Anne Vierzig

Early administration of surfactant in spontaneous breathing with nCPAP: feasibility and outcome in extremely premature infants (postmenstrual age ≤27 weeks)

Background:  Spontaneous breathing supported by nasal continuous positive airway pressure (nCPAP) is thought to have some advantages compared with mechanical ventilation in extremely premature infants. In addition, early or prophylactic surfactant administration has been shown to be superior to delayed use. A strategy to combine these two principles was tested in our neonatal intensive care unit (NICU). The aim of this feasibility study was to describe the procedure and compare short‐term results with a historical control.

A prospective, randomized, multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant

OBJECTIVES To compare high-frequency oscillatory ventilation (HFOV) and intermittent positive pressure ventilation (IPPV) as a primary ventilation mode in preterm infants with respiratory distress syndrome. Primary end points were survival and maintenance of the randomized ventilation mode. STUDY DESIGN Prospective, multicenter, randomized clinical trial. SETTING Level III neonatal intensive care units at three university childrens hospitals. PATIENTS Ninety-six premature infants (gestational age < 32 weeks) randomly assigned to HFOV or IPPV within the first 2 hours of life. All patients received a natural surfactant. No differences were found between the study groups with respect to the demographic data or the severity of respiratory distress syndrome. Infants were stratified at randomization, by birth weight, into two groups: 750 to 1000 gm (n = 32) and 1001 to 1500 gm (n = 64). The centers involved complied with a study protocol that planned a reduction in respiratory pressures when the infants oxygen requirement had reached a fractional concentration of inspired oxygen of 0.6. RESULTS Five patients in the HFOV group died, and eight patients did not respond to the randomized ventilation mode; whereas four patients in the IPPV group died, and nine were switched to HFOV. No differences were found in gas exchange or ventilator support over the first 72 hours. Premature infants with a birth weight < 1000 gm had a significantly shorter course to reach fractional concentration of inspired oxygen of 0.21 while receiving IPPV than those receiving HFOV (9.3+/-4.5 days vs 27.5+/-10.2 days, p = 0.01). No differences were found between the groups in extraalveolar air (HFOV seven; IPPV, seven) and intracranial bleeding (HFOV, nine; IPPV, eight). CONCLUSION After surfactant treatment, HFOV, as a primary ventilation mode in premature infants with respiratory distress syndrome, is as safe and efficacious as conventional ventilation.

Early surfactant in spontaneously breathing with nCPAP in ELBW infants--a single centre four year experience.

Objective: To evaluate whether the experience with a method to administer surfactant during spontaneous breathing with nasal continuous positive airway pressure (nCPAP) as primary respiratory support in infants with respiratory distress syndrome (RDS) influences the frequency of its use and affects the outcome of patients.

Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study

BACKGROUND Molybdenum cofactor deficiency (MoCD) is characterised by early, rapidly progressive postnatal encephalopathy and intractable seizures, leading to severe disability and early death. Previous treatment attempts have been unsuccessful. After a pioneering single treatment we now report the outcome of the complete first cohort of patients receiving substitution treatment with cyclic pyranopterin monophosphate (cPMP), a biosynthetic precursor of the cofactor. METHODS In this observational prospective cohort study, newborn babies with clinical and biochemical evidence of MoCD were admitted to a compassionate-use programme at the request of their treating physicians. Intravenous cPMP (80-320 μg/kg per day) was started in neonates diagnosed with MoCD (type A and type B) following a standardised protocol. We prospectively monitored safety and efficacy in all patients exposed to cPMP. FINDINGS Between June 6, 2008, and Jan 9, 2013, intravenous cPMP was started in 16 neonates diagnosed with MoCD (11 type A and five type B) and continued in eight type A patients for up to 5 years. We observed no drug-related serious adverse events after more than 6000 doses. The disease biomarkers urinary S-sulphocysteine, xanthine, and urate returned to almost normal concentrations in all type A patients within 2 days, and remained normal for up to 5 years on continued cPMP substitution. Eight patients with type A disease rapidly improved under treatment and convulsions were either completely suppressed or substantially reduced. Three patients treated early remain seizure free and show near-normal long-term development. We detected no biochemical or clinical response in patients with type B disease. INTERPRETATION cPMP substitution is the first effective therapy for patients with MoCD type A and has a favourable safety profile. Restoration of molybdenum cofactor-dependent enzyme activities results in a greatly improved neurodevelopmental outcome when started sufficiently early. The possibility of MoCD type A needs to be urgently explored in every encephalopathic neonate to avoid any delay in appropriate cPMP substitution, and to maximise treatment benefit. FUNDING German Ministry of Education and Research; Orphatec/Colbourne Pharmaceuticals.

Prolonged survival in alveolar capillary dysplasia syndrome.

Survival for up to 101 days is reported in an infant with congenital alveolar capillary dysplasia (ACD) with misalignment of pulmonary veins using inhaled nitric oxide thereby offering the prospect of survival until lung transplantation can be performed. The patient was a 3040 g Caucasian girl delivered at 39 weeks gestation. She developed cyanosis, tachypnoea, and hypoxaemia at 12 h of age. Echocardiography demonstrated atrial and ductal right-to-left shunt and suprasystemic right ventricular pressure. Following evaluation of the effect of different dosages of inhaled nitric oxide (iNO) during cardiac catheterisation, the therapeutic dose was chosen to be between 2–10 ppm, with a target O2 saturation of 95%. Right ventricular pressure decreased from 90–110 mmHg before to 60–65 mmHg after starting NO inhalation. Mean systolic arterial blood pressure was 55–75 mmHg. Breathing rate ranged from 30 to 50/min. A sibling had died 5 years earlier at the age of 17 days from a similar clinical presentation and ACD had been diagnosed at autopsy. At the age of 23 days, an open lung biopsy was performed. Pulmonary lobules were abnormally developed and showed thickened immature septa. Alveolar capillaries were frequently located in a central position deep inside the septa and were rarely in contact with the alveolar epithelium. Pulmonary veins could be found within the bronchovascular bundles adjacent to the pulmonary arteries instead of their normal intra-acinar course away from the arterial branches (‘‘misalignment’’). Pulmonary arteries showed thickened muscular walls reflecting persistent pulmonary hypertension. In addition, prematurely muscularised arterioles were found within the pulmonary acini, the typical findings of ACD combined with misalignment of pulmonary veins (MPV). Pathological changes in ACD/MPV resemble a normal fetal lung at the canalicular stage and can therefore also be seen as an arrest of pulmonary development at this stage [3]. Over a period of about 3 months the infant developed normally. The child underwent evaluation for possible lung transplantation. However, starting at the age of 13 weeks, the child developed sudden attacks of oxygen desaturation whilst breathing normally. The attacks were resistant to therapy. At the age of 101 days, the child did not recover from one of these attacks. An autopsy was not performed. The course of ACD/MPV in female siblings of one mother and two different fathers is different from the inheritance pattern in the literature and eliminates a possible recessive pedigree [5]. The first child died during the neonatal period (day 17), the second, reported here in detail, after 101 days of life, both of respiratory distress and permanent pulmonary hypertension (PPHN). When the second child showed similar symptoms after delivery, and after other causes for respiratory distress and PPHN had been ruled out, ACD/MPV was assumed, and subsequently proven. To date, ACD/MPV is a fatal disease [2,6]. Progress in lung transplantation in infants during the past years offers a therapeutic option for patients with ACD/MPV. As demonstrated by our report, prolonged survival using treatment with iNO could serve as a bridge to lung transplantation [1,4]. C. Licht (&) Æ A. Vierzig Æ B. Roth Department of Paediatrics, Children s Hospital, University of Cologne, Joseph-Stelzmann-Strasse 9, 50924 Cologne, Germany E-mail: christoph.licht@uni-koeln.de Tel.: +49-221-4784391 Fax: +49-221-4785835

Determination of thiamin diphosphate in whole blood samples by high-performance liquid chromatography-A method suitable for pediatric diagnostics

An improved and easy to use method for the determination of thiamin diphosphate (TDP) in 100 microl of whole blood was developed. The small sample volume makes it possible to assess the nutritional status of vitamin B(1) in infants and even in preterm infants. Sample preparation comprises the extraction of TDP from whole blood by hemolysis, protein precipitation with trichloroacetic acid, and subsequent centrifugation. Potassium ferricyanide is used for pre-column derivatization of TDP to its fluorescent thiochrome derivative. Chromatographic separation was carried out using a reversed-phase column and an isocratic elution which consisted of a phosphate buffer and acetonitrile. TDP was detected fluorimetrically and quantified by external standardization. Method validation showed a high precision, almost complete recovery, and a high sensitivity. The lower limit of detection and the lower limit of quantification were 0.2 ng/ml and 4 ng/ml, respectively. Linearity was demonstrated over the expected concentration range of 4-400 ng/ml. In conclusion, we present a convenient HPLC method for the determination of TDP which is precise, sensitive and suitable for pediatric diagnostics.

Clinical experiences with high-frequency oscillatory ventilation in newborns with severe respiratory distress syndrome

Objective: To generate hypotheses about which subgroups of newborns with severe respiratory distress syndrome might benefit most from high‐frequency oscillatory ventilation. Design: Retrospective analysis of a case series of newborns with severe respiratory distress syndrome who were treated in our department with high‐frequency oscillatory ventilation. Setting: Referral center for neonatal and pediatric intensive care medicine. Patients: All newborns (n = 18), admitted between June 1991 and February 1993, of various gestational ages (26 to 41 wks), with severe respiratory distress syndrome caused by various underlying pulmonary diseases who did not respond to conventional therapy and who thus were treated with high‐frequency oscillatory ventilation. Main Outcome Measures: Survival until discharge from our unit and persistent improvement of gas exchange. Results: Eight (44%) of 18 patients survived; ten (55%) patients died. Four (22%) survivors showed marked clinical improvement with the initiation of high‐frequency oscillatory ventilation. Four (22%) survivors did not respond to high‐frequency oscillatory ventilation. The responder group consisted of term or near‐term neonates (gestational age at least 35 wks) with pulmonary disease that was complicated by persistent pulmonary hypertension. The group of premature neonates with a gestational age of <35 wks did not respond to high‐frequency oscillatory ventilation. Conclusions: As a result of our analysis, we hypothesize that term newborns with severe respiratory distress syndrome complicated by persistent pulmonary hypertension and hypercarbia can benefit from high‐frequency oscillatory ventilation. Premature neonates with ventilation‐induced lung injury are not likely to respond to high‐frequency oscillatory ventilation. (Crit Care Med 1994; 22:S83‐S87)

Observations on the effects of inhaled isoflurane in long-term sedation of critically Ill children using a modified AnaConDa©-system.

Long-term intravenous sedation may present problems due to dependence and side effects. Medical records of children who were administered isoflurane were reviewed. 15 patients (9 boys, 6 girls) with a mean age of 11.8 month (+2.4) were analysed.Analgesia and sedation was given in mean 9.7+1.1 days before commencing inhalation using a modified application device (AnaConDa©). Administration was given over a period of 7.2+1.4 days. Depth of sedation was monitored by using Comfort- and Hartwig-scores. Observations included continuous monitoring of heart-rate, pulse oxymetry, blood pressure and cerebral tissue oxygenation.Within 4 h post administration of isoflurane a satisfactory increase in the depth of sedation was seen and kept till extubation. 6/15 patients received tracheostomies during the observation period. None of the patients observed suffered life-critical events of the modified application of isoflurane proceeded without complications. Ketamine and clonidine infusion rates were significantly reduced (p<0.005) as well as the use and overall infusion rate of midazolam, γ-hydroxy butyrate, fentanyl and morphine (p<0.05).Isoflurane inhalation may provide an additional option for long-term sedation in a specific group of critically ill infants but neurodegenerative toxic effects will have to be taken into account when using volatile anesthetics at any time during infancy.

Increased risk of interstitial lung disease in children with a single R288K variant of ABCA3.

The ABCA3 gene encodes a lipid transporter in type II pneumocytes critical for survival and normal respiratory function. The frequent ABCA3 variant R288K increases the risk for neonatal respiratory distress syndrome among term and late preterm neonates, but its role in children’s interstitial lung disease has not been studied in detail. In a retrospective cohort study of 228 children with interstitial lung disease related to the alveolar surfactant system, the frequency of R288K was assessed and the phenotype of patients carrying a single R288K variant further characterized by clinical course, lung histology, computed tomography and bronchoalveolar lavage phosphatidylcholine PC 32:0. Cell lines stably transfected with ABCA3-R288K were analyzed for intracellular transcription, processing and targeting of the protein. ABCA3 function was assessed by detoxification assay of doxorubicin, and the induction and volume of lamellar bodies. We found nine children with interstitial lung disease carrying a heterozygous R288K variant, a frequency significantly higher than in the general Caucasian population. All identified patients had neonatal respiratory insufficiency, recovered and developed chronic interstitial lung disease with intermittent exacerbations during early childhood. In vitro analysis showed normal transcription, processing, and targeting of ABCA3-R288K, but impaired detoxification function and smaller lamellar bodies. We propose that the R288K variant can underlie interstitial lung disease in childhood due to reduced function of ABCA3, demonstrated by decelerated detoxification of doxorubicin, reduced PC 32:0 content and decreased lamellar body volume.

Thiamin status of premature infants assessed by measurement of thiamin diphosphate in whole blood.

Premature infants constitute a risk group for thiamin deficiency but only little is known about their thiamin status. The aim of the present study was to investigate the thiamin status of premature infants by determination of thiamin diphosphate (TDP) and to identify risk factors for low TDP concentrations. In a prospective, longitudinal study TDP was determined by HPLC in whole blood in the first days of life and approximately every 2 weeks. Demographical data, weight gain, type of nutrition and thiamin intake were recorded. A total of 111 premature infants were included at the Children’s Hospital of the University of Cologne, Germany from May 2009 until December 2010 and 222 blood samples were analysed. TDP concentrations showed an age-dependent decline (age 0–10 d, mean TDP = 110.6 ng/ml; age 11–20 d, mean TDP = 95.4 ng/ml; age 21–103 d, mean TDP = 33.6 ng/ml). There was no significant difference between males and females. Young gestational age and low birth weight were associated with low TDP concentrations. No infant was diagnosed with thiamin deficiency. The current nutritional regimen in our hospital did not lead to thiamin deficiency in the study cohort. Further research is required to evaluate how TDP concentrations are regulated in premature infants.