Kai König

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.

Systematic Review of the Safety of Regular Preventive Asthma Medications During Pregnancy

Objective: To review the safety of regular preventive asthma medications during pregnancy. Data Sources: The following databases were searched from inception to February 2011: Ovid MEDLINE, PubMed, Cochrane Library, EMBASE and CINAHL Plus. Study Selection and Data Extraction: The search was limited to human studies published in the English language. Titles of all articles were screened for relevance. Abstracts of relevant articles were scrutinized to confirm relevance before obtaining full text. Data Synthesis: Selected articles were read by 2 authors and the accuracy of the data extracted was confirmed. Results: Thirty-three articles were included in the final review. Small sample size, missing data, inadequate control for confounding factors, and poor documentation of dosage range were common limitations of the studies reviewed. The use of inhaled corticosteroids, cromolyns, and long-acting β2 agonists during pregnancy was not associated with any particular adverse event, although the fluticasone/salmeterol combination has been associated with poor outcomes in postmarketing studies. Congenital malformations have been reported with leukotriene receptor antagonist exposure during pregnancy, but those women also had exposure to other medications, including oral corticosteroids. Conclusions: Some negative outcomes of preventive asthma medications have been reported, although their direct link with medication use is inconclusive. Selection of preventive medications for asthma management during pregnancy should be based on an assessment of the risks and benefits of medication use versus the risks of poorly controlled asthma.

Comparison of the pharyngeal pressure provided by two heated, humidified high-flow nasal cannulae devices in premature infants

This study aims to determine if there is a difference in the pharyngeal pressure, measured as a surrogate for continuous positive distending airway pressure, delivered to premature infants between two commonly used heated, humidified high‐flow nasal cannulae (HHHFNC) devices: Fisher & Paykel Healthcare HHHFNC and Vapotherm 2000i.

Noise Levels of Neonatal High-Flow Nasal Cannula Devices - An in-vitro Study

Background: Excessive ambient noise levels have been identified as a potential risk factor for adverse outcome in very preterm infants. Noise level measurements for continuous positive airway pressure (CPAP) devices demonstrated that these constantly exceed current recommendations. The use of high-flow nasal cannula (HFNC) as an alternative non-invasive ventilation modality has become more popular in recent years in neonatal care. Objective: To study noise levels of two HFNC devices commonly used in newborns. As a comparison, noise levels of a continuous flow CPAP device were also studied. Methods: In-vitro study. The noise levels of two contemporary HFNC devices (Fisher & Paykel NHF™ and Vapotherm Precision Flow®) and one CPAP device (Dräger Babylog® 8000 plus) were measured in the oral cavity of a newborn manikin in an incubator in a quiet environment. HFNC flows of 4-8 l/min and CPAP pressures of 4-8 cm H2O were applied. The CPAP flow was set at 8 l/min as per unit practice. Results: Vapotherm HFNC generated the highest noise levels, measuring 81.2-91.4 dB(A) with increasing flow. Fisher & Paykel HFNC noise levels were between 78.8 and 81.2 dB(A). The CPAP device generated the lowest noise levels between 73.9 and 77.4 dB(A). Conclusions: Both HFNC devices generated higher noise levels than the CPAP device. All noise levels were far above current recommendations of the American Academy of Pediatrics. In light of the long duration of non-invasive respiratory support of very preterm infants, less noisy devices are required to prevent the potentially adverse effects of continuing excessive noise exposure in the neonatal intensive care unit.

The effect of sildenafil on evolving bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled pilot study

Abstract Objective: Sildenafil has been shown to preserve alveolar growth and lung angiogenesis in a rat model of bronchopulmonary dysplasia. We conducted a proof-of-concept randomised controlled pilot study to assess the feasibility of oral sildenafil treatment in extremely preterm infants with evolving bronchopulmonary dysplasia. Methods: Preterm infants <28 weeks gestational age were eligible if they were mechanically ventilated on day 7 of life. Infants were randomised to a 4-weeks course of either oral sildenafil (3 mg/kg/day) or placebo solution. Pre-discharge cardiorespiratory outcomes and medication side effects were collected. Results: Twenty infants were randomised, 10 received sildenafil (mean gestational age 24 + 5 weeks (SD 4.9 days), mean weight 692 g (SD 98)) and 10 received placebo (mean gestational age 24 + 5 weeks (SD 6.5 days), mean weight 668 g (SD 147)). One infant in the sildenafil group did not receive treatment because of an early pneumoperitoneum. Two infants did not complete the study (transferred out). Of the remaining seven treated infants, three died (two from respiratory-related causes). One infant in the control group died from a non-respiratory cause. Sildenafil did not reduce length of invasive (median 688 versus 227 h) or non-invasive ventilation (median 1609 versus 1416 h). More infants in the sildenafil group required postnatal steroid treatment. One infant developed hypotension following sildenafil administration and was excluded after three doses. Conclusions: In this pilot study, oral sildenafil treatment did not improve any short-term respiratory outcomes in extremely preterm infants.

Accuracy of infrared thermometers in very low birth weight infants and impact on newborn behavioural states

To study the impact on newborn behavioural states and accuracy of three infrared thermometers compared with digital axillary thermometer measurements in very low birth weight infants.

Fulminant herpes simplex virus hepatic failure in pregnancy requiring liver transplantation.

Herpes simplex virus hepatitis is a rare but potentially fatal condition that usually affects the immunocompromised, including pregnant women. This case report details the course of fulminant hepatic failure in a woman at 31 weeks gestation resulting in emergent delivery of the fetus and liver transplant in the mother.

Association of BNP, NTproBNP, and early postnatal pulmonary hypertension in very preterm infants

Summary Objective B-type natriuretic peptide (BNP) has been shown to correlate with pulmonary hypertension (PH) in term neonates with persistent pulmonary hypertension of the newborn or congenital diaphragmatic hernia, and in very preterm infants with bronchopulmonary dysplasia. This study investigated the potential association of BNP and N-terminal-pro-BNP (NTproBNP) and PH within the first 72 hr of life in very preterm infants. Methods Preterm infants <32 weeks gestational age who received an echocardiogram within the first 72 hr of life were eligible. BNP and NTproBNP were sampled at the time of the echocardiogram. Right ventricular systolic pressure (RVSP) was calculated as a surrogate marker of PH. Simple and multiple linear regression analysis was performed to examine associations and potential confounding factors. Results Sixty-one infants were included with a median (IQR) birth weight of 983 g (826–1,167) and a median (IQR) gestational age of 272 weeks (262–286). There was no difference between BNP or NTproBNP levels for infants with or without measurable RVSP. There was no significant correlation of BNP and RVSP in multiple linear regression analysis (regression coefficient −0.0035 (95%CI: −0.020 to 0.013), P = 0.67). Also, NTproBNP and RVSP were not significantly correlated in multiple linear regression analysis (regression coefficient 0.0071 (95%CI: −0.019 to 0.033), P = 0.58). Conclusion B-type natriuretic peptides did not correlate with RVSP in the early postnatal period of very preterm infants. Pediatr Pulmonol.

Bronchopulmonary dysplasia in preterm infants managed with non-invasive ventilation or surfactant and a brief period of mechanical ventilation: a 6-year cohort study.

Abstract Objective: Non-invasive ventilation (NIV) is increasingly used as first-line management of respiratory distress syndrome in preterm infants to avoid the lung-damaging effects of mechanical ventilation (MV). We hypothesised that even a short period of MV following surfactant treatment would increase the rate of bronchopulmonary dysplasia (BPD). Methods: Retrospective study including preterm infants <30 weeks gestational age over a six-year period if they required surfactant followed by MV not longer than 24 h (SURF&MV group) or if managed exclusively with NIV (NIV group). Baseline and morbidity variables such as gestation, birth weight, sex, place of birth, antenatal steroids, sepsis, pneumothorax, intraventricular haemorrhage, necrotising enterocolitis, and patent ductus arteriosus were analysed in a multivariate model for potential confounding. Results: 289 infants were included: 150 in the NIV group and 139 in the SURF&MV group. Seventeen infants in the NIV group and 23 in the SURF&MV group developed BPD (odds ratio: 1.55; 95% confidence interval (CI): 0.79–3.05; p = 0.202). After adjusting for potential confounders, the odds ratio was 1.09 for the SURF&MV group to develop BPD (95% CI: 0.52–2.28; p = 0.812). Conclusion: The rate of BPD did not differ between infants managed with NIV or with surfactant administration followed by ≤24 h of MV after adjusting for confounding factors.

BNP, troponin I, and YKL-40 as screening markers in extremely preterm infants at risk for pulmonary hypertension associated with bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is often complicated by pulmonary hypertension (PH). We investigated three biomarkers potentially suitable as screening markers for extremely preterm infants at risk of BPD-associated PH. In this prospective observational cohort study conducted in a tertiary neonatal intensive care unit, 83 preterm infants with BPD born <28-wk gestation and still inpatients at 36-wk corrected age received an echocardiogram and blood tests of B-type natriuretic peptide (BNP), troponin I, and YKL-40. Infants were analyzed according to echocardiographic evidence of tricuspid regurgitation (TR). Thirty infants had evidence of TR on echocardiogram at 36-wk corrected age. Infants with or without TR had similar baseline demographics: mean ± SD gestational age 261 ± 12 vs. 261 ± 11 wk and birth weight 830 ± 206 vs. 815 ± 187 g, respectively. There was no difference in duration of respiratory support. The right ventricular systolic pressure of infants with evidence of TR was 40 ± 16 mmHg. BNP was the only biomarker that proved to be significantly higher in infants with evidence of TR: median (interquartile range) serum level 54.5 (35-105) vs. 41.5 (30-59) pg/ml, P = 0.043. Subgroup analysis of infants with severe BPD requiring discharge on home oxygen or BPD-related mortality revealed similar results. There was no difference between groups for troponin I and YKL-40. In conclusion, increased serum levels of BNP were associated with evidence of TR at 36-wk corrected gestational age in extremely preterm infants, suggesting a potential role as a screening biomarker for BPD-associated PH.