildenafil or inhaled prostacyclin use between the two cohorts. No infants received IV treprostinil in the historical cohort, compared with eight infants in the post-guideline cohort (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006). This reflected a shift in practice with treprostinil being added as a pulmonary vasodilator in the post-guideline cohort, but not for the historical cohort. Inhaled nitric oxide use during the hospital stay showed a decreased trend from 74.6% to 56.6% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.065) with a significant decrease in iNO use during the first 48 hours of life from 62.2% to 28.3% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in the post-guideline cohort. In infants with cardiac dysfunction, iNO use in the first 48 hours dropped significantly from 94.7% to 36.3% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) of infants. PGE1 therapy increased in the post-guideline cohort from 3.9% to 43.4% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Together, these data support recognition and treatment of cardiac dysfunction with targeted vasoactive therapy as part of comprehensive care guidelines to optimize outcomes in infants with CDH.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the largest single-center cohort study reporting early identification and treatment of cardiac dysfunction in infants with CDH. Early identification of cardiac dysfunction, implementation of a core multidisciplinary CDH team, and physiology-driven resuscitation and care guidelines resulted in an increase in survival and decrease in ECMO requirement overall and in infants with cardiac dysfunction in our single center.\u003c/p\u003e \u003cp\u003eCenter variation in outcomes is not unique to CDH and is widely reported for many neonatal specific diseases such as the incidence of bronchopulmonary dysplasia (BPD) \u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e, very low birth weight (VLBW) infants \u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, gastroschisis \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e, and congenital heart disease \u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. Prior reports have suggested high volume (\u0026gt;\u0026thinsp;7\u0026ndash;10 cases per year) CDH centers have improved mortality \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e and lower recurrence rates \u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. There also exist individual high performing centers \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e whose reported outcomes are better than national datasets. This association between higher volumes of infants with CDH and improved outcomes suggests that increased exposure and expertise in complex cardiorespiratory physiology is a modifiable factor in improving outcomes. While center volume remained consistent at a median of 9 CDH infants a year, we improved expertise and exposure via creation of a focused CDH care team and geographic cohorting of infants. This approach has been described for other NICU-specific diagnoses with the creation of BPD-specific teams \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e and teams dedicated to the care of VLBW infants \u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e. With this consistent care team, we have seen our primary outcome of survival to discharge improve to 88.7% and ECMO utilization decrease to 26.4%. The existence of a dedicated team, however, does not guarantee improved outcomes. The care delivered must be consistently guided by physiology coupled with current literature and a quality improvement mentality to bridge remaining gaps in evidence \u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. We hypothesized that early recognition and treatment of cardiac dysfunction is another modifiable factor to improve outcomes in infants with CDH based on several reports which identify ventricular function as a determinant in outcomes \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e. Increasing recognition of cardiac dysfunction and its interplay with pulmonary hypertension have led to the identification of specific phenotypes that can guide targeted therapy for infants with CDH \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. These phenotypes, while imperfect, allow for identification of a mild phenotype, an RV phenotype with pulmonary hypertension and RV dysfunction, and a LV or RV\u0026thinsp;+\u0026thinsp;LV dysfunction phenotype with post-capillary pulmonary hypertension. We describe performing an early echocardiogram so that subsequent therapy can target the specific phenotype present (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). We did not see any physiologic disturbance or intolerance during the early postnatal echo in infants with CDH. We found that two-thirds of the post-guideline cohort had some form of cardiac dysfunction. Our results mirror that of Patel et al with RV and RV\u0026thinsp;+\u0026thinsp;LV dysfunction being more common than isolated LV dysfunction \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. No infants with normal cardiac function on the first postnatal echo developed dysfunction later in their course, and cardiac function was normal by 72 hours in 86.8% of the cohort (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). The 6 infants with RV\u0026thinsp;+\u0026thinsp;LV dysfunction that did not normalize ultimately required ECMO support. This is consistent with, and reinforces, data demonstrating that infants with biventricular dysfunction are at the greatest risk for morbidity and mortality \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Early identification of RV\u0026thinsp;+\u0026thinsp;LV dysfunction may allow for targeted treatment to improve outcomes in this cohort and provides additional data for use in the decision around need for ECMO support.\u003c/p\u003e \u003cp\u003eIn addition, the new approach couples the treatment of cardiac dysfunction with guidelines to decrease inhaled nitric oxide (iNO) use in the setting of LV or RV\u0026thinsp;+\u0026thinsp;LV dysfunction and to discontinue the use of dopamine \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e. The historical approach to blood pressure management in the NICU was to utilize dopamine as a first line vasoactive after fluid administration. However, dopamine has a dose-dependent receptor selectivity resulting in variable physiologic effects and has an unfavorable action on PVR \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Instead, we implemented a more targeted vasoactive approach to complex CDH physiology. If cardiac dysfunction was identified, we intervened with low-dose epinephrine and calcium gluconate infusions. We sought to balance the treatment of cardiac dysfunction and pulmonary hypertension by utilizing a ventilator strategy that prevents hyperinflation, and subsequent elevations in PVR, and decreases in lung compliance. This was coupled with maintenance of ductal patency with PGE1 in infants with systemic or suprasystemic pulmonary hypertension \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Our data show that dopamine use was discontinued, targeted treatment of cardiac dysfunction was common, and that PGE1 use increased significantly in the post-guideline cohort. A complete approach to infants with CDH is necessary for success. It is not just identification of cardiac dysfunction, but a treatment strategy that focuses on concomitant pulmonary hypoplasia and pulmonary hypertension.\u003c/p\u003e \u003cp\u003eWhile this is the largest single center CDH cohort reporting early identification and treatment of cardiac dysfunction, it remains limited by the single-center nature. We do not use targeted neonatal echocardiography (TNE) at our center, therefore while LV function is objective, there remains subjectivity in the identification of RV dysfunction. There was a great deal of heterogeneity in the care of infants with CDH in the historical cohort, so we cannot say with certainty which intervention has resulted in improved outcomes. However, it is clear from this data that cardiac dysfunction is prevalent and can complicate the transition to extra-uterine life in infants with CDH. The strength of this study is that we leverage a NICU team approach with existing pediatric cardiology resources to identify cardiac dysfunction. This approach does not require additional training in TNE or neonatal hemodynamics and is a generalizable approach for centers that do not have a neonatal hemodynamics program.\u003c/p\u003e \u003cp\u003eThese data add to the growing body of literature that recognition and intervention of cardiac dysfunction is equally as important as the care of pulmonary hypoplasia and pulmonary hypertension. We present our approach to the management of cardiac dysfunction, but we do not want to overshadow the role gentle ventilation, targeted use of pulmonary vasodilators, excellent surgical partnership, nutrition \u003csup\u003e\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e, and high fidelity ECMO \u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e play in the outcomes of infants with CDH. The ability of a multi-disciplinary team to work together to deliver high fidelity intensive care is key to improving outcomes in this population.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eA dedicated care team improves expertise and consistency in the care of infants with CDH and cardiac dysfunction is prevalent in early postnatal echocardiograms of infants with CDH. A targeted postnatal echo is well tolerated and often yields clinically relevant information. We report a generalizable approach to identification and treatment of cardiac dysfunction that improved outcomes in our single-center cohort. Infants with RV\u0026thinsp;+\u0026thinsp;LV dysfunction have the highest ECMO utilization and highest mortality in our cohort. This phenotype remains the most refractory cohort to treatment, suggesting additional study and development of specific care strategies to decrease ECMO utilization and improve survival are needed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConflict of Interest:\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;All authors declare no competing financial interests.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics and Consent to Participate:\u003c/em\u003e\u003c/strong\u003eThis study was approved by the Washington University in St. Louis Institutional Review Board (#202510238)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding:\u003c/em\u003e\u003c/strong\u003eNo sources of funding were received for the completion of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthor Contributions:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatrick E. Sloan: data collection, designed the study, statistical analysis, and drafting of the manuscript.\u003c/p\u003e\n\u003cp\u003eLila S. Sanning: review, statistical analysis and drafting of the manuscript\u003c/p\u003e\n\u003cp\u003eCaren Liviskie: review and statistical analysis of the manuscript\u003c/p\u003e\n\u003cp\u003eKristen Clark: review of the manuscript\u003c/p\u003e\n\u003cp\u003eKylie Bushroe: review of the manuscript\u003c/p\u003e\n\u003cp\u003eMelissa Riley: review of the manuscript\u003c/p\u003e\n\u003cp\u003eAnna Lijowksa: review of the manuscript\u003c/p\u003e\n\u003cp\u003eJesse Vrecenak: designed the study and review of the manuscript\u003c/p\u003e\n\u003cp\u003eTasnim Najaf: designed the study, statistical analysis, and drafting of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eThe authors thank Gina Myers, RN and Amy Distler, RN at St. Louis Children’s Hospital for their roles in maintaining the clinical database used for cohort identification and data acquisition. We also acknowledge infants with CDH, their families, and all caregivers who promote excellence in this patient population.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMontalva L, Zani A. Assessment of the nitrofen model of congenital diaphragmatic hernia and of the dysregulated factors involved in pulmonary hypoplasia. \u003cem\u003ePediatr Surg Int\u003c/em\u003e 2019, \u003cstrong\u003e35\u003c/strong\u003e(1)\u003cstrong\u003e:\u003c/strong\u003e 41-61.\u003c/li\u003e\n\u003cli\u003eBhombal S, Patel N. Diagnosis \u0026amp; management of pulmonary hypertension in congenital diaphragmatic hernia. \u003cem\u003eSemin Fetal Neonatal Med\u003c/em\u003e 2022, \u003cstrong\u003e27\u003c/strong\u003e(4)\u003cstrong\u003e:\u003c/strong\u003e 101383.\u003c/li\u003e\n\u003cli\u003eMontalva L, Antounians L, Zani A. 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Developing a Small Baby Program for the Extremely Low Birth Weight: The Wee CARE Team. \u003cem\u003eNeonatal Netw\u003c/em\u003e 2021, \u003cstrong\u003e40\u003c/strong\u003e(4)\u003cstrong\u003e:\u003c/strong\u003e 233-241.\u003c/li\u003e\n\u003cli\u003ePhillips R, Solomon J, Dixon L, Altimier L. Neuroprotective Infant and Family-Centered Developmental Care for the Tiniest Babies: Perspectives from Key Members of the Neonatal Intensive Care Unit Small Baby Team. \u003cem\u003eCrit Care Nurs Clin North Am\u003c/em\u003e 2024, \u003cstrong\u003e36\u003c/strong\u003e(2)\u003cstrong\u003e:\u003c/strong\u003e 167-184.\u003c/li\u003e\n\u003cli\u003ePatel N, Massolo AC, Kipfmueller F. Congenital diaphragmatic hernia-associated cardiac dysfunction. \u003cem\u003eSemin Perinatol\u003c/em\u003e 2020, \u003cstrong\u003e44\u003c/strong\u003e(1)\u003cstrong\u003e:\u003c/strong\u003e 151168.\u003c/li\u003e\n\u003cli\u003eSeri I. Cardiovascular, renal, and endocrine actions of dopamine in neonates and children. \u003cem\u003eJ Pediatr\u003c/em\u003e 1995, \u003cstrong\u003e126\u003c/strong\u003e(3)\u003cstrong\u003e:\u003c/strong\u003e 333-344.\u003c/li\u003e\n\u003cli\u003eSloan P, Johng S, Daniel JM, Rhee CJ, Mahmood B, Gravari E\u003cem\u003e, et al.\u003c/em\u003e A clinical consensus guideline for nutrition in infants with congenital diaphragmatic hernia from birth through discharge. \u003cem\u003eJ Perinatol\u003c/em\u003e 2024, \u003cstrong\u003e44\u003c/strong\u003e(5)\u003cstrong\u003e:\u003c/strong\u003e 694-701.\u003c/li\u003e\n\u003cli\u003eKays DW. ECMO in CDH: Is there a role? \u003cem\u003eSemin Pediatr Surg\u003c/em\u003e 2017, \u003cstrong\u003e26\u003c/strong\u003e(3)\u003cstrong\u003e:\u003c/strong\u003e 166-170.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9216925/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9216925/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eIdentify how a core congenital diaphragmatic hernia (CDH) team coupled with early recognition and treatment of cardiac dysfunction changed outcomes for infants with CDH.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e A retrospective chart review compared a historical cohort from 2015\u0026ndash;2019 (n\u0026thinsp;=\u0026thinsp;51) with a post-guideline cohort from 2020\u0026ndash;2025 (n\u0026thinsp;=\u0026thinsp;53). Statistical analysis was performed with Fisher\u0026rsquo;s exact, unpaired t-test, and Mann Whitney U-test.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSurvival improved from 68.6% to 88.7% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016) and ECMO utilization decreased, 51.0% to 26.4% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015). Infants with cardiac dysfunction had increased survival (47.3% vs. 81.8%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014) and less ECMO utilization (68.4% vs. 36.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.043). Vasoactive choices evolved with dopamine replaced by norepinephrine, low-dose epinephrine, or calcium gluconate. Inhaled nitric oxide (iNO) use in the first 48 hours decreased significantly while prostaglandin E1 (PGE1) use increased.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eWe implemented a core CDH team focused on a generalizable, physiology-driven approach to identify and treat cardiac dysfunction using standard neonatal echocardiography to improve outcomes.\u003c/p\u003e","manuscriptTitle":"Team-based care with early recognition and treatment of cardiac dysfunction for infants with CDH","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-31 06:54:29","doi":"10.21203/rs.3.rs-9216925/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2026-05-05T16:26:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-02T03:22:28+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-04-27T21:25:12+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-04-09T02:56:00+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-04-02T20:56:20+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-03-27T00:29:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-26T11:51:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-25T01:47:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Perinatology","date":"2026-03-25T01:47:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"892f669b-ed90-4c67-962d-237e3a15aaf8","owner":[],"postedDate":"March 31st, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"revise","date":"2026-05-05T16:26:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-02T03:22:28+00:00","index":1,"fulltext":"This content is not available."}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":65222194,"name":"Health sciences/Health care/Paediatrics"},{"id":65222195,"name":"Biological sciences/Physiology/Cardiovascular biology"},{"id":65222196,"name":"Health sciences/Diseases/Gastrointestinal diseases"}],"tags":[],"updatedAt":"2026-05-05T16:35:23+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-31 06:54:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9216925","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9216925","identity":"rs-9216925","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}