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Featured researches published by Ingram Schulze-Neick.


Circulation | 2003

Intravenous Sildenafil Is a Potent Pulmonary Vasodilator in Children With Congenital Heart Disease

Ingram Schulze-Neick; Paulina Hartenstein; Jia Li; Brigitte Stiller; Nicola Nagdyman; Michael Hübler; Ghazwan Butrous; Andy Petros; Peter Lange; Andrew N. Redington

Background—Increased pulmonary vascular resistance (PVR) because of congenital heart disease (CHD) may be caused by a dysfunction in endogenous pulmonary endothelial nitric oxide (NO) production. In other forms of pulmonary vascular disease with increased PVR, an elevated activity of a phosphodiesterase type 5 (PDE-5), responsible for the degradation of cyclic guanidine monophosphate (cGMP), the second messenger of endothelially produced NO, has been demonstrated. This study compares the effects of inhaled NO before and after the specific inhibition of the PDE-5 by intravenous sildenafil (Viagra™) in pre- and postoperative children with increased PVR because of CHD. Methods and Results—12 children with congenital heart disease (age 0.2 to 15.7 years, median 2.4 years) and increased mean pulmonary arterial pressure, and 12 postoperative children (age 0.11 to 0.65 years, median 0.32 years) with increased PVR (8.3±1.0 Wood Units*m2) were studied during cardiac catheterization (“cath laboratory”), or within 2 hours after return from cardiac surgery (“post op”), respectively. All were sedated, tracheally intubated and paralyzed. During alveolar hyperoxygenation (FiO2=0.65), the effects of inhaled NO (20 ppm) were compared before and after the stepwise infusion of sildenafil (“cath laboratory”, 1 mg/kg; post op, 0.25 mg/kg). Intravenous sildenafil more effectively reduced PVR than NO (11.5% versus 4.3% in the “cath laboratory” patient group, P <0.05, and 25.8% versus 14.6% in the post op patient group, P =0.09. The increase in cGMP in response to NO was potentiated (2- to 2.4-fold) by PDE-5 inhibition. While the vasodilating effects of sildenafil showed pulmonary selectivity, its infusion was associated with increased intrapulmonary shunting in the postoperative patients (Qs/Qt=16.5±4.7% to 25.5±18.2%P =0.04). Conclusions—Intravenous sildenafil is as effective as inhaled NO as a pulmonary vasodilator in children with congenital heart disease. Although clinically insignificant in this study, increased intrapulmonary shunting with sildenafil may be disadvantageous in some patients after CHD surgery.


British Journal of Clinical Pharmacology | 2009

Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study

Maurice Beghetti; Sheila G. Haworth; Damien Bonnet; Robyn J. Barst; Philippe Acar; Alain Fraisse; D. Dunbar Ivy; Xavier Jaïs; Ingram Schulze-Neick; Nazzareno Galiè; Adele Morganti; Jasper Dingemanse; Andjela Kusic-Pajic; Rudolphus Berger

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 parents and clinicians 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.


European Respiratory Journal | 2013

Diagnostic evaluation of paediatric pulmonary hypertension in current clinical practice.

Maurice Beghetti; Rolf M.F. Berger; Ingram Schulze-Neick; Ronald W. Day; Tomás Pulido; Jeffrey A. Feinstein; Robyn J. Barst; Tilman Humpl

Current paediatric pulmonary hypertension (PH) diagnostic algorithms include some testing specifically for paediatrics, but it is unclear if this is used in clinical practice. We describe the current diagnostic workup of the TOPP (Tracking Outcomes and Practice in Paediatric Pulmonary hypertension) registry for suspected PH. We investigated 456 patients enrolled until February 2010. The majority had ECGs (94%), echocardiograms (96%) and/or chest radiographs (89%) performed and these were the noninvasive tests most frequently used for evaluation of suspected PH. No patient had all three tests considered normal, suggesting the potential for the combined use to rule out PH. For evaluation of complications associated with heart catheterisation (HC) we analysed a total of 908 HCs reported until February 2012. Of these, 554 were at diagnosis and 354 in follow-up. Complications were reported in 5.9% with five deaths considered related to HC, suggesting a higher rate of HC complications compared to adult studies. However, current recommendations support HC in paediatric PH. A proper application of the risk/benefit ratio for HC requires further data. Most children did not undergo the diagnostic workup currently recommended for adults, which highlights either incomplete awareness of current guidelines and/or challenges their appropriateness for children. Most PH children don’t undergo full diagnostic evaluations; despite complications, catheterisation is used for diagnosis http://ow.ly/mx4GW


The Journal of Thoracic and Cardiovascular Surgery | 2000

Oxygen consumption after cardiopulmonary bypass surgery in children: determinants and implications.

Jia Li; Ingram Schulze-Neick; Christopher Lincoln; Darryl F. Shore; Michael Scallan; Andrew Bush; Andrew N. Redington; Daniel J. Penny

OBJECTIVE We sought to assess oxygen consumption and its determinants in children shortly after undergoing cardiopulmonary bypass operations. METHODS Twenty children, aged 2 months to 15 years (median, 3.75 years), undergoing hypothermic cardiopulmonary bypass operations were studied during the first 4 hours after arrival in the intensive care unit. Central and peripheral temperatures were monitored. Oxygen consumption was continuously measured by using respiratory mass spectrometry. Oxygen delivery was calculated from oxygen consumption and arterial and mixed venous oxygen contents, which were sampled every 30 minutes. Oxygen extraction was derived by the ratio of oxygen consumption and oxygen delivery. Arterial blood lactate levels were measured every 30 minutes. RESULTS There was a correlation between oxygen consumption and age in patients older than 3 months (r = -0.76). Mean oxygen consumption increased by 14.7% during the study. The increase in oxygen consumption was correlated with the increase in central temperature (r = 0.73). Nine patients had an arterial lactate level above 2 mmol/L on arrival. There were no significant differences in oxygen consumption, oxygen delivery, and oxygen extraction between the group with lactate levels between 2 and 3 mmol/L and the groups with normal lactate levels both on arrival and at 2 hours. One patient with a peak lactate level of 6.8 mmol/L had initially low oxygen delivery (241.3 mL. min(-1). m(-2)). CONCLUSIONS During the early hours after a pediatric cardiac operation, the increase in oxygen consumption is mainly attributed to the increase in central temperature. Oxygen consumption is negatively related to age. Mild lactatemia is common and does not appear to reflect oxygen delivery or oxygen consumption or a more complicated recovery.


Circulation-cardiovascular Imaging | 2013

Prognostic Significance of Cardiac Magnetic Resonance Imaging in Children with Pulmonary Hypertension

Shahin Moledina; Bejal Pandya; Margarita Bartsota; Kristian H. Mortensen; Merlin R. McMillan; Sadia Quyam; Andrew M. Taylor; Sheila G. Haworth; Ingram Schulze-Neick; Vivek Muthurangu

Background— There are very few validated prognostic markers in pediatric pulmonary hypertension. Cardiac MRI is a useful, noninvasive method for determining prognosis in adults. The present study is the first to assess its prognostic value in children. Methods and Results— A total of 100 children with pulmonary hypertension (median, 10.4 years; range, 0.5–17.6 years) were evaluated (idiopathic, n=60; repaired congenital heart disease, n=22; miscellaneous, n=18). In all patients, ventricular volumes and great vessel flow were measured. Volumetric data were obtained using retrospectively gated cine imaging (n=37) or real-time imaging (n=63), depending on the patient’s ability to hold his or her breath. During a median follow-up of 1.9 years, 11 patients died and 3 received lung transplantation. Of the cardiac MR parameters measured, right ventricular ejection fraction and left ventricular stroke volume index were most strongly predictive of survival on univariate analysis (2.6- and 2.5-fold increase in mortality for every 1-SD decrease, respectively; P<0.05). These results were reflected in good separation of tertile-based Kaplan-Meier survival curves for these variables. Conclusions— Cardiac MR measures correlate with clinical status and prognosis in children with pulmonary hypertension. Cardiac MR is feasible and may be useful in clinical decision making in pediatric pulmonary hypertension.


Critical Care Medicine | 2003

Measured versus estimated oxygen consumption in ventilated patients with congenital heart disease: The validity of predictive equations

Jia Li; Andrew Bush; Ingram Schulze-Neick; Daniel J. Penny; Andrew N. Redington; Lara S. Shekerdemian

ObjectiveTo determine the validity of predictive equations in calculating oxygen consumption (Vo2) in ventilated patients with congenital heart disease. DesignProspective study. SettingCardiac catheterization laboratories and intensive care units of two university teaching hospitals. PatientsA total of 126 patients with congenital heart disease were studied. Of these, 75 patients received anesthesia in the pediatric cardiac catheterization laboratory, and 51 were deeply sedated in the intensive care unit after open heart surgery. Measurements and Main ResultsVo2 was measured directly in all patients using respiratory mass spectrometry. Estimated values for absolute Vo2 (mL/min) and indexed Vo2 (mL·min−1·m−2) were calculated from the four predictive equations published by LaFarge and Miettinen, Lundell et al., Wessel et al., and Lindahl. The agreement between measured and estimated Vo2 was evaluated by calculating their bias and limits of agreement. A failure of agreement between measured and estimated Vo2 was noted in both groups of patients, irrespective the equation used, and the agreement was poorer in patients in the intensive care unit. The equation by LaFarge and Miettinen produced the closest estimation in patients at cardiac catheterization with a bias of 4.5 mL/min for absolute Vo2 and 6.9 mL·min−1·m−2 for indexed Vo2. A systematic error of overestimating lower and underestimating higher indexed Vo2 mL·min−1·m−2 was introduced in both groups ConclusionPredictive equations do not accurately estimate Vo2 in ventilated patients with congenital heart disease.


European Respiratory Journal | 2011

Long-term efficacy of bosentan in treatment of pulmonary arterial hypertension in children

A.A. Hislop; S. Moledina; H. Foster; Ingram Schulze-Neick; S. G Haworth

The aim of the present study was to evaluate a 5-yr experience of bosentan in children with pulmonary arterial hypertension (PAH). A retrospective, observational study was made of children in the UK Pulmonary Hypertension Service for Children (Great Ormond Street Hospital for Children, London, UK) who were given bosentan as monotherapy or in combination, from February 2002 to May 2008 and followed up for ≥6 months. Detailed studies were made of 101 children with idiopathic PAH (IPAH) (n = 42) and PAH associated with congenital heart disease (n = 59). Before treatment, World Health Organization (WHO) functional class, 6-min walk distance (6MWD), height, weight and haemodynamic data were determined. Evaluations were analysed after 6 months and annually to a maximum of 5 yrs. Median duration of treatment was 31.5 months. Initial improvement in WHO functional class and 6MWD was maintained for up to 3 yrs. Height and weight increased but the z-scores did not improve. After 3 yrs, bosentan was continued as monotherapy in only 21% of children with IPAH, but in 69% of repaired cases and 56% of those with Eisenmenger syndrome. The Kaplan–Meier survival estimates for the 101 patients were 96, 89, 83 and 60% at 1, 2, 3 and 5 yrs, respectively. A treatment regime that includes bosentan is safe and appears to be effective in slowing disease progression in children with PAH.


Heart | 2011

Fractal branching quantifies vascular changes and predicts survival in pulmonary hypertension: a proof of principle study

Shahin Moledina; Annemijn de Bruyn; Silvia Schievano; Catherine M. Owens; Carol Young; Sheila G. Haworth; Andrew M. Taylor; Ingram Schulze-Neick; Vivek Muthurangu

Objectives To develop a non-invasive method of assessing disease severity in pulmonary hypertension by quantifying the overall degree of vascular pruning using fractal geometry. Design A retrospective analysis of ECG-gated CT pulmonary angiograms. Setting A single national referral centre for the investigation and treatment of children with pulmonary hypertension. Patients Consecutive CT pulmonary angiograms in children and young adults (mean age 10.3 years, range 0.7–19.1) with pulmonary arterial hypertension assessed between January 2007 and April 2009. Main outcome measures The fractal dimension (FD) of skeletonised CT pulmonary angiograms was calculated using the box counting method. The FD was compared with pulmonary vascular resistance, the percentage of predicted 6-min walk distance, WHO functional class and survival. Results Diagnostic plots confirmed that the pulmonary artery angiograms were all fractal. The FD correlated negatively with the pulmonary vascular resistance index (r=−0.55, p=0.01, n=21) and with WHO functional class (p<0.01, n=31) while it correlated positively with the percentage of predicted 6-min walk distance (r=0.43, p=0.04, n=24). A lower FD was associated with poorer survival (HR 5.6; 95% CI 1.2 to 25; p=0.027) for every SD reduction in FD. Conclusion The FD derived from CT can be used to quantify vascular changes in pulmonary hypertension. This non-invasive technique may be useful in monitoring disease progression and response to therapy.


Intensive Care Medicine | 2000

Negative pressure ventilation as haemodynamic rescue following surgery for congenital heart disease

Lara Shekerdemian; Ingram Schulze-Neick; A. N. Redington; Andrew Bush; Daniel J. Penny

Abstract A low cardiac output state is an important cause of morbidity and mortality following repair of tetralogy of Fallot (ToF). This is often refractory to conventional measures. The cardiac output of these patients is highly dependent on diastolic pulmonary arterial flow which is enhanced during spontaneous respiration, but much reduced by intermittent positive pressure ventilation (IPPV).¶We report the successful use of negative pressure ventilation (NPV) as haemodynamic therapy in three children with a low output secondary to restrictive right ventricular (RV) physiology following ToF repair. NPV produced a significant haemodynamic improvement, with increases in cardiac output of greater than 100 % in two of the children. By augmenting pulmonary blood flow, and hence cardiac output, NPV has a role as adjunctive haemodynamic therapy in patients with a low output secondary to diastolic RV dysfunction, in whom early extubation is not possible.


Current Cardiology Reviews | 2010

The adult patient with eisenmenger syndrome: a medical update after dana point part I: epidemiology, clinical aspects and diagnostic options.

Harald Kaemmerer; Siegrun Mebus; Ingram Schulze-Neick; Andreas Eicken; Pedro T. Trindade; Alfred Hager; Erwin Oechslin; Koichiro Niwa; Irene Lang; John R. Hess

Eisenmenger syndrome is the most severe form of pulmonary arterial hypertension and arises on the basis of congenital heart disease with a systemic-to-pulmonary shunt. Due to the chronic slow progressive hypoxemia with central cyanosis, adult patients with the Eisenmenger syndrome suffer from a complex and multisystemic disorder including coagulation disorders (bleeding complications and paradoxical embolisms), renal dysfunction, hypertrophic osteoarthropathy, heart failure, reduced quality of life and premature death. For a long time, therapy has been limited to symptomatic options or lung or combined heart-lung transplantation. As new selective pulmonary vasodilators have become available and proven to be beneficial in various forms of pulmonary arterial hypertension, this targeted medical treatment has been expected to show promising effects with a delay of deterioration also in Eisenmenger patients. Unfortunately, data in Eisenmenger patients suffer from small patient numbers and a lack of randomized controlled studies. To optimize the quality of life and the outcome, referral of Eisenmenger patients to spezialized centers is required. In such centers, specific interdisciplinary management strategies of physicians specialized on congenital heart diseases and PAH should be warranted. This medical update emphasizes the current diagnostic and therapeutic options for Eisenmenger patients with particularly focussing on epidemiology, clinical aspects and specific diagnostic options.

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Peter Lange

University of Copenhagen

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Damien Bonnet

Paris Descartes University

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Shahin Moledina

Great Ormond Street Hospital

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D. Dunbar Ivy

University of Colorado Denver

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