Irwin Reiss

Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats

BackgroundMast cells (MCs) are implicated in inflammation and tissue remodeling. Accumulation of lung MCs is described in pulmonary hypertension (PH); however, whether MC degranulation and c-kit, a tyrosine kinase receptor critically involved in MC biology, contribute to the pathogenesis and progression of PH has not been fully explored.MethodsPulmonary MCs of idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline-injected rats (MCT-rats) were examined by histochemistry and morphometry. Effects of the specific c-kit inhibitor PLX and MC stabilizer cromolyn sodium salt (CSS) were investigated in MCT-rats both by the preventive and therapeutic approaches. Hemodynamic and right ventricular hypertrophy measurements, pulmonary vascular morphometry and analysis of pulmonary MC localization/counts/activation were performed in animal model studies.ResultsThere was a prevalence of pulmonary MCs in IPAH patients and MCT-rats as compared to the donors and healthy rats, respectively. Notably, the perivascular MCs were increased and a majority of them were degranulated in lungs of IPAH patients and MCT-rats (p < 0.05 versus donor and control, respectively). In MCT-rats, the pharmacological inhibitions of MC degranulation and c-kit with CSS and PLX, respectively by a preventive approach (treatment from day 1 to 21 of MCT-injection) significantly attenuated right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). Moreover, vascular remodeling, as evident from the significantly decreased muscularization and medial wall thickness of distal pulmonary vessels, was improved. However, treatments with CSS and PLX by a therapeutic approach (from day 21 to 35 of MCT-injection) neither improved hemodynamics and RVH nor vascular remodeling.ConclusionsThe accumulation and activation of perivascular MCs in the lungs are the histopathological features present in clinical (IPAH patients) and experimental (MCT-rats) PH. Moreover, the accumulation and activation of MCs in the lungs contribute to the development of PH in MCT-rats. Our findings reveal an important pathophysiological insight into the role of MCs in the pathogenesis of PH in MCT- rats.

Cutaneous microcirculation in preterm neonates: comparison between sidestream dark field (SDF) and incident dark field (IDF) imaging.

Incident dark field imaging (IDF) is a new generation handheld microscope for bedside visualization and quantification of microcirculatory alterations. IDF is the technical successor of sidestream dark field imaging (SDF), currently the most used device for microcirculatory measurements. In (pre)term neonates the reduced thickness of the skin allows non-invasive transcutaneous measurements. The goal of this study was to compare the existing device (SDF) and its technical successor (IDF) in preterm neonates. We hypothesized that IDF imaging produces higher quality images resulting in a higher vessel density. After written informed consent was given by the parents, skin microcirculation was consecutively measured on the inner upper arm with de SDF and IDF device. Images were exported and analyzed offline using existing software (AVA 3.0). Vessel density and perfusion were calculated using the total vessel density (TVD) proportion of perfused vessels (PPV) and perfused vessel density. The microcirculation images quality score was used to evaluate the quality of the video images. In a heterogeneous group of twenty preterm neonates (median GA 27.6xa0weeks, range 24–33.4) IDF imaging visualized 19.9xa0% more vessels resulting in a significantly higher vessel density (TVD 16.9 vs. 14.1/mm, p value <xa00.001). The perfusion of vessels could be determined more accurately in the IDF images, resulting in a significant lower PPV (88.7 vs. 93.9xa0%, p value 0.002). The IDF video images scored optimal in a higher percentage compared to the SDF video images. IDF imaging of the cutaneous microcirculation in preterm neonates resulted in a higher vessel density and lower perfusion compared to the existing SDF device.

Management of pulmonary hypertension in neonates with congenital diaphragmatic hernia.

Pulmonary hypertension associated with congenital diaphragmatic hernia is still one of the major challenges in neonatal intensive care units. Several relevant pathways in its pathogenesis have been described and studied, but the absence of well-designed randomized controlled trials and the scattered data on the pharmacokinetics and pharmacodynamics of most of the drugs used in these patients hamper progress significantly. This review aims to give an overview of current management strategies in the antenatal and neonatal phase, and provides founded clinical recommendations.

Nasal high-frequency oscillation ventilation in neonates: a survey in five European countries

AbstractNasal high-frequency oscillation ventilation (nHFOV) is a non-invasive ventilation mode that applies an oscillatory pressure waveform to the airways using a nasal interface. nHFOV has been shown to facilitate carbon dioxide expiration, but little is known about its use in neonates. In a questionnaire-based survey, we assessed nHFOV use in neonatal intensive care units (NICUs) in Austria, Switzerland, Germany, the Netherlands, and Sweden. Questions included indications for nHFOV, equipment used, ventilator settings, and observed side effects. Of the clinical directors of 186 NICUs contacted, 172 (92xa0%) participated. Among those responding, 30/172 (17xa0%) used nHFOV, most frequently in premature infants <1500xa0g (27/30) for the indication nasal continuous positive airway pressure (nCPAP) failure (27/30). Binasal prongs (22/30) were the most common interfaces. The median (range) mean airway pressure when starting nHFOV was 8 (6–12) cm H2O, and the maximum mean airway pressure was 10 (7–18) cm H2O. The nHFOV frequency was 10 (6–13) Hz. Abdominal distension (11/30), upper airway obstruction due to secretions (8/30), and highly viscous secretions (7/30) were the most common nHFOV side effects.n Conclusion: In a number of European NICUs, clinicians use nHFOV. The present survey identified differences in nHFOV equipment, indications, and settings. Controlled clinical trials are needed to investigate the efficacy and side effects of nHFOV in neonates.

Clinical evaluation of propofol as sedative for endotracheal intubation in neonates

To determine the effects of propofol for endotracheal intubation in neonates in daily clinical practice.

Invasive ventilation modes in children: a systematic review and meta-analysis

IntroductionThe purpose of the present study was to critically review the existing body of evidence on ventilation modes for infants and children up to the age of 18 years.MethodsThe PubMed and EMBASE databases were searched using the search terms artificial respiration, instrumentation, device, devices, mode, and modes. The review included only studies comparing two ventilation modes in a randomized controlled study and reporting one of the following outcome measures: length of ventilation (LOV), oxygenation, mortality, chronic lung disease and weaning. We quantitatively pooled the results of trials where suitable.ResultsFive trials met the inclusion criteria. They addressed six different ventilation modes in 421 children: high-frequency oscillation (HFO), pressure control (PC), pressure support (PS), volume support (VS), volume diffusive respirator (VDR) and biphasic positive airway pressure. Overall there were no significant differences in LOV and mortality or survival rate associated with the different ventilation modes. Two trials compared HFO versus conventional ventilation. In the pooled analysis, the mortality rate did not differ between these modes (odds ratio = 0.83, 95% confidence interval = 0.30 to 1.91). High-frequency ventilation (HFO and VDR) was associated with a better oxygenation after 72 hours than was conventional ventilation. One study found a significantly higher PaO2/FiO2 ratio with the use of VDR versus PC ventilation in children with burns. Weaning was studied in 182 children assigned to either a PS protocol, a VS protocol or no protocol. Most children could be weaned within 2 days and the weaning time did not significantly differ between the groups.ConclusionsThe literature provides scarce data for the best ventilation mode in critically ill children beyond the newborn period. There is no evidence, however, that high-frequency ventilation reduced mortality and LOV. Longer-term outcome measures such as pulmonary function, neurocognitive development, and cost-effectiveness should be considered in future studies.

Limited effects of intravenous paracetamol on patent ductus arteriosus in very low birth weight infants with contraindications for ibuprofen or after ibuprofen failure

AbstractFinding the optimal pharmacological treatment of a patent ductus arteriosus (PDA) in preterm neonates remains challenging. There is a growing interest in paracetamol as a new drug for PDA closure. In this prospective observational cohort study, we evaluated the effectiveness of intravenous paracetamol in closing a PDA in very low birth weight infants with a hemodynamically significant PDA who either did not respond to ibuprofen or had a contraindication for ibuprofen. They received high-dose paracetamol therapy (15xa0mg/kg/6xa0h intravenous) for 3–7xa0days. Cardiac ultrasounds were performed before and 3 and 7xa0days after treatment. Thirty-three patients were included with a median gestational age of 251/7xa0weeks (IQR 1.66), a median birth weight of 750xa0g (IQR 327), and a median postnatal age of 14xa0days (IQR 12). Paracetamol was ineffective in 27/33 patients (82xa0%). Even more, after previous exposure to ibuprofen, this was even 100xa0%.n Conclusion: In this study, paracetamol after ibuprofen treatment failure was not effective for PDA closure in VLBW infants. From the findings of this study, paracetamol treatment for PDA closure cannot be recommended for infants with a postnatal age >2xa0weeks. Earlier treatment with paracetamol for PDA might be more effective.What is known:• The ductus arteriosus fails to close after birth in 30 to 60u2009% of prematurely born neonates and is a significant cause of morbidity and mortality in these infants.• Paracetamol gained importance as an alternative drug in PDA closure.What is new:• Paracetamol for PDA closure after ibuprofen treatment failure was not effective in VLBW infants.• Effect of paracetamol on PDA closure was observed when given as primary treatment.

Histological characterization of mast cell chymase in patients with pulmonary hypertension and chronic obstructive pulmonary disease

Our previous findings demonstrated an increase in pulmonary mast cells (MCs) in idiopathic pulmonary arterial hypertension (IPAH). Also, literature suggests a potential role for MCs in chronic obstructive pulmonary disease (COPD). However, a comprehensive investigation of lungs from patients is still needed. We systematically investigated the presence/expression of MCs/MC chymase in the lungs of IPAH and COPD patients by (immuno)histochemistry and subsequent quantification. We found that total and perivascular chymase-positive MCs were significantly higher in IPAH patients than in donors. In addition, chymase-positive MCs were located in proximity to regions with prominent expression of big-endothelin-1 in the pulmonary vessels of IPAH patients. Total and perivascular MCs around resistant vessels were augmented and a significant majority of them were degranulated (activated) in COPD patients. While the total chymase-positive MC count tended to increase in COPD patients, the perivascular number was significantly enhanced in all vessel sizes analyzed. Surprisingly, MC and chymase-positive MC numbers positively correlated with better lung function in COPD. Our findings suggest that activated MCs, possibly by releasing chymase, may contribute to pulmonary vascular remodeling in IPAH. Pulmonary MCs/chymase may have compartment-specific (vascular vs. airway) functions in COPD. Future studies should elucidate the mechanisms of MC accumulation and the role of MC chymase in pathologies of these severe lung diseases.

Lung CT imaging in patients with bronchopulmonary dysplasia: A systematic review

Bronchopulmonary dysplasia (BPD) is a common respiratory complication of preterm birth and associated with long‐term respiratory sequelae. Chest computed tomography (CT) is a sensitive tool to obtain insight in structural lung abnormalities and may be a predictor for later symptoms.

Effect of hypothermia and extracorporeal life support on drug disposition in neonates

Extracorporeal membrane oxygenation (ECMO) is a valuable treatment modality in neonates with reversible cardiopulmonary failure in therapy-resistant pulmonary hypertension after perinatal asphyxia, septic shock or ECMO cardiopulmonary resuscitation. Neonates with severe perinatal asphyxia are currently treated with therapeutic hypothermia to improve neurological outcome. Consequently, therapeutic hypothermia may be indicated in the neonatal ECMO population. Both ECMO and hypothermia have been associated with changes in drug disposition. However, little is known about the combined effects of these treatment modalities. This review will explore the available literature, identify possible changes in pharmacokinetics and make suggestions for future research directions.