...funding research, sharing discoveries.
David D Ivy
Chief and Selby's Chair of Pediatric Cardiology, University of Colorado Denver School of Medicine
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Physiological measurement 2010 May; 31(6)
Measurement uncertainty in pulmonary vascular input impedance and characteristic impedance estimated from pulsed-wave Doppler ultrasound and pressure: clinical studies on 57 pediatric patients.
Pulmonary vascular input impedance better characterizes right ventricular (RV) afterload and disease outcomes in pulmonary hypertension compared to the standard clinical diagnostic, pulmonary vascular resistance (PVR). Early efforts to measure impeda... expand abstractnce were not routine, involving open-chest measurement. Recently, the use of pulsed-wave (PW) Doppler-measured velocity to non-invasively estimate instantaneous flow has made impedance measurement more practical. One critical concern remains with clinical use: the measurement uncertainty, especially since previous studies only incorporated random error. This study utilized data from a large pediatric patient population to comprehensively examine the systematic and random error contributions to the total impedance uncertainty and determined the least error prone methodology to compute impedance from among four different methods. We found that the systematic error contributes greatly to the total uncertainty and that one of the four methods had significantly smaller propagated uncertainty; however, even when this best method is used, the uncertainty can be large for input impedance at high harmonics and for the characteristic impedance modulus. Finally, we found that uncertainty in impedance between normotensive and hypertensive patient groups displays no significant difference. It is concluded that clinical impedance measurement would be most improved by advancements in instrumentation, and the best computation method is proposed for future clinical use of the input impedance. collapse abstract
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British journal of clinical pharmacology 2009 Nov; 68(6)
Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Exposure to bosentan was lower in paediatric pulmonary arterial hypertension (PAH) patients treated with the marketed adult formulation at a dose of about 2 mg kg(-1) when compared with adult PAH patients. ... expand abstract* In healthy adult subjects, bosentan pharmacokinetics are less than dose-proportional at doses of >or=500 mg. WHAT THIS STUDY ADDS: * The pharmacokinetics of a new paediatric bosentan formulation were characterized in paediatric PAH patients. * The level of exposure to bosentan as observed in adult PAH patients cannot be reached in paediatric patients with b.i.d. dosing. * In paediatric PAH patients, nondose-proportional pharmacokinetics of bosentan occur at lower doses when compared with healthy adult subjects. AIM: To show equivalent bosentan exposure in paediatric patients with pulmonary arterial hypertension (PAH) when compared with a cohort of historical controls of adult PAH patients using a newly developed paediatric formulation. METHODS: Thirty-six paediatric PAH patients were enrolled in this multicentre, prospective, open-label, noncontrolled study and treated for 4 weeks with bosentan 2 mg kg(-1) b.i.d. and then for 8 weeks with 4 mg kg(-1) b.i.d. Blood samples were taken for pharmacokinetic purposes. Exploratory efficacy measurements included World Health Organization (WHO) functional class and parent's and clinician's Global Clinical Impression scales. RESULTS: Comparing children with a historical group of adults, the geometric mean ratio (90% confidence interval) of the area under the plasma concentration-time curve was 0.54 (0.37, 0.78), i.e. children had lower exposure to bosentan than adults. Bosentan concentrations following doses of 2 and 4 mg kg(-1) were similar. Improvements in WHO functional class and the Global Clinical Impression scales occurred mainly in bosentan-naive patients, whereas the rare worsenings occurred in patients already on bosentan prior to study initiation. The paediatric formulation was well accepted and bosentan well tolerated in this study. No cases of elevated liver enzymes or anaemia were reported. CONCLUSIONS: Exposure to bosentan, as shown comparing the results from this study with those from a study in adults, was different in paediatric and adult PAH patients. Since FUTURE-1 and past studies suggest a favourable benefit-risk profile for bosentan at 2 mg kg(-1) b.i.d., this dose is recommended for children with PAH. The new paediatric formulation was well tolerated. collapse abstract
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Journal of pediatric gastroenterology and nutrition 2009 Oct; 49(5)
Pulmonary vascular complications in asymptomatic children with portal hypertension.
OBJECTIVES:: To determine the prevalence of portopulmonary hypertension, hepatopulmonary syndrome (HPS), and intrapulmonary vascular shunting (IPVS) in children with clinically stable portal hypertension and to assess the value of vasoactive peptide ... expand abstractlevels, biochemical tests and clinical signs or symptoms to predict these conditions. PATIENTS AND METHODS:: A prospective, cross-sectional analysis was conducted on 33 children, ages 4 to 17 years, with stable cirrhosis (n = 28) or extrahepatic portal hypertension (n = 5). The children were screened for IPVS and hypoxia with contrast-enhanced echocardiography (cECHO) and pulse oximetry, and screened for pulmonary hypertension with Doppler echocardiography. Chemistries, radiographs, physical examinations, and levels of vasoactive peptides were compared between subjects with IPVS and those with normal cECHO. RESULTS:: No subject had pulmonary hypertension. Six (19%) had IPVS, all of which had intrahepatic causes of portal hypertension, and 1 of whom had HPS. Compared with subjects with normal cECHO, those with IPVS had biochemical evidence of more advanced liver disease and higher b-type natriuretic peptide levels. CONCLUSIONS:: Prevalence of portopulmonary hypertension and HPS appear to be rare in clinically stable children with portal hypertension. Intrapulmonary vascular shunting was present in 19% of these patients. A novel finding of this study is the elevation of b-type natriuretic peptide in children with IPVS. collapse abstract
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Infection control and hospital epidemiology : the official journal of the Society of Hospital Epidemiologists of America 2009 Aug; 30(9)
Closed-hub systems with protected connections and the reduction of risk of catheter-related bloodstream infection in pediatric patients receiving intravenous prostanoid therapy for pulmonary hypertension.
BACKGROUND: Intravenous prostanoids (epoprostenol and treprostinil) are effective therapies for pulmonary arterial hypertension but carry a risk of catheter-related bloodstream infection (CR-BSI). Prevention of CR-BSI during long-term use of indwelli... expand abstractng central venous catheters is important. OBJECTIVE: To evaluate whether using a closed-hub system and waterproofing catheter hub connections reduces the rate of CR-BSI per 1,000 catheter-days. DESIGN: Single-center open observational study (January 2003-December 2008). PATIENTS: Pediatric patients with pulmonary arterial hypertension who received intravenous prostanoids. METHODS: In July 2007, CR-BSI preventive measures were implemented, including the use of a closed-hub system and the waterproofing of catheter hub connections during showering. Rates of CR-BSI before and after implementing preventive measures were compared with respect to medication administered and type of bacterial infection. RESULTS: Fifty patients received intravenous prostanoid therapy for a total of 41,840 catheter-days. The rate of CR-BSI during the study period was 0.51 infections per 1,000 catheter-days for epoprostenol and 1.38 infections per 1,000 catheter-days for treprostinil, which differed significantly (P < .01). CR-BSIs caused by gram-negative pathogens occurred more frequently with treprostinil than with epoprostenol (0.91 infections per 1,000 catheter-days vs 0.08 infections per 1,000 catheter-days; P < .01). Patients treated with treprostinil after the implemented changes had a significant decrease in CR-BSI rate (1.95 infections per 1,000 catheter-days vs 0.19 infections per 1,000 catheter-days; P < .01). CONCLUSION: The closed-hub system and the maintenance of dry catheter hub connections significantly reduced the incidence of CR-BSI (particularly infections caused by gram-negative pathogens) in patients receiving intravenous treprostinil. collapse abstract
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Journal of the American College of Cardiology 2009 Aug; 54(8)
Outcome of extracorporeal membrane oxygenation for early primary graft failure after pediatric heart transplantation.
OBJECTIVES: We sought to analyze the indications and outcome of extracorporeal membrane oxygenation (ECMO) for early primary graft failure and determine its impact on long-term graft function and rejection risk. BACKGROUND: Early post-operative graft... expand abstract failure requiring ECMO can complicate heart transplantation. METHODS: A retrospective review of all children requiring ECMO in the early period after transplantation from 1990 to 2007 was undertaken. RESULTS: Twenty-eight (9%) of 310 children who underwent transplantation for cardiomyopathy (n = 5) or congenital heart disease (n = 23) required ECMO support. The total ischemic time was significantly longer for ECMO-rescued recipients compared with our overall transplantation population (276 +/- 86 min vs. 242 +/- 70 min, p < 0.01). The indication for transplantation, for ECMO support, and the timing of cannulation had no impact on survival. Hyperacute rejection was uncommon. Fifteen children were successfully weaned off ECMO and discharged alive (54%). Mean duration of ECMO was 2.8 days for survivors (median 3 days) compared with 4.8 days for nonsurvivors (median 5 days). There was 100% 3-year survival in the ECMO survivor group, with 13 patients (46%) currently alive at a mean follow-up of 8.1 +/- 3.8 years. The graft function was preserved (shortening fraction 36 +/- 7%), despite an increased number of early rejection episodes (1.7 +/- 1.6 vs. 0.7 +/- 1.3, overall transplant population, p < 0.05) and hemodynamically comprising rejection episodes (1.3 +/- 1.9 vs. 0.7 +/- 1.3, overall transplant population, p < 0.05). CONCLUSIONS: Overall survival was 54%, with all patients surviving to at least 3 years after undergoing transplantation. None of the children requiring >4 days of ECMO support survived. Despite an increased number of early and hemodynamically compromising rejections, the long-term graft function is similar to our overall transplantation population. collapse abstract
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Pediatric cardiology 2009 Apr; 30(4)
Long-term outcome of palliation with internal pulmonary artery bands after primary heart transplantation for hypoplastic left heart syndrome.
The purpose of this study was to describe the long-term outcome of infants with hypoplastic left heart syndrome (HLHS) who underwent placement of internal pulmonary artery bands as part of a transcatheter palliation procedure followed by primary hear... expand abstractt transplantation. Transcatheter palliation included stenting of the ductus arteriosus, decompression of the left atrium by atrial septostomy, and internal pulmonary artery band placement. Cardiac hemodynamics, pulmonary artery architecture, and pulmonary artery growth since transplantation are described. Nine infants with HLHS had internal pulmonary artery bands placed and underwent successful heart transplant. No infant required reconstruction of the pulmonary arteries at the time of transplant. At 1 year after transplant, all of the recipients had normal mean pulmonary artery pressure, pulmonary vascular resistance, and transpulmonary gradient. Pulmonary angiography performed at 1 year after transplant demonstrated no distortion of pulmonary artery anatomy with significant interval growth of the branch pulmonary arteries. There was 100% survival to hospital discharge after transplant in this cohort of infants. Transcatheter placement of internal pulmonary artery bands for HLHS offers protection of the pulmonary vascular bed while preserving pulmonary artery architecture and growth with good long-term outcome. collapse abstract
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European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2009 Mar; 35(4)
Implications of incising the ventricular septum in double outlet right ventricle and in the Ross-Konno operation.
OBJECTIVE: Incision into the ventricular septum in complex biventricular repair is controversial, and has been blamed for impairing left ventricular function. This retrospective study evaluates the risk of a ventricular septal incision in patients un... expand abstractdergoing double outlet right ventricle (DORV) repair and Ross-Konno procedure. METHODS: From January 2003 to September 2007, 11 patients with DORV had a ventricular septum (VS) incision and 12 DORV patients did not. Sixteen patients had a Ross-Konno, and 16 had an isolated Ross procedure. The ventricular septal incision was made to match at least the diameter of a normal aortic annulus. In DORV, the VSD was enlarged superiorly and to the left. In the Ross-Konno, the aortic annulus was enlarged towards the septum posteriorly and to the left. RESULTS: The median follow-up for the study is 19 months (1 month-4 years). For DORV, there were no significant differences in discharge mortality (p=0.22), late mortality (p=0.48), or late mortality plus heart transplant (p=0.093). Although patients with DORV and VSD enlargement have a more complex postoperative course, there were no differences in ECMO use (p=0.093), occurrence of permanent AV block (p=0.55), left ventricular ejection fraction (LVEF) (p=0.40), or shortening fraction (LVSF) (p=0.50). Similarly, for the Ross-Konno there were no significant differences in discharge mortality (p=0.30), late mortality (p=NS), LVEF (p=0.90) and LVSF (p=0.52) compared to the Ross, even though the Ross-Konno patients were significantly younger (p<0.0001). CONCLUSION: Making a ventricular septal incision in DORV repair and in the Ross-Konno operation does not increase mortality and does not impair the LV function. The restriction of the VSD remains an important issue in the management of complex DORV. These encouraging results need to be confirmed by larger series. collapse abstract
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The Journal of pediatrics 2009 Feb; 154(3)
Effects of long-term sildenafil treatment for pulmonary hypertension in infants with chronic lung disease.
OBJECTIVE: To determine the clinical course and outcomes of infants with chronic lung disease (CLD) and pulmonary hypertension (PH) who received prolonged sildenafil therapy. STUDY DESIGN: We conducted a retrospective review of 25 patients <2 years o... expand abstractf age with CLD in whom sildenafil was initiated for the treatment of PH while they were hospitalized from January 2004 to October 2007. Hemodynamic improvement was defined by a 20% decrease in the ratio of pulmonary to systemic systolic arterial pressure or improvement in the degree of ventricular septal flattening with serial echocardiograms. RESULTS: Chronic sildenafil therapy (dose range, 1.5-8.0 mg/kg/d) was initiated at a median of 171 days of age (range, 14-673 days of age) for a median duration of 241 days (range, 28-950 days). Twenty-two patients (88%) achieved hemodynamic improvement after a median treatment duration of 40 days (range, 6-600 days). Eleven of the 13 patients with interval estimates of systolic pulmonary artery pressure with echocardiogram showed clinically significant reductions in PH. Five patients (20%) died during the follow-up period. Adverse events leading to cessation or interruption of therapy occurred in 2 patients, 1 for recurrent erections, and the other had the medication held briefly because of intestinal pneumatosis. CONCLUSION: These data suggest that chronic sildenafil therapy is well-tolerated, safe, and effective for infants with PH and CLD. collapse abstract
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Cardiology in the young 2008 Nov; 18(6)
A curious isolated cystic lesion of the membranous atrioventricular septum.
We present the case of an isolated cystic lesion of the atrioventricular component of the membranous septum of unclear aetiology, but responsible for cardiomegaly and benign disturbances of cardiac rhythm. As far as we are aware, this type of lesion ... expand abstracthas not previously been documented. collapse abstract
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Neurogenetics 2009 Mar; 10(2)
Chromosomal microarray mapping suggests a role for BSX and Neurogranin in neurocognitive and behavioral defects in the 11q terminal deletion disorder (Jacobsen syndrome).
We performed a prospective analysis on 14 11q- patients to determine the relationship between the degree of cognitive impairment and relative deletion size. Seventeen measures of cognitive function were assessed. All nine patients with a deletion of ... expand abstractat least 12.1 Mb had severe global cognitive impairment, with full-scale IQ <50, whereas all five patients with smaller deletions,
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Chest 2009 Feb; 135(3)
Brain natriuretic peptide levels in managing pediatric patients with pulmonary arterial hypertension.
BACKGROUND: Pulmonary arterial hypertension (PAH) is an important determinant of morbidity and mortality in children. In this study, we aimed to investigate the value of brain natriuretic peptide (BNP) in a cohort of children with PAH, with respect t... expand abstracto monitoring disease severity as assessed by hemodynamic and echocardiographic parameters. METHODS: We performed a prospective study to determine whether BNP varies over time in this population and whether these changes track with hemodynamic or echocardiographic parameters. The population included a group of 78 pediatric patients from January 2005 to April 2008. All patients had received a diagnosis of PAH and had serum BNP, catheterization, and echocardiographic variables collected longitudinally. RESULTS: The median BNP level, for all observations, was 36 pg/mL (interquartile range, 18 to 76 pg/mL). There was no strong correlation found between commonly used echocardiographic or hemodynamic data and BNP. However, using a bivariate model, the change in BNP measurements over time significantly correlated with the change in the hemodynamic and echocardiographic parameters. Patients with a BNP value > 180 pg/mL had a decreased survival rate. CONCLUSIONS: BNP could be a useful marker to monitor disease severity in pediatric PAH. We show that simple correlations between variables and BNP are not likely to illustrate its usefulness due to variations in the normative levels. Instead, we propose that patient BNP levels should be monitored over time, as changes in BNP within a patient are likely to be more informative. collapse abstract
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The Annals of thoracic surgery 2008 Sep; 86(4)
Outcomes of reparative and transplantation strategies for multilevel left heart obstructions with mitral stenosis.
BACKGROUND: 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 approac... expand abstracthes for Shone's complex. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. collapse abstract
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Circulation 2008 Sep; 118(14 Suppl)
Performance of cavopulmonary palliation at elevated altitude: midterm outcomes and risk factors for failure.
BACKGROUND: 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 objecti... expand abstractve 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 . m(2) versus 1.52+/-0.9 Wood U . m(2), P=0.007). CONCLUSIONS: 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 . m(2). collapse abstract
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Congenital heart disease 2008 Feb; 3(2)
Noninvasive methods for determining pulmonary vascular function in children with pulmonary arterial hypertension: application of a mechanical oscillator model.
OBJECTIVE: Noninvasive diagnostics for pulmonary arterial hypertension (PAH) have traditionally sought to predict main pulmonary artery pressure from qualitative or direct quantitative measures of the flow velocity pattern obtained from spectral Dopp... expand abstractler ultrasound examination of the main pulmonary artery. A more detailed quantification of flow velocity patterns in the systemic circuit has been obtained by parameterizing the flow trace with a simple dynamic system model. Here, we investigate such a model's utility as a noninvasive predictor of total right heart afterload and right heart function. DESIGN: Flow velocity and pressure was measured within the main pulmonary artery during right heart catheterization of patients with normal hemodynamics (19 subjects, 20 conditions) and those with PAH undergoing reactivity evaluation (34 patients, 69 conditions). Our model parameters were obtained by least-squares fitting the model velocity to the measured flow velocity. RESULTS: Five parameter means displayed significant (P < .05) differences between normotensive and hypertensive groups. The model stiffness parameter correlated to actual pulmonary vascular resistance (r = 0.4924), pulmonary vascular stiffness (r = 0.6811), pulmonary flow (r = 0.6963), and stroke work (r = 0.7017), while the model initial displacement parameter had good correlation to stiffness (r = 0.6943) and flow (r = 0.6958). CONCLUSIONS: As predictors of total right heart afterload (resistance and stiffness) and right ventricle work, the model parameters of stiffness and initial displacement offer more comprehensive measures of the disease state than previous noninvasive methods and may be useful in routine diagnostic monitoring of patients with PAH. collapse abstract
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The Journal of pediatrics 2008 Jan; 152(2)
Left ventricular diastolic dysfunction in bronchopulmonary dysplasia.
We report 2 infants with severe bronchopulmonary dysplasia in whom left ventricular diastolic dysfunction contributed to clinical abnormalities, including pulmonary hypertension and recurrent pulmonary edema. We speculate that close monitoring for le... expand abstractft ventricular diastolic dysfunction may assist with clinical management and improve outcomes of infants with severe bronchopulmonary dysplasia. collapse abstract
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Pediatrics 2008 Jan; 121(2)
Clinical utility of echocardiography for the diagnosis and management of pulmonary vascular disease in young children with chronic lung disease.
OBJECTIVE: The goal was to determine the clinical utility of Doppler echocardiography in predicting the presence and severity of pulmonary hypertension in patients with chronic lung disease who subsequently underwent cardiac catheterization. METHODS:... expand abstract A retrospective review of data for all patients < 2 years of age with a diagnosis of bronchopulmonary dysplasia, congenital diaphragmatic hernia, or lung hypoplasia who underwent echocardiography and subsequently underwent cardiac catheterization for evaluation of pulmonary hypertension was performed. The accuracy of echocardiography in diagnosing pulmonary hypertension, on the basis of estimated systolic pulmonary artery pressure, was compared with the detection of pulmonary hypertension with the standard method of cardiac catheterization. RESULTS: Thirty-one linked measurements for 25 children were analyzed. Systolic pulmonary artery pressure could be estimated in 61% of studies, but there was poor correlation between echocardiography and cardiac catheterization measures of systolic pulmonary artery pressure in these infants. Compared with cardiac catheterization measurements, echocardiographic estimates of systolic pulmonary artery pressure diagnosed correctly the presence or absence of pulmonary hypertension in 79% of the studies in which systolic pulmonary artery pressure was estimated but determined the severity of pulmonary hypertension (severe pulmonary hypertension was defined as pulmonary/systemic pressure ratio of > or = 0.67) correctly in only 47% of those studies. Seven (58%) of 12 children without estimated systolic pulmonary artery pressure demonstrated pulmonary hypertension during subsequent cardiac catheterization. In the absence of estimated systolic pulmonary artery pressure, qualitative echocardiographic findings, either alone or in combination, had worse predictive value for the diagnosis of pulmonary hypertension. CONCLUSION: As used in clinical practice, echocardiography often identifies pulmonary hypertension in young children with chronic lung disease; however, estimates of systolic pulmonary artery pressure were not obtained consistently and were not reliable for determining the severity of pulmonary hypertension. collapse abstract
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Journal of the American College of Cardiology 2008 Jan; 51(2)
Short- and long-term effects of inhaled iloprost therapy in children with pulmonary arterial hypertension.
OBJECTIVES: This study investigated the short- and long-term outcome of children with pulmonary arterial hypertension (PAH) treated with inhaled iloprost. BACKGROUND: Inhaled iloprost has been approved for the treatment of adults with PAH, but little... expand abstract is known about the effects in children with PAH. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. collapse abstract
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American heart journal 2007 Dec; 155(1)
Pulmonary vascular input impedance is a combined measure of pulmonary vascular resistance and stiffness and predicts clinical outcomes better than pulmonary vascular resistance alone in pediatric patients with pulmonary hypertension.
BACKGROUND: 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 pulsat... expand abstractile effects. We recently developed and validated a 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. Here we show that input impedance can be measured routinely and easily in the catheterization laboratory, that impedance provides PVR and pulmonary vascular stiffness from a single measurement, and that impedance is a better predictor of disease outcomes compared with PVR. METHODS: Pressure and velocity waveforms within the main pulmonary artery were measured during right heart catheterization of patients with normal pulmonary artery 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. RESULTS: Exceptional correlation was found between the indexed zero harmonic of impedance and indexed PVR (y = 1.095x + 1.381, R2 = 0.9620). In addition, the modulus sum of the first 2 harmonics of impedance was found to best correlate with indexed pulse pressure over stroke volume (y = 13.39x - 0.8058, R2 = 0.7962). Among a subset of patients with PAH (n = 25), cumulative logistic regression between outcomes to total indexed impedance was better (R(L)2 = 0.4012) than between outcomes and indexed PVR (R(L)2 = 0.3131). CONCLUSIONS: Input impedance can be consistently and easily obtained from pulse-wave Doppler and a single catheter pressure measurement, provides comprehensive characterization of the main components of RV afterload, and better predicts patient outcomes compared with PVR alone. collapse abstract
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Pediatrics 2007 Apr; 119(5)
Importance of the clinical recognition of Loeys-Dietz syndrome in the neonatal period.
We describe 5 patients who presented with musculoskeletal abnormalities in the neonatal period. All patients were initially suspected to have Larsen syndrome or Beals syndrome but were subsequently diagnosed with a TGFBR2 mutation diagnostic of Loeys... expand abstract-Dietz syndrome. Patients had progressive aortic enlargement, which necessitated surgical intervention for 3 patients and resulted in the death of 1 patient. Delay in diagnosis of Loeys-Dietz syndrome may be associated with adverse prognosis. collapse abstract
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Journal of biomechanical engineering 2007 Mar; 129(2)
Application of a microstructural constitutive model of the pulmonary artery to patient-specific studies: validation and effect of orthotropy.
We applied a statistical mechanics based microstructural model of pulmonary artery mechanics, developed from our previous studies of rats with pulmonary arterial hypertension (PAH), to patient-specific clinical studies of children with PAH. Our previ... expand abstractous animal studies provoked the hypothesis that increased cross-linking density of the molecular chains may be one biological remodeling mechanism by which the PA stiffens in PAH. This study appears to further confirm this hypothesis since varying molecular cross-linking density in the model allows us to simulate the changes in the P-D loops between normotensive and hypertensive conditions reasonably well. The model was combined with patient-specific three-dimensional vascular anatomy to obtain detailed information on the topography of stresses and strains within the proximal branches of the pulmonary vasculature. The effect of orthotropy on stressstrain within the main and branch PAs obtained from a patient was explored. This initial study also puts forward important questions that need to be considered before combining the microstructural model with complex patient-specific vascular geometries. collapse abstract
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Anesthesia and analgesia 2007 Feb; 104(3)
Perioperative complications in children with pulmonary hypertension undergoing noncardiac surgery or cardiac catheterization.
BACKGROUND: Pulmonary arterial hypertension (PAH) can lead to significant cardiac dysfunction and is considered to be associated with an increased risk of perioperative cardiovascular complications. METHODS: We reviewed the medical records of childre... expand abstractn with PAH who underwent anesthesia or sedation for noncardiac surgical procedures or cardiac catheterizations from 1999 to 2004. The incidence, type, and associated factors of complications occurring intraoperatively through 48 h postoperatively were examined. RESULTS: Two hundred fifty-six procedures were performed in 156 patients (median age 4.0 yr). PAH etiology was 56% idiopathic (primary), 21% congenital heart disease, 14% chronic lung disease, 4% chronic airway obstruction, and 4% chronic liver disease. Baseline pulmonary artery pressure was subsystemic in 68% patients, systemic in 19%, and suprasystemic in 13%. The anesthetic techniques were 22% sedation, 58% general inhaled, 20% general IV. Minor complications occurred in eight patients (5.1% of patients, 3.1% of procedures). Major complications, including cardiac arrest and pulmonary hypertensive crisis, occurred in seven patients during cardiac catheterization procedures (4.5% of patients, 5.0% of cardiac catheterization procedures, 2.7% of all procedures). There were two deaths associated with pulmonary hypertensive crisis (1.3% of patients, 0.8% of procedures). Baseline suprasystemic PAH was a significant predictor of major complications by multivariate logistic regression analysis (OR = 8.1, P = 0.02). Complications were not significantly associated with age, etiology of PAH, type of anesthetic, or airway management. CONCLUSION: Children with suprasystemic PAH have a significant risk of major perioperative complications, including cardiac arrest and pulmonary hypertensive crisis. collapse abstract
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The American journal of cardiology 2007 Feb; 99(5)
Transition of stable pediatric patients with pulmonary arterial hypertension from intravenous epoprostenol to intravenous treprostinil.
Intravenous epoprostenol was the first agent approved by the United States Food and Drug Administration for the management of pulmonary arterial hypertension (PAH). However, epoprostenol therapy carries the risks of a short half-life (<6 minutes) and... expand abstract side effects, including jaw pain, flushing, and headache. Recently, intravenous treprostinil has been studied, primarily in adults with PAH, and found to provide effective therapy. The effects of continuous intravenous treprostinil were retrospectively evaluated in 13 children with stable PAH who had been treated with epoprostenol for >1 year. Children were transitioned in the hospital over 24 hours using a rapid or slow strategy. The children were a mean age of 11 years (range 3 to 17) and were transitioned to treprostinil from August 2004 to August 2005. The baseline 6-minute walking distance was on average 516 +/- 115 m (n = 9) and did not change after transition. Patients were treated with treprostinil for 1.1 +/- 0.5 years. There were 2 deaths, and 2 patients transitioned to other therapy. Seven patients experienced > or =1 central-line infection. Despite a higher dose of treprostinil, the side effects were subjectively diminished. In conclusion, treprostinil provides an alternative therapy in children with PAH, with fewer side effects. However, evaluation regarding rates of infection requires further exploration. collapse abstract
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The Annals of thoracic surgery 2006 Sep; 82(4)
Birth weight and complexity are significant factors for the management of hypoplastic left heart syndrome.
BACKGROUND: Classic options for treatment of hypoplastic left heart syndrome include the Norwood procedure (NW) and heart transplantation (HT). Recently off-pump palliative procedures were introduced in the management of these patients. Risk factors ... expand abstractinfluencing the decision between the NW with staged reconstruction or off-pump palliation and HT were assessed. METHODS: Between January 2002 and January 2006, 69 patients with hypoplastic left heart syndrome were referred for either a NW (n = 33) or HT (n = 36). Patients referred for HT underwent off-pump palliation (catheter-based, n = 20, or surgical hybrid procedures, n = 7) until a donor organ became available: including patent ductus arteriosus stenting (80.6%), atrial septostomy (41.7%), and branch pulmonary artery banding (55.6%). RESULTS: Heart transplantation patients were more complex, based on a higher Aristotle Comprehensive Complexity score calculated at birth (HT 18.8 +/- 2.4 versus NW 17.7 +/- 1.7; p < 0.05). Presurgical death was significantly greater for HT referrals (HT 27.8% versus NW 3.0%; p < 0.01); however, there was no difference between the two groups in operative (HT 11.5% versus NW 21.9%; not significant) or overall mortality (HT 36.1% versus NW 24.2%; not significant). No independent risk factors for death were identified with HT; however, a lower birth weight (<2.5 kg) and a higher Aristotle score (>20) correlated with surgical death with NW (p < 0.01). Noticeably, surgical survival was 85.7% for infants with birth weight of 2.5 kg or greater undergoing NW. CONCLUSIONS: Overall survival is similar for hypoplastic left heart syndrome patients referred for the NW or HT. Lower birth weight and higher complexity are risk factors for patients undergoing NW. Off-pump palliation followed by HT or further staged palliation should be considered for these high-risk hypoplastic left heart syndrome patients. collapse abstract
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Journal of biomechanical engineering 2006 Jul; 128(4)
Simulations of congenital septal defect closure and reactivity testing in patient-specific models of the pediatric pulmonary vasculature: A 3D numerical study with fluid-structure interaction.
Clinical imaging methods are highly effective in the diagnosis of vascular pathologies, but they do not currently provide enough detail to shed light on the cause or progression of such diseases, and would be hard pressed to foresee the outcome of su... expand abstractrgical interventions. Greater detail of and prediction capabilities for vascular hemodynamics and arterial mechanics are obtained here through the coupling of clinical imaging methods with computational techniques. Three-dimensional, patient-specific geometric reconstructions of the pediatric proximal pulmonary vasculature were obtained from x-ray angiogram images and meshed for use with commercial computational software. Two such models from hypertensive patients, one with multiple septal defects, the other who underwent vascular reactivity testing, were each completed with two sets of suitable fluid and structural initial and boundary conditions and used to obtain detailed transient simulations of artery wall motion and hemodynamics in both clinically measured and predicted configurations. The simulation of septal defect closure, in which input flow and proximal vascular stiffness were decreased, exhibited substantial decreases in proximal velocity, wall shear stress (WSS), and pressure in the post-op state. The simulation of vascular reactivity, in which distal vascular resistance and proximal vascular stiffness were decreased, displayed negligible changes in velocity and WSS but a significant drop in proximal pressure in the reactive state. This new patient-specific technique provides much greater detail regarding the function of the pulmonary circuit than can be obtained with current medical imaging methods alone, and holds promise for enabling surgical planning. collapse abstract
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Journal of biomechanics 40(4)
Comparison of mechanical behavior among the extrapulmonary arteries from rats.
Results of comparative tests on pulmonary arteries from untreated Long-Evans rats are presented from three sections of the artery: the trunk, and the right and left main extrapulmonary arteries. Analyses were conducted looking for mechanical differen... expand abstractces between the flow (longitudinal) and circumferential directions, between the right and left main arteries, and between each of the mains and the trunk. The mechanical properties of rat pulmonary arteries were obtained with a bubble inflation technique. A flat disk of rat pulmonary artery was constrained at the periphery and inflated, and the geometry of the resulting bubble of material recorded from six different angles. To analyze the data, the area under the stress-strain curve was calculated for each test and orientation. This area, related to the strain-energy density, was calculated at stress equal to 200kPa, for the purpose of statistical comparison. The mean values for the area show that the trunk is less compliant than the main arteries; this difference is supported by histological evidence. When comparing the circumferential and longitudinal properties of the arteries, differences are found for the trunk and left main arteries, but with opposite orientations being more compliant. The mean values for the two orientations for the right main artery are statistically identical. There was indication of significant difference in mechanical properties between the trunk and the main arteries. The left main artery in the circumferential orientation is highly compliant and appears to strongly influence the likelihood that significant differences will exist when included in a statistical population. These data show that each section of the extrapulmonary arterial system should not be expected to behave identically, and they provide the baseline mechanical behavior of the pulmonary artery from normotensive rats. collapse abstract
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