Continuous Prostanoid Initiation in Severe Pulmonary Hypertension in the Pediatric Cardiac Intensive Care Unit.

OBJECTIVE: Limited data exists regarding prostanoid (PGI2) use in critically ill patients with pulmonary hypertension. (PH) in the pediatric cardiac intensive care unit (CICU) setting. MATERIALS AND METHODS: Single center, retrospective study of patients with diagnosis of PH who received continuous PGI2 and were admitted to CICU from January/2015 to April/2022. Data collected included patient demographics and clinical characteristics including diagnosis, etiology of PH, vasoactive and ventilatory support, length of stay, and survival. Type, initial, maximum, and final dose of PGI2 as well as hemodynamic data was obtained. Data reported as mean ± standard deviation. Significance taken p value < 0.05. RESULTS: 24 patients received PGI2 therapy at a mean age of 3.1 years, range (0-16.6 years). PGI2 was in the form of IV epoprostenol in 12 patients, IV treprostinil in 6, and SQ treprostinil in 6 patients. Mean initial dose was 2.79 ng/kg/min, max dose 18.75 ng/kg/min, and mean duration of therapy was 38.5 days. At PGI2 initiation, 21 (87.5%) were on vasoactive infusions, 19 (79.2%) mechanically ventilated (MV), and 6 (25%) were on extracorporeal membrane oxygenation (ECMO). The in-hospital mortality rate was 37.5% (n = 9). Patients MV and on ECMO support had higher risk of death (p = 0.04, and < 0.01, respectively). CONCLUSION: PGI2 therapy was tolerated in approximately 50% of patients with the most common side effect being hypotension leading to discontinuation in 1/3rd of patients. Ongoing evaluation of the benefits of PGI2 for patients in the CICU setting will help better identify patient selection, type, and dosing of PGI2.

Total vascular resistance increases during volume-unloading in asymptomatic single ventricle patients.

OBJECTIVE: While the surgical stages of single ventricle (SV) palliation serve to separate pulmonary venous and systemic venous return, and to volume-unload the SV, staged palliation also results in transition from parallel to series circulation, increasing total vascular resistance. How this transition affects pressure loading of the SV is as yet unreported. METHODS: We performed a retrospective chart review of Stage I, II, and III cardiac catheterization (CC) and echocardiographic data from 2001-2017 in all SV pts, with focus on systemic, pulmonary, and total vascular resistance (SVR, PVR, TVR respectively). Longitudinal analyses were performed with log-transformed variables. Effects of SVR-lowering medications were analyzed using Wilcoxon rank-sum testing. RESULTS: There were 372 total patients who underwent CC at a Stage I (median age of 4.4 months, n=310), Stage II (median age 2.7 years, n = 244), and Stage III (median age 7.3 years, n = 113). Total volume loading decreases with progression to Stage III (P< 0.001). While PVR gradually increases from Stage II to Stage III, and SVR increases from Stage I to Stage III, TVR dramatically increases with progress towards series circulation. TVR was not affected by use of systemic vasodilator therapy. TVR, PVR, SVR, and CI did not correlate with indices of SV function at Stage III. CONCLUSIONS: TVR steadily increases with an increasing contribution from SVR over progressive stages. TVR was not affected by systemic vasodilator agents. TVR did not correlate with echo-based indices of SV function. Further studies are needed to see if modulating TVR can improve exercise tolerance and outcomes.

Risk Factors for Adverse Events in Children with Pulmonary Hypertension Undergoing Cardiac Catheterization.

Pulmonary hypertension (PH) can lead to progressive heart failure with high morbidity and mortality. Cardiac catheterization (CC) is the gold standard for diagnosis and response to vasodilatory medications. The invasive nature of CC and associated anesthesia predispose this patient population to adverse events including death. Catheterization records were queried from 1/1/2011 to 10/31/2016. Patients with PH, defined as pulmonary vascular resistance (PVR) greater than 3 WU m2, pulmonary artery pressure above 20 mmHg, and pulmonary wedge pressure less than or equal to 15 mmHg, who underwent hemodynamic CC were included in this retrospective study. Both patients with and without congenital heart disease were included. There were 198 CC in 191 patients. Adverse events (n = 28, 14.1%) included cardiac arrest, increased respiratory support requiring ICU care, PH crisis, bradycardia/hypotension requiring intervention, and arrhythmias. Odds of an adverse event increased by 22% for every 15-min increase in procedure times (OR 1.22, CI 1.01-1.39, p = 0.002) and were significantly increased for procedures longer than 80 min (OR 3.75, CI 1.56-9.00, p = 0.007) (Fig. 1). Patients with an adverse event had higher mean pulmonary artery pressures while breathing oxygen (43 [35-58] versus 34 [27-44] mmHg, p = 0.017) and oxygen with inhaled nitric oxide (37 [32-56] versus 32 [25-40] mmHg, p = 0.026). Females carried more risk than males (OR 3.88, CI 1.44-10.40, p = 0.007). Younger age, medication regimens, prematurity, and genetic disease did not carry an increased risk. Adverse events are common in pediatric patients with PH undergoing CC. The risk of adverse events correlates with greater procedure times and higher mean pulmonary artery pressure. Minimizing procedure time may improve patient outcomes.

N-terminal pro-B-type-natriuretic peptide as a screening tool for pulmonary hypertension in the paediatric population.

BACKGROUND: Although cardiac catheterisation (cath) is the diagnostic test for pulmonary hypertension, it is an invasive procedure. Echocardiography (echo) is commonly used for the non-invasive diagnosis of pulmonary hypertension but maybe limited by lack of adequate signals. Therefore, emphasis has been placed on biomarkers as a potential diagnostic tool. No prior paediatric studies have simultaneously compared N-terminal pro-B-type-natriuretic peptide (NTproBNP) with cath/echo as a potential diagnostic tool. The aim of this study was to determine if NTproBNP was a reliable diagnostic tool for pulmonary hypertension in this population. METHODS: Patients were divided into Study (echo evidence/established diagnosis of pulmonary hypertension undergoing cath) and Control (cath for small atrial septal defect/patent ductus arteriosus and endomyocardial biopsy post cardiac transplant) groups. NTproBNP, cath/echo data were obtained. RESULTS: Thirty-one patients met inclusion criteria (10 Study, 21 Control). Median NTproBNP was significantly higher in the Study group. Echo parameters including transannular plane systolic excursion z scores, pulmonary artery acceleration time and right ventricular fractional area change were lower in the Study group and correlated negatively with NTproBNP. Receiver operation characteristic curve analysis demonstrated NTproBNP > 389 pg/ml was 87% specific for the diagnosis of pulmonary hypertension with the addition of pulmonary artery acceleration time improving the specificity. CONCLUSIONS: NTproBNP may be a valuable adjunctive diagnostic tool for pulmonary hypertension in the paediatric population. Echo measures of transannular plane systolic excursion z score, pulmonary artery acceleration time and right ventricular fractional area change had negative correlations with NTproBNP. The utility of NTproBNP as a screening tool for pulmonary hypertension requires validation in a population with unknown pulmonary hypertension status.

Aicardi goutières syndrome is associated with pulmonary hypertension.

While pulmonary hypertension (PH) is a potentially life threatening complication of many inflammatory conditions, an association between Aicardi Goutières syndrome (AGS), a rare genetic cause of interferon (IFN) overproduction, and the development of PH has not been characterized to date. We analyzed the cardiac function of individuals with AGS enrolled in the Myelin Disorders Bioregistry Project using retrospective chart review (n = 61). Additional prospective echocardiograms were obtained when possible (n = 22). An IFN signature score, a marker of systemic inflammation, was calculated through the measurement of mRNA transcripts of type I IFN-inducible genes (interferon signaling genes or ISG). Pathologic analysis was performed as available from autopsy samples. Within our cohort, four individuals were identified to be affected by PH: three with pathogenic gain-of-function mutations in the IFIH1 gene and one with heterozygous TREX1 mutations. All studied individuals with AGS were noted to have elevated IFN signature scores (Mann-Whitney p < .001), with the highest levels in individuals with IFIH1 mutations (Mann-Whitney p < .0001). We present clinical and histologic evidence of PH in a series of four individuals with AGS, a rare interferonopathy. Importantly, IFIH1 and TREX1 may represent a novel cause of PH. Furthermore, these findings underscore the importance of screening all individuals with AGS for PH.

Risk Factors for Development of Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia: Systematic Review and Meta-Analysis.

OBJECTIVES: Preterm infants with bronchopulmonary dysplasia (BPD) are at increased risk for development of Pulmonary Hypertension (PHT). We performed a systematic review and meta-analysis to identify risk factors for development of PHT in infants with BPD. STUDY DESIGN: A systematic review identified risk factors for the development of PHT in infants with BPD. A meta-analysis of the pooled data was performed for each individual risk factor. RESULT: Of the 20 risk factors identified, 10 were repeated more than once in nine studies. Meta analysis showed that duration of mechanical ventilation, length of stay, oligohydramnios, use of high frequency ventilation, small for gestational age, sepsis and severity of BPD were significant risk factors; while birth weight and gestational age were inversely related. CONCLUSION: Several clinical variables are predictive of the development of PHT in infants with BPD. Prospective studies are needed to transform these risk factors into a risk-based scoring system.

Early characteristics of infants with pulmonary hypertension in a referral neonatal intensive care unit.

BACKGROUND: Approximately 8-23% of premature infants develop pulmonary hypertension (PH), and this diagnosis confers a higher possibility of mortality. As a result, professional societies recommend PH screening in premature infants. However, the risk factors for and the outcomes of PH may differ depending on the timing of its diagnosis, and little evidence is available to determine at-risk infants in the referral neonatal population. ï»¿The objective of this study was to define clinical and echocardiographic characteristics of infants with pulmonary hypertension during the neonatal hospital course and at or near-term. METHODS: Infants who had the following billing codes: < 32 weeks, birth weight < 1500 g, neonatal unit, and echocardiograph had records abstracted from a data warehouse at Children's Healthcare of Atlanta. The outcome was defined as late PH on the final echocardiogram for all patients, and, separately, for patients with multiple studies. Descriptive statistics, univariable, and multivariable models were evaluated, and odds ratios and 95% confidence intervals are expressed below as (OR, CI). RESULTS: 556 infants were included in the overall study, 59 had PH on their final echocardiogram (11%). In multivariable analyses, atrial septal defect (2.9, 1.4-6.1), and intrauterine growth restriction (2.7, 1.2-6.3) increased the odds of late PH, whereas caffeine therapy decreased PH (0.4, 0.2-0.8). When the analyses were restricted to 32 infants who had multiple echocardiograms during their hospitalization, the association between atrial septal defect (5.9, 2.0-16.5) and growth restriction (3.7, 1.3-10.7) and late PH was strengthened, but the effect of caffeine therapy was no longer significant. In this smaller subgroup, infants with late PH had their final echocardiogram at a median of 116 days of life, and 42-74% of them had right ventricular pathology. CONCLUSIONS: Early clinical variables are associated with PH persistence in a referral neonatal population. Identification of early clinical factors may help guide the ascertainment of infant risk for late PH, and may aid in targeting sub-groups that are most likely to benefit from PH screening.

Quantitative Assessment of Ventricular Septal Contour for Estimation of Right Ventricular Pressure.

BACKGROUND: Qualitative assessment of ventricular septal flattening is commonly used in pediatric patients with pulmonary hypertension (PH) who lack adequate tricuspid regurgitation (TR) Doppler signal. We sought to determine the relation between quantitative measures of septal flattening including the eccentricity index (EIs) and a novel marker, the septal flattening angle (SFA) with right ventricular systolic pressure (RVSP). METHODS: Subjects (≤18 years) with an anatomically normal heart, an adequate TR signal to obtain a peak velocity, and a simultaneous systemic systolic blood pressure (SBP) was included. RVSP was derived using TR gradient. Eccentricity index (EIs) and the SFA in systole were measured offline and correlated with RVSP/SBP. RESULTS: Of the 108 subjects, RVSP/SBP was < 50% in 77 and ≥ 50% in 31. In those with RVSP/SBP ≥50%, the median SFA was significantly lower (7.4° vs. 22°, p < 0.0001), and the median EIs was higher (1.61 vs. 1.07, p < 0.0001). SFA and EIs had a significant correlation with RVSP/SBP (rs = -0.70 and 0.61, respectively). Area under the curve was higher for SFA compared to EIs (0.92 and 0.85, respectively). The sensitivity and specificity of SFA for predicting an RVSP/SBP ≥ 50% using a cut point of 16° was 84% and 95% and for an EIs cut point of 1.35 was 74.2% and 96.1%, respectively. CONCLUSION: Septal flattening angle and EIs are quantitative measures of ventricular septal flattening that correlate well with RVSP/SBP and should be considered more routinely in clinical practice, especially in patients with inadequate TR Doppler signal.

Elevated tricuspid regurgitant velocity as a marker for pulmonary hypertension in children with sickle cell disease: less prevalent and predictive than previously thought?

Although elevated tricuspid regurgitant velocity (TRV), an echocardiographic marker for pulmonary hypertension, has previously been tied to mortality in adult patients with sickle cell disease, recent data demonstrated that it correlates poorly with catheterization findings. We describe the largest echocardiographic evaluation of pediatric patients with sickle cell disease to date, specifically the results of a protocol whereby a TRV≥250 cm/s prompted further evaluation. We investigated if elevated TRV would independently identify patients at risk for increased morbidity. A clinical echocardiographic database containing 630 patients with sickle cell disease was retrospectively reviewed; 120 patients (19%) met inclusion criteria and were compared 1:1 to randomly selected age-matched controls from the same database. By multivariate analysis, the elevated TRV cohort did not differ from controls in likelihood of acute chest episodes, hospitalization, or stroke. The study cohort's mean TRV in fact decreased to 242±33 cm/s at follow-up without a discernible and comprehensive intervention to explain the improvement. Three patients had catheterization-proven pulmonary hypertension. In conclusion, elevated TRV in children with sickle cell disease is less prevalent than previously thought and is not independently associated with increased short-term morbidity.

Improvement in Tricuspid Annular Plane Systolic Excursion with Pulmonary Hypertension Therapy in Pediatric Patients.

BACKGROUND: Tricuspid annular plane systolic excursion (TAPSE) has emerged as a novel and reliable measure of right ventricular (RV) function. The purpose of this study was to determine the effect of pulmonary hypertension (PH) therapy on TAPSE in pediatric patients and compare TAPSE to other quantitative measures of RV function. METHODS: A retrospective review of medical records and echocardiograms of patients in the PH clinic from January 2011 to August 2013 was done. Echocardiograms were analyzed prior to initiation or addition of a PH drug and at least 8 weeks later. Following quantitative measures of RV function were compared: TAPSE, TAPSE age-based z-score, RV fractional area change (RVFAC), tricuspid annular S', tricuspid inflow E/tricuspid annular E' velocity (TV E/E'), and RV myocardial performance index (RVMPI). RESULTS: Of the 37 patients included in this study (median age 0.6 years), 23 (62.2%) were treatment naive and others had a new PH drug added to their regimen at the time of the baseline echocardiogram. The median duration between the baseline and follow-up echocardiogram was 8 (2-25) months. There was a significant improvement in TAPSE and TAPSE age-based z-score on the follow-up echocardiogram. RVFAC, tricuspid S', TV E/E', and RVMPI did not show a statistically significant change. CONCLUSION: In contrast to the other echocardiographic markers of RV function, TAPSE, and TAPSE age-based z-score significantly improve after initiation or addition of PH therapy and can be used for serial noninvasive monitoring of RV function in pediatric PH patients.

Pulmonary hypertension in Kawasaki disease.

This report describes the case of two pediatric patients who demonstrated echocardiographic evidence of pulmonary hypertension (PH) during the acute phase of Kawasaki disease. The etiology of PH development in this setting is currently unknown, but the authors hypothesize that pulmonary vasculitis may play a significant role. Fortunately, the PH appeared to be self-limited and resolved in both cases with routine treatment of Kawasaki disease.

Maternal antibody-associated fetal second-degree heart block and atrial flutter: case report and review.

Exposure to maternal anti-Ro (SS-A) and anti-La (SS-B) antibodies is a well-described risk factor for the development of fetal atrioventricular (AV) block. The role of maternal fluorinated steroids in the treatment and prevention of antibody-mediated fetal AV block is controversial. Fetal atrial flutter has rarely been described in association with maternal antibodies. This report describes a case of fetal exposure to maternal anti-Ro antibodies with associated second-degree AV block and atrial flutter. Interestingly, the reported patient had 2:1 AV conduction during both normal atrial rates (consistent with AV node conduction disease) and episodes of flutter (consistent with physiologic AV node functionality). The fetus was treated with transplacental digoxin and dexamethasone, which resolved both rhythm disturbances. The case report is followed by a brief discussion of AV block and atrial flutter associated with maternal antibody exposure.

Prevalence of pulmonary hypertension in obstructive sleep apnea and relation to disease severity.

STUDY OBJECTIVES: The purpose of this study is to examine the prevalence of pulmonary hypertension (PHTN) in children with obstructive sleep apnea (OSA) using echocardiographic (ECHO) parameters and to examine ECHO findings as they relate to severity of OSA. METHODS: A retrospective cohort study of subjects with OSA undergoing polysomnogram (PSG) and ECHO within 30 days of each other, between 01/01/15 - 12/31/20 was performed, excluding cardiac disease. ECHO evidence of PHTN was defined as ≥ 2 of the following: tricuspid regurgitation (TR) velocity > 3.0 m/sec, pulmonary acceleration/ejection time (AT/ET) ratio < 0.3, left ventricular eccentricity index (EI) > 1.5, right ventricular (RV) dysfunction or abnormal geometry. ECHO parameters were compared to OSA severity using obstructive apnea-hypopnea index (AHI), % time with oxygen saturation < 90%, and % time with end-tidal carbon dioxide > 50 mmHg. Odds ratios were calculated for each comorbidity to evaluate for risk factors. RESULTS: Of 509 subjects, 4.3% were found to have echocardiographic evidence of PHTN. Neither oAHI severity, nor worsening hypoxemia or hypercarbia correlated with worsening ECHO parameters. Comorbidities including bronchopulmonary dysplasia (OR 5.22, 2.01 - 13.53), prematurity (OR 3.10, 1.28 - 7.47), and autism (OR 3.69, 1.01 - 13.49) were associated with increased odds of PHTN. CONCLUSIONS: Significant echocardiographic evidence of PHTN was seen in 4.3% of children with OSA. ECHO findings of PHTN did not correlate with PSG parameters. Comorbidities, particularly bronchopulmonary dysplasia, prematurity, and autism, appear to be a risk factor for developing PHTN in patients with OSA.

Oral treprostinil use in children: a multicenter, observational experience.

Pulmonary arterial hypertension is a progressive, incurable disease that occurs in adults and children alike. Therapeutic options for children are limited and infrequently described, including newer agents such as treprostinil, an oral prostanoid. Herein, we describe the pooled pediatric experience in 28 patients from four pediatric pulmonary hypertension programs over two years. This descriptive, observational study describes the various methods of initiation of oral treprostinil in both prostanoid-naïve patients and those transitioning from parenteral or inhaled prostanoids. The youngest patient was four years old and the smallest weighed 16 kg. We describe adverse reactions and their management. Most patients in this study (27/28) were able to successfully initiate therapy. However, gastrointestinal adverse reactions were common; half of the patients started on this therapy had discontinued it within the two-year study period.

Atrial Septal Defects Accelerate Pulmonary Hypertension Diagnoses in Premature Infants.

Between 4 and 16% of extremely premature infants have late pulmonary hypertension (PH) (onset >30 days of life), and infants with PH have a higher risk of tracheostomy and death. Atrial septal defects (ASD) increase pulmonary blood flow and may promote PH in at-risk infants. The objective of this study was to determine if infants with ASD develop PH sooner than those without ASD. Infants who were born at < 32 weeks' gestation, with an echocardiogram on day of life > 30, and without congenital anomalies were included. Infants with and without ASD were evaluated for the time to PH diagnosis, defined as the day of the first echocardiogram that showed PH. A multivariable model with ASD and significant variables on PH and a Cox proportional hazard model evaluating time to PH was determined. Of the 334 infants with echocardiograms, 57 had an ASD and 26% of these developed PH vs. 12% without ASD (p = 0.006). Infants with PH had lower gestational age (25.2 vs. 26.2 weeks, p = 0.005), smaller birthweight (699 vs. 816 gm, p = 0.001), and more prematurity complications than infants without PH. More PH infants had maternal African-American race (63.9 vs. 36.1%), right ventricular dysfunction (23.9 vs. 3.2%, p < 0.001), right ventricular dilation (52.1 vs. 8.6%, p < 0.001), or right ventricular hypertrophy (51.2 vs. 10.1%, p < 0.001), than infants without PH. At 150 days of life, 78.1% (95% CI 64.6-86.9%) of infants with ASD survived without PH, compared with 90.9% (95% CI 86.7-93.8%) of infants without ASD, and the unadjusted hazard for development of PH for infants with ASD was 2.37 (95% CI 1.29-4.36). When significant clinical variables were controlled, infants with ASD had a 2.44-fold (95% CI 1.27-4.68) increase in PH, compared with infants without ASD. Most PH in infants with or without ASD was diagnosed by day of life 150, but infants with ASD had an over 2-fold increased hazard for PH during their neonatal hospitalization. Premature infants with ASD should be followed closely for PH development and further studies to investigate the optimal timing of closure are needed.

Accelerated intravenous rehydration.

To determine whether accelerated intravenous (i.v.) rehydration using a new Isotonic Dehydration Worksheet results in: (1) complications in serum sodium or volume status, and (2) decreased duration of i.v. fluid therapy or length of hospital stay, we conducted a retrospective cohort study utilizing chart review. An intervention group of 98 children, ages 1 month to 12 years, treated with the Isotonic Dehydration Worksheet from December 2000 through March 2001 was compared to a control group of 61 children treated from December 1999 through March 2000 before introduction of the Worksheet. Complication rates were low and did not differ between the 2 groups. Mean unadjusted lengths of i.v. therapy (35.3 vs. 33.7 hours) and of hospital stay (47.0 vs. 49.3 hours) were not significantly different between the 2 groups. Introduction of an accelerated rehydration protocol was well-tolerated by patients but did not result in a significant decrease in the outcome variables examined. Other factors may have a greater impact on the outcome variables, and a prospective study to address these questions is planned.

Accelerated intravenous rehydration.

This study was undertaken to determine whether accelerated intravenous (i.v.) rehydration using a new Isotonic Dehydration Worksheet results in: (1) complications in serum sodium or volume status; and (2) decreased duration of i.v. fluid therapy or length of hospital stay. A retrospective cohort study utilizing chart review method was used. An intervention group of 98 children ages 1 month to 12 years treated with the Isotonic Dehydration Worksheet from December 2000 to March 2001 was compared to a control group of 61 children treated from December 1999 to March 2000 before introduction of the worksheet. Complication rates were low and did not differ between the 2 groups. Mean unadjusted lengths of i.v. therapy (35.3 vs. 33.7 hours) and of hospital stay (47.0 vs. 49.3 hours) were not significantly different between the 2 groups. Introduction of an accelerated rehydration protocol was well tolerated by patients, but did not result in a significant decrease in the outcome variables examined. Other factors may have a greater impact on the outcome variables, and a prospective study to address these questions is planned.