To investigate the clinical presentation, manifestations, and response to therapy of portopulmonary hypertension (PPHTN) in pediatric patients.
This study was a retrospective chart review describing the evaluation and course of 7 patients with PPHTN.
Causes of portal hypertension (HTN) included biliary atresia (3 cases), cavernous transformation of the portal vein (2 cases), and primary sclerosing cholangitis and cryptogenic cirrhosis (1 case each). The median interval from the diagnosis of portal HTN to PPHTN was 12.1 years. Four patients presented with a new heart murmur, 4 presented with syncope, and 3 presented with dyspnea. Although electrocardiograms (ECGs) and chest x-rays were normal in 3 and 2 patients, respectively, echocardiograms diagnosed pulmonary HTN in all 7 patients. Five patients had cardiac catheterizations; the average mean pulmonary artery pressure was 65 ± 20 mm Hg. Response to therapy was variable, and 4 patients died. Postmortem lung tissue examination revealed plexiform lesions and pulmonary arteriopathy.
Because symptoms are subtle and may be overlooked, pediatric patients with portal HTN who develop a new heart murmur, dyspnea, syncope, or who are being evaluated for liver transplantation require evaluation for PPHTN. ECG and chest x-ray are insensitive screens for PPHTN. An echocardiogram and cardiology evaluation is essential for the diagnosis.
Therapeutic approaches in pediatric pulmonary arterial hypertension (PAH) are based primarily on clinician experience, in contrast to the evidence-based approach in adults with pulmonary hypertension. There is a clear and present need for non-invasive and objective biomarkers to guide the accurate diagnosis, treatment, and prognosis of this disease in children. The multifaceted spectrum of disease, clinical presentation, and association with other diseases makes this a formidable challenge. However, as more progress is being made in the understanding and management of adult PAH, the potential to apply this knowledge to children has never been greater. This review explores the state of the art with regard to non-invasive biomarkers in PAH, with an eye toward those adult PAH biomarkers potentially suitable for application in pediatric PAH.
pulmonary arterial hypertension; pediatric; biomarkers; imaging; magnetic resonance; echocardiography; right ventricle
Cardiopulmonary exercise testing is widely used in a variety of cardiovascular conditions. Ventilatory efficiency slope can be derived from submaximal exercise testing. The present study sought to evaluate the relationship between ventilatory efficiency slope and functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension.
Seventy six children and young adults with a diagnosis of pulmonary hypertension (PH) performed 258 cardiopulmonary exercise tests from 2001 to 2011. Each individual PH test was matched to a control test. Ventilatory efficiency slope was compared to traditional measures of functional capacity and disease severity including WHO functional classification, peak oxygen consumption, and invasive measures of pulmonary arterial pressures and pulmonary vascular resistance.
Ventilatory efficiency slope was significantly higher in patients with pulmonary arterial hypertension, with an estimated increase of 7.2 for each increase in WHO class (p < 0.0001), compared with normal control subjects (38.9 vs. 30.9, p<0.001). Ventilatory efficiency slope correlated strongly with invasive measures of disease severity including pulmonary vascular resistance index (r =0.61), pulmonary artery pressure (r =0.58), mean pulmonary artery pressure/mean aortic pressure ratio (r =0.52), and peak VO2 (r=−0.58). Ventilatory efficiency slope in 12 patients with poor outcomes (9 death, 3 lung transplant), was significantly elevated compared to patients who did not (51.1 vs. 37.9, p<0.001).
Ventilatory efficiency slope correlates well with invasive and noninvasive markers of disease severity including peak VO2, WHO functional class, and catheterization variables in pediatric patients with PH. Ventilatory efficiency slope may be a useful noninvasive marker for disease severity.
Ventilatory efficiency slope; VE/VCO2 slope; Pulmonary hypertension; Cardiopulmonary exercise testing; Pediatric
Recent trials in adult PAH revealed the efficacy of ambrisentan. However, in children with PAH, the clinical safety and pharmacokinetics of ambrisentan has not been well studied. Our aim was to investigate the clinical safety, pharmacokinetics, tolerability, and efficacy of endothelin receptor antagonist therapy with ambrisentan in children with pulmonary arterial hypertension (PAH). This retrospective cohort study provides clinical data from pediatric patients with PAH receiving ambrisentan as add-on therapy or transition from bosentan. Safety included evaluation of adverse events including aminotransferase abnormalities. The clinical impact was evaluated by improvement from baseline in clinical variables. A total of 38 pediatric patients with PAH received ambrisentan. Fifteen of 38 patients were switched from bosentan to ambrisentan. The remaining 23 children were treated with ambrisentan as an add-on therapy due to disease progression. In both transition and add-on cases, mean pulmonary artery pressure significantly improved (transition; 55 ± 18 vs. 45 ± 20 mmHg, n = 13, P = 0.04, add-on; 52 ± 17 vs. 45 ± 19 mmHg, n = 13, P = 0.03) during the follow-up. World Health Organization functional class improved in 31% of patients, but one patient required an atrial septostomy due to disease progression during the follow-up period (median, range; 20, 4–44 months). Five patients (13%) discontinued ambrisentan due to severe headache, lack of clinical efficacy, or near syncope. Ten patients (26%) had side effects associated with ambrisentan treatment, including nasal congestion, headache, and flushing. However, no patients had aminotransferase abnormalities and there were no deaths after initiation of ambrisentan during follow-up. Pharmacokinetics were evaluated in sixteen children treated with ambrisentan from 2.5 mg to 10.0 mg; the mean peak plasma concentration was 738 ± 452 ng/ml, mean time to peak plasma concentration was 3.2 ± 2.1 hours, and mean area under the curve plasma concentration was 6657 ± 4246 ng·hour/ml. In conclusion, initial experience with ambrisentan in children suggests that treatment is safe with similar pharmacokinetics to those in adults and may improve PAH in some children.
endothelin receptor antagonists; safety; tolerability; World Health Organization
Dexmedetomidine, an α-2 receptor agonist, is widely used in children with cardiac disease. Significant hemodynamic responses, including systemic and pulmonary vasoconstriction, have been reported after dexmedetomidine administration. Our primary goal of this prospective, observational study was to quantify the effects of dexmedetomidine initial loading doses on mean pulmonary artery pressure (PAP) in children with and without pulmonary hypertension.
Subjects were children undergoing cardiac catheterization for either routine surveillance after cardiac transplantation (n = 21) or pulmonary hypertension studies (n = 21). After anesthetic induction with sevoflurane and tracheal intubation, sevoflurane was discontinued and anesthesia was maintained with midazolam 0.1 mg/kg IV (or 0.5 mg/kg orally preoperatively) and remifentanil IV infusion 0.5 to 0.8 μg/kg/min. Ventilation was mechanically controlled to maintain Pco2 35 to 40 mm Hg. When end-tidal sevoflurane was 0% and fraction of inspired oxygen (Fio2) was 0.21, baseline heart rate, mean arterial blood pressure, PAP, right atrial pressure, pulmonary artery occlusion pressure, right ventricular end-diastolic pressure, cardiac output, and arterial blood gases were measured, and indexed systemic vascular resistance, indexed pulmonary vascular resistance, and cardiac index were calculated. Each subject then received a 10-minute infusion of dexmedetomidine of 1 μg/kg, 0.75 μg/kg, or 0.5 μg/kg. Measurements and calculations were repeated at the conclusion of the infusion.
Most hemodynamic responses were similar in children with and without pulmonary hypertension. Heart rate decreased significantly, and mean arterial blood pressure and indexed systemic vascular resistance increased significantly. Cardiac index did not change. A small, statistically significant increase in PAP was observed in transplant patients but not in subjects with pulmonary hypertension. Changes in indexed pulmonary vascular resistance were not significant.
Dexmedetomidine initial loading doses were associated with significant systemic vasoconstriction and hypertension, but a similar response was not observed in the pulmonary vasculature, even in children with pulmonary hypertension. Dexmedetomidine does not appear to be contraindicated in children with pulmonary hypertension.
Because most medications for pediatric pulmonary hypertension (PH) are used off label and based on adult trials, little information is available on pediatric-specific adverse events (AEs). Although drug manufacturers are required to submit postmarket AE reports to the Food and Drug Administration (FDA), this information is rarely transmitted to practitioners. In the setting of a recent FDA warning for sildenafil, the authors sought to give a better description of the AEs associated with current therapies in pediatric PH. In January 2010, a written request was made to the Food and Drug Administration for AE records of commonly used PH medications. Reports were screened for pediatric patients, analyzed in terms of AEs, and compared with the medical literature. Arbitrarily, AEs that could be attributed to concomitant medications were not attributed to the PH medication in question. Adverse events occurring in more than 5 % of events for each drug were assumed to be associated with the targeted PH medication. Between November 1997 and December 2009, 588 pediatric AE reports (death in 257 cases) were reported for the three most commonly used therapies: bosentan, epoprostenol, and sildenafil. Many of the AEs were similar to those reported previously. However, 27 AEs not previously reported in the literature (e.g., pulmonary hemorrhage, hemoptysis, and pneumonia) were found. The FDA postmarket records for PH medications in pediatric patients show a significant number of AEs. The discovery of AEs not previously reported will better inform those caring for these complex and critically ill children, and the large number of deaths suggest they may be underreported in current literature.
Adverse drug events; Pediatrics; Pulmonary; hypertension
Pulmonary arterial hypertension (PAH) is a devastating disease with significant morbidity and mortality. At the macroscopic level, disease progression is observed as a complex interplay between mean pulmonary artery pressure, pulmonary vascular resistance, pulmonary vascular stiffness, arterial size, and flow. Wall shear stress (WSS) is known to mediate or be dependent on a number of these factors. Given that WSS is known to promote architectural vessel remodeling, it is imperative that the changes of this factor be quantified in the presence of PAH.
In this study, we analyzed phase contrast imaging of the right pulmonary artery derived from cardiovascular magnetic resonance to quantify the local, temporal and circumferentially averaged WSS of a PAH population and a pediatric control population. In addition, information about flow and relative area change were derived.
Although the normotensive and PAH shear waveform exhibited a WSS profile which is uniform in magnitude and direction along the vessel circumference at systole, time-averaged WSS (2.2 ± 1.6 vs. 6.6 ± 3.4 dynes/cm2, P = 0.018) and systolic WSS (8.2 ± 5.0 v. 20.0 ± 9.1 dynes/cm2, P = 0.018) was significantly depressed in the PAH population as compared to the controls. BSA-indexed PA diameter was significantly larger in the PAH population (1.5 ± 0.4 vs. 0.7 ± 0.1 cm/m2, P = 0.003).
In the presence of preserved flow rates through a large PAH pulmonary artery, WSS is significantly decreased. This may have implications for proximal pulmonary artery remodeling and cellular function in the progression of PAH.
Vessel size; Pulmonary hypertension; Wall shear stress; Cardiovascular magnetic resonance
Pediatric patients with severe pulmonary arterial hypertension (PAH) are treated with intravenous epoprostenol or intravenous or subcutaneous treprostinil. Little is known about longitudinal hemodynamics and outcomes of epoprostenol, treprostinil, and transitions from epoprostenol to treprostinil.
This was retrospective study of 77 pediatric patients (47 idiopathic PAH, 24 congenital heart disease-PAH) receiving epoprostenol or treprostinil from 1992 to 2010 at 2 centers. Outcomes were defined as living vs dead/transplant.
Mean age at baseline was 7.7 ± 5.2 years, with follow-up of 4.3 ± 3.4 years. Thirty-seven patients were treated with epoprostenol, 20 with treprostinil, and 20 were transitioned from epoprostenol to treprostinil. Mean pulmonary-to-systemic vascular resistance ratio (Rp/Rs) for epoprostenol was 1.0 ± 0.4, 0.8 ± 0.4, 0.8 ± 0.4, 1.0 ± 0.4, and 1.2 ± 0.4, respectively, at baseline, 1, 2, 3, and 4 years. For treprostinil, Rp/Rs was 0.9 ± 0.3, 0.7 ± 0.3, 0.5 ± 0.2, (p < 0.01 vs baseline), and 1.1 ± 0.2, respectively, at baseline, 1, 2, and 3 to 4 years, respectively. There were similar changes in mean pulmonary artery pressure and pulmonary vascular resistance index. The Rp/Rs 1 year after epoprostenol to treprostinil transition increased from 0.6 to 0.8 (n = 7). Changes not statistically significant unless noted. Eight patients died or received a transplant within 2 years of baseline; compared with the rest of the cohort, mean baseline Rp/Rs, right atrial pressure, and pulmonary vascular resistance index were significantly worse in this group. Thirty-nine patients remain on prostanoids, 17 are off, 16 died, and 5 received heart-lung transplant. Kaplan-Meier 5-year transplant-free survival was 70% (95% confidence interval, 56%-80%).
There was improvement in Rp/Rs on both therapies at 1 to 2 years that was not sustained. The 5-year transplant-free survival was better than in similar adult studies.
pediatric patients; pulmonary arterial hypertension; epoprostenol; treprostinil; hemodynamics
The prognosis for children with IPAH unresponsive to therapy is poor. We investigated the plasma proteome for a molecular basis of good versus poor outcome to long-term vasodilator therapy.
Plasma was collected at baseline or shortly after therapy initiation and following chronic vasodilator therapy, then divided into those with good outcome (n = 8), and those with a poor outcome (n = 7). To identify proteins unique to either outcome, we used differential gel electrophoresis and mass spectrometry. Results were confirmed by commercial enzyme-linked immunosorbent assay.
Before and after therapy, SAA-4 was 4-fold lower in those with good outcome compared to those with poor outcome, while serum paraoxonase/arylesterase-1 was increased 2-fold in those with good outcome versus poor outcome. After therapy, haptoglobin and hemopexin were 1.45- and 1.8-fold lower, respectively, in those with a good versus poor outcome. Among those with a good outcome, SAP was 1.3-fold lower prior to therapy.
Conclusions and clinical relevance
SAP and SAA-4 regulate circulating mononuclear phagocytes. As such, they may contribute to the differential response to chronic vasodilator therapy in the context of inflammation in IPAH.
Inflammation; Pulmonary hypertension; Vasodilators
Endothelin-1 is a potent vasoactive peptide that occurs in chronically high levels in humans with pulmonary hypertension and in animal models of the disease. Recently, the unfolded protein response was implicated in a variety of diseases, including pulmonary hypertension. In addition, evidence is increasing for pathological, persistent inflammation in the pathobiology of this disease. We investigated whether endothelin-1 might engage the unfolded protein response and thus link inflammation and the production of hyaluronic acid by pulmonary artery smooth muscle cells. Using immunoblot, real-time PCR, immunofluorescence, and luciferase assays, we found that endothelin-1 induces both a transcriptional and posttranslational activation of the three major arms of the unfolded protein response. The pharmacologic blockade of endothelin A receptors, but not endothelin B receptors, attenuated the observed release, as did a pharmacologic blockade of extracellular signal–regulated kinases 1 and 2 (ERK-1/2) signaling. Using short hairpin RNA and ELISA, we observed that the release by pulmonary artery smooth muscle cells of inflammatory modulators, including hyaluronic acid, is associated with endothelin-1–induced ERK-1/2 phosphorylation and the unfolded protein response. Furthermore, the synthesis of hyaluronic acid induced by endothelin-1 is permissive for persistent THP-1 monocyte binding. These results suggest that endothelin-1, in part because it induces the unfolded protein response in pulmonary artery smooth muscle cells, triggers proinflammatory processes that likely contribute to vascular remodeling in pulmonary hypertension.
unfolded protein response; endothelin; pulmonary artery smooth muscle; hyaluronic acid; inflammation
In pulmonary hypertension, as in many other diseases, there is a need for a smarter approach to evaluating new treatments. The traditional randomized controlled trial has served medical science well, but constrains the development of treatments for rare diseases. A workshop was established to consider alternative clinical trial designs in pulmonary hypertension and here discusses their merits, limitations and challenges to implementation of novel approaches.
pulmonary arterial hypertension; clinical trial design; adaptive designs; modeling and simulation; Bayesian modeling; group sequential designs; population enrichment
Background. Management of pediatric pulmonary hypertension (PH) remains challenging. We have assessed a panel of circulating proteins in children with PH to investigate their value as predictive and/or prognostic biomarkers. From these determinations, we aim to develop a practical, noninvasive tool to aid in the management of pediatric PH. Methods. Twelve cytokines and growth factors putatively associated with lung or vascular disease were examined in plasma specimens from 70 children with PH using multiplex protein array technology. Associations between hemodynamics, adverse events, and protein markers were evaluated. Results. Epidermal growth factor (EGF) and IL-6 were associated with important hemodynamics. Of the twelve proteins, VEGF and IL-6 were significantly, univariately associated with the occurrence of an adverse event, with odds ratios (95% confidence intervals) of 0.56 (0.33–0.98) and 1.69 (1.03–2.77), respectively. When hemodynamic predictors were combined with protein markers, the ability to predict adverse outcomes within the following year significantly increased. Conclusions. Specific circulating proteins are associated with hemodynamic variables in pediatric PH. If confirmed in additional cohorts, measurement of these proteins could aid patient care and design of clinical trials by identifying patients at risk for adverse events. These findings also further support a role for inflammation in pediatric PH.
Paediatric pulmonary hypertension, is an important cause of morbidity and mortality, and is insufficiently characterised in children. The Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry is a global, prospective study designed to provide information about demographics, treatment, and outcomes in paediatric pulmonary hypertension.
Consecutive patients aged 18 years or younger at diagnosis with pulmonary hypertension and increased pulmonary vascular resistance were enrolled in TOPP at 31 centres in 19 countries from Jan 31, 2008, to Feb 15, 2010. Patient and disease characteristics, including age at diagnosis and at enrolment, sex, ethnicity, presenting symptoms, pulmonary hypertension classification, comorbid disorders, medical and family history, haemodynamic indices, and functional class were recorded. Follow-up was decided by the patients’ physicians according to the individual’s health-care needs.
362 of 456 consecutive patients had confirmed pulmonary hypertension (defined as mean pulmonary artery pressure ≥25 mm Hg, pulmonary capillary wedge pressure ≤12 mm Hg, and pulmonary vascular resistance index ≥3 WU/m32). 317 (88%) patients had pulmonary arterial hypertension (PAH), which was idiopathic [IPAH] or familial [FPAH] in 182 (57%), and associated with other disorders in 135 (43%), of which 115 (85%) cases were associated with congenital heart disease. 42 patients (12%) had pulmonary hypertension associated with respiratory disease or hypoxaemia, with bronchopulmonary dysplasia most frequent. Finally, only three patients had either chronic thromboembolic pulmonary hypertension or miscellaneous causes of pulmonary hypertension. Chromosomal anomalies, mainly trisomy 21, were reported in 47 (13%) of patients with confirmed disease. Median age at diagnosis was 7 years (IQR 3–12); 59% (268 of 456) were female. Although dyspnoea and fatigue were the most frequent symptoms, syncope occurred in 31% (57 of 182) of patients with IPAH or FPAH and in 18% (eight of 45) of those with repaired congenital heart disease; no children with unrepaired congenital systemic-to-pulmonary shunts had syncope. Despite severe pulmonary hypertension, functional class was I or II in 230 of 362 (64%) patients, which is consistent with preserved right-heart function.
TOPP identifies important clinical features specific to the care of paediatric pulmonary hypertension, which draw attention to the need for paediatric data rather than extrapolation from adult studies.
The hemodynamic state of the pulmonary arteries is challenging to routinely measure in children due to the vascular circuit's position in the lungs. The resulting relative scarcity of quantitative clinical diagnostic and prognostic information impairs management of diseases such as pulmonary hypertension, or high blood pressure of the pulmonary circuit, and invites new techniques of measurement. Here we examine recent applications of macro-scale computational mechanics methods for fluids and solids – traditionally used by engineers in the design and virtual testing of complex metal and composite structures – applied to study the pulmonary vasculature, both in healthy and diseased states. In four subject areas, we briefly outline advances in computational methodology and provide examples of clinical relevance.
To assess protocols, demographics, and hemodynamics in pediatric patients undergoing catheterization for pulmonary hypertension (PH).
Pediatric specific data is limited on PH.
Review of the Mid-Atlantic Group of Interventional Cardiology (MAGIC) collaboration PH registry dataset.
Between November 2003 and October 2008, seven institutions submitted data from 177 initial catheterizations in pediatric patients with suspected PH. Pulmonary arterial hypertension associated with congenital heart disease (APAH-CHD) (n = 61, 34%) was more common than idiopathic PAH (IPAH) (n = 36, 20%). IPAH patients were older with higher mean pulmonary arterial pressures (mPAP) (P < 0.01). Oxygen lowered mPAP in patients with IPAH (P < 0.01) and associated PAH not related to congenital heart disease (APAH-non CHD) (P < 0.01). A synergistic effect was seen with inhaled Nitric Oxide (iNO) (P < 0.01). Overall 9/30 (29%) patients with IPAH and 8/48 (16%) patients with APAH-non CHD were reactive to vasodilator testing. Oxygen lowered pulmonary vascular resistance index (PVRI) in patients with APAH-CHD (P < 0.01). There was no additive effect with iNO but a subset of patients required iNO to lower PVRI below 5 WU·m2. General anesthesia (GA) lowered systemic arterial pressure (P < 0.01) with no difference between GA and procedural sedation on mPAP or PVRI. Adverse events were rare (n = 7) with no procedural deaths.
Pediatric patients with PH demonstrate a higher incidence of APAH-CHD and neonatal specific disorders compared to adults. Pediatric PH patients may demonstrate baseline mPAP < 40 mm Hg but > 50% systemic illustrating the difficulty in applying adult criteria to children with PH. Catheterization in children with PH is relatively safe.
pulmonary hypertension; pediatric; cardiac catheterization; hemodynamics; vasoreactivity
Treatment algorithms in pediatric PAH are derived from clinical trials in adult populations, and from clinical practice, but experience in children is limited. In this retrospective cohort study, we analyzed outcomes in a previously identified cohort of 86 consecutive children with pulmonary arterial hypertension (PAH) treated with bosentan as part of their treatment regimen. All children with idiopathic PAH (IPAH) or heritable PAH, and PAH associated with congenital heart disease (PAH-CHD) or connective tissue disease (PAH-CTD) who started bosentan treatment between May 2001 and April 2003 in two tertiary pediatric referral centers were followed with data collection ending August 2006. 86 children (37 males; 49 females) aged 11±5 years with IPAH/HPAH (n=36), PAH-CHD (n=48) or PAH-CTD (n=2) received bosentan as monotherapy (n=42) or as add-on to pre-existing continuous intravenous epoprostenol or subcutaneous treprostinil (n=44). Median observation period was 39 months (range 2–60). 34 patients (40%) received at least one additional PAH-specific therapy during follow-up. At end of data collection, 25 patients (29%) remained on bosentan, 43 (50%) had stopped bosentan, 11 (13%) had died while on bosentan, and 7 were lost to follow-up. At 4 years, the Kaplan-Meier estimate of disease progression in patients while on bosentan was 54% (7 patients at risk) with a survival estimate of 82% (16 patients at risk). Risk factors significantly associated with survival were WHO FC and indexed PVR. In conclusion, outcome in children with PAH managed with current treatment regimens, appears favorable. However, despite current therapy options, disease progression remains a concern.
Bosentan; pulmonary arterial hypertension; pediatrics; prostacyclin
The purpose of this study was to investigate the effect of sildenafil in patients with failing Fontan physiology.
A retrospective chart review was performed to compare history and available data in patients with Fontan circulations before and after starting sildenafil. The paired and unpaired Student’s t-tests were used for statistical analyses.
Six patients at our institution with Fontan physiology, persistent symptoms of cyanosis or effusion, and poor hemodynamics as measured in the catheterization laboratory were placed on sildenafil. One patient was not included in the analysis because of insufficient length of treatment. All patients had symptoms of failing Fontan hemodynamics with either persistent cyanosis or effusions. In this group, the mean pulmonary artery pressure was greater than 15 mm Hg (17.4 ± 1.5 mm Hg) with mean estimated pulmonary vascular resistance of 3.5 ± 1.0 Wood units × m2 prior to starting sildenafil.
Sildenafil significantly increased the systemic arterial oxyhemoglobin saturation in this group (82.8 ± 7.3% pre-treatment vs. 91.0 ± 5.5% post-treatment, P = .017). In the four out of five patients who have had follow-up catheterizations, there was a significant decrease in pulmonary artery pressure (17.4 ± 1.5 mm Hg pre-treatment vs. 13.8 ± 2.1 mm Hg post-treatment, P = .018) and in estimated pulmonary vascular resistance pre- and post-sildenafil treatment (3.5 ± 1.0 Wood units × m2 pre-treatment vs. 2.0 ± 0.4 Wood units × m2 post-treatment, P = .031).
Sildenafil may be a useful adjunct to therapy in patients with failing Fontan physiology likely through its function as a pulmonary vasodilator.
Single Ventricle; Fontan; Sildenafil; Pulmonary Vascular Resistance
Pulmonary vascular resistance (PVR) is the current standard for evaluating reactivity in children with pulmonary arterial hypertension (PAH). However, PVR measures only the mean component of right ventricular afterload and neglects pulsatile effects. We recently developed and validated an method to measure pulmonary vascular input impedance, which revealed excellent correlation between the zero-harmonic impedance value and PVR, and suggested a correlation between higher harmonic impedance values and pulmonary vascular stiffness (PVS). Here we show that input impedance can be measured routinely and easily in the catheterization laboratory, that impedance provides PVR and PVS from a single measurement, and that impedance is a better predictor of disease outcomes compared to PVR.
Pressure and velocity waveforms within the main PA were measured during right-heart catheterization of patients with normal PA hemodynamics (n=14) and those with PAH undergoing reactivity evaluation (49 subjects; 95 conditions). A correction factor needed to transform velocity into flow was obtained by calibrating against cardiac output. Input impedance was obtained off-line by dividing Fourier-transformed pressure and flow waveforms.
Exceptional correlation was found between the indexed zero harmonic of impedance and indexed PVR (y=1.095·x+1.381, R2=0.9620). Additionally, the modulus sum of the first two harmonics of impedance was found to best correlate with indexed pulse pressure over stroke volume (PP/SV) (y=13.39·x-0.8058, R2=0.7962). Amongst a subset of PAH patients (n=25), cumulative logistic regression between outcomes to total indexed impedance was better (RL2=0.4012) than between outcomes and indexed PVR (RL2=0.3131).
Input impedance can be consistently and easily obtained from PW Doppler and a single catheter pressure measurement, provides comprehensive characterization of the main components of RV afterload, and better predicts patient outcomes compared to PVR alone.
hypertension; pulmonary; pulmonary heart disease; pediatrics; echocardiography; hemodynamics
In 7 of 8 children with idiopathic pulmonary arterial hypertension treated with intravenous epoprostenol for > 1 year, concomitant use of bosentan allowed a reduction of epoprostenol and decreased its associated side effects without deterioration of clinical and hemodynamic parameters. In 3 children with normal or near-normal pulmonary artery pressure on epoprostenol, the addition of bosentan allowed discontinuation of epoprostenol and stabilization of hemodynamics for up to 1 year.
Outcomes of patients undergoing cavopulmonary palliation for single ventricle physiology may be impacted by living at altitude, as the passive pulmonary circulation is dependent on the resistance of the pulmonary vascular bed. The objective of this study is to identify risk factors for failure of cavopulmonary palliation at elevated altitude.
Methods and Results
Between January 1995 and March 2007, 122 consecutive patients living at a mean altitude of 1600 m (range 305 to 2570) underwent a bidirectional Glenn (BDG). There was one in-hospital mortality and 7 late deaths. 52 have proceeded to the Fontan procedure. Survival after BDG was 92.4% at 5 years. Freedom from palliation failure, defined as death, transplant, BDG/Fontan takedown, or revision was 81% at 5 years. At a mean follow-up of 39.8 months, 90 patients (75%) were in New York Heart Association class I. Patients with failing cavopulmonary circulation had higher pre-BDG pulmonary artery pressure (PAP) (18.3±6.1 mm Hg versus 14.8±5.1 mm Hg, P=0.016) and higher pre-BDG transpulmonary gradient (TPG) (11.2±6.2 mm Hg versus 7.7±4.3 mm Hg, P=0.014). Post-BDG, patients with palliation failure had increased PAP (15.0±5.7 mm Hg versus 10.8±2.8 mm Hg, P=0.008) and indexed pulmonary vascular resistance (PVRI) (2.43±1.0 Wood U · m2 versus 1.52±0.9 Wood U · m2, P=0.007).
The majority of patients at moderate altitude have favorable outcomes after BDG or Fontan palliation. Risk factors for palliation failure at elevated altitude include PAP >15 mm Hg, TPG >8 mm Hg, and PVRI >2.5 Wood U · m2.
Fontan procedure; single ventricle; altitude
Conventional management for multilevel left heart obstructions and mitral stenosis (Shone’s complex) involves multiple operations that carry additive risks. This study reviews our experience with reconstructive and transplantation approaches for Shone’s complex.
Between 1987 and 2007, 43 patients with mitral stenosis and one or more left-sided obstructions were identified: supramitral ring (n = 13), subaortic stenosis (n = 25), aortic stenosis (n = 24), hypoplastic arch (n = 20), and coarctation (n = 38). Thirty patients underwent a staged reparative approach, including 27 mitral and 51 left ventricular outflow tract operations. Thirteen patients were referred for transplantation. Patients with severe hypoplasia of the left ventricle were excluded.
There was one in-hospital death (2.5%) and six late deaths (14.2%). Actuarial 5- and 10-year survival for staged surgical and transplantation was 88% vs 61.3% and 83.1% vs 61.3% (p = 0.035). At a mean follow-up of 7.9 years, freedom from mitral reoperation was 83.3% and freedom from reoperation for subaortic stenosis was 78.0%. Wait-list mortality was 13.3% (2 of 13). Wait-list time exceeding 90 days was an incremental risk factor for death after transplantation (p = 0.005).
Despite the challenges of a reparative strategy for Shone’s complex, favorable survival and durability outcomes can be expected. Heart transplantation, although avoiding the pitfalls of staged repair, confers increased risks from ongoing physiologic derangements due to uncorrected left heart inflow and outflow obstructions during the wait for donor heart availability.
Purpose of review
Pulmonary artery hypertension (PAH) in children contributes significantly to morbidity and mortality in diverse pediatric cardiac, lung, hematologic and other diseases. Advances in pulmonary vascular biology over the past few decades have significantly expanded therapeutic strategies; however, many unique issues persist regarding our understanding of pediatric PAH.
Recent studies of pediatric PAH include those that highlight gaps in our understanding of pediatric diseases associated with PAH from those of adult onset, emphasizing the strong need for specific studies regarding unique aspects of the pathogenesis and treatment of children with PAH. Registries have begun to provide new data showing differences in physiology, course, and genetics between adult and pediatric forms of PAH. Unfortunately, therapeutic strategies in pediatric pulmonary hypertension are often limited to small observational studies in children and are dependent on results from larger adult studies. In addition, clinical endpoints for studies and care remain poorly defined in infants and children.
Despite many advances, long-term outcomes for children with PAH remain guarded and substantial challenges persist, especially with regard to understanding mechanisms and approach to severe PAH. Future studies are needed to develop novel biomarkers, clinical endpoints and interventions for young children with diverse causes of PAH.
bronchopulmonary dysplasia; congenital heart disease; endothelin; nitric oxide; phosphodiesterase inhibitors; prostacyclin
This study investigated the short- and long-term outcome of children with pulmonary arterial hypertension (PAH) treated with inhaled iloprost.
Inhaled iloprost has been approved for the treatment of adults with PAH, but little is known about the effects in children with PAH.
We evaluated the acute effects of inhaled iloprost on hemodynamic status and lung function and the response to long-term therapy in 22 children (range 4.5 to 17.7 years) with PAH (idiopathic, n = 12; congenital heart disease, n = 10). Cardiac catheterization, standard lung function testing before and after iloprost inhalation, 6-min walk test, World Health Organization functional class, and hemodynamic parameters were monitored.
Acute administration of inhaled iloprost lowered mean pulmonary artery pressure equivalent to the response to inhaled nitric oxide with oxygen. Acute iloprost inhalation reduced forced expiratory volume in 1 s and mid-volume forced expiratory flow by 5% and 10%, respectively, consistent with acute bronchoconstriction. At 6 months, functional class improved in 35%, decreased in 15%, and remained unchanged in 50% of children. Sixty-four percent of patients continued receiving long-term iloprost therapy, 36% stopped iloprost, due to lower airway reactivity, clinical deterioration, or death. In 9 patients on chronic intravenous prostanoids, 8 transitioned from intravenous prostanoids to inhaled iloprost, which continued during follow-up.
Inhaled iloprost caused sustained functional improvement in some children with PAH, although inhaled iloprost occasionally induced bronchoconstriction. Most patients tolerated the transition from intravenous to inhaled prostanoid therapy. Clinical deterioration, side effects, and poor compliance, owing to the frequency of treatments, could limit chronic treatment in children.
We sought to analyze the outcome of hemodynamically significant acute graft rejection in pediatric heart transplant recipients from a single-center experience. Acute graft rejection remains a major cause of morbidity and mortality for patients who undergo orthotopic heart transplantation and has been associated with the severity of the rejection episode. A retrospective review of all children experiencing a hemodynamically significant rejection episode after orthotopic heart transplantation was performed. Fifty-three patients with 54 grafts had 70 rejection episodes requiring intravenous inotropic support. Forty-one percent of these patients required high-dose inotropic support, with the remaining 59% of patients requiring less inotropic support. Overall graft survival to hospital discharge was 41% for patients in the high-dose group compared to 94% in the low-dose group. Six-month graft survival in patients who required high-dose inotropes remained at 41% compared to 44% in the low-dose group. Hemodynamically significant acute graft rejection in pediatric heart transplant recipients is a devastating problem with poor short- and long-term outcomes. Survival to hospital discharge is dismal in patients who require high-dose inotropic support. In contrast, survival to discharge is quite good in patients who require only low-dose inotropic support; however, six-month graft survival in this group is low secondary to a high incidence of graft failure related to worsening or aggressive transplant coronary artery disease.
Acute graft rejection; Pediatric heart transplant