Prognostic model for predicting survival in very preterm infants: an external validation study.

OBJECTIVE: To perform a temporal and geographical validation of a prognostic model, considered of highest methodological quality in a recently published systematic review, for predicting survival in very preterm infants admitted to the neonatal intensive care unit. The original model was developed in the UK and included gestational age, birthweight and gender. DESIGN: External validation study in a population-based cohort. SETTING: Dutch neonatal wards. POPULATION OR SAMPLE: All admitted white, singleton infants born between 23+0 and 32+6 weeks of gestation between 1 January 2015 and 31 December 2019. Additionally, the model's performance was assessed in four populations of admitted infants born between 24+0 and 31+6 weeks of gestation: white singletons, non-white singletons, all singletons and all multiples. METHODS: The original model was applied in all five validation sets. Model performance was assessed in terms of calibration and discrimination and, if indicated, it was updated. MAIN OUTCOME MEASURES: Calibration (calibration-in-the-large and calibration slope) and discrimination (c statistic). RESULTS: Out of 6092 infants, 5659 (92.9%) survived. The model showed good external validity as indicated by good discrimination (c statistic 0.82, 95% CI 0.79-0.84) and calibration (calibration-in-the-large 0.003, calibration slope 0.92, 95% CI 0.84-1.00). The model also showed good external validity in the other singleton populations, but required a small intercept update in the multiples population. CONCLUSIONS: A high-quality prognostic model predicting survival in very preterm infants had good external validity in an independent, nationwide cohort. The accurate performance of the model indicates that after impact assessment, implementation of the model in clinical practice in the neonatal intensive care unit could be considered. TWEETABLE ABSTRACT: A high-quality model predicting survival in very preterm infants is externally valid in an independent cohort.

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia.

The pharmacokinetics (PK) of amoxicillin in asphyxiated newborns undergoing moderate hypothermia were quantified using prospective data (N = 125). The population PK was described by a 2-compartment model with a priori birthweight (BW) based allometric scaling. Significant correlations were observed between clearance (Cl) and postnatal age (PNA), gestational age (GA), body temperature (TEMP), and urine output (UO). For a typical patient with GA 40 weeks, BW 3,000 g, 2 days PNA (i.e., TEMP 33.5°C), and normal UO, Cl was 0.26 L/h (interindividual variability (IIV) 41.9%) and volume of distribution of the central compartment was 0.34 L/kg (IIV of 114.6%). For this patient, Cl increased to 0.41 L/h at PNA 5 days and TEMP 37.0°C. The respective contributions of both covariates were 23% and 27%. Based on Monte Carlo simulations we recommend 50 and 75 mg/kg/24h amoxicillin in three doses for patients with GA 36-37 and 38-42 weeks, respectively.

Irradiance levels of phototherapy devices: a national study in Dutch neonatal intensive care units.

OBJECTIVE: The objective of this study is to determine whether irradiance levels of phototherapy (PT) devices in Dutch neonatal intensive care units (NICUs) increased between 2008 and 2013. STUDY DESIGN: Irradiance of all types of PT devices, used in combination with incubators, was measured with a Dale 40 Radiometer (Fluke Biomedical, Everett, WA, USA) in all 10 Dutch NICUs. RESULTS: Irradiance increased in seven NICUs. Median (range) irradiance increased from 9.7 (4.3-32.6) to 16.4 (6.8-41) µW cm-2 nm-1 for 24 overhead devices (P=0.004) and from 6.8 (0.8-15.6) to 22.3 (1.1-36.3) µW cm-2 nm-1 for 12 underneath devices (P=0.014). Five light-emitting diode (LED)-based devices were used in 2013 and one in 2008. The mean distance between overhead PT device and infant decreased by ~9 cm (P<0.001). Significantly more devices delivered minimal (10 µW cm-2 nm-1) recommended irradiance levels (80 vs ~45%; P=0.002). CONCLUSION: Irradiance of PT devices still varies, but has markedly improved since 2008 due to shorter distances between PT device and infant, and introduction of better performing LED-based devices.

Surfactant nebulisation: lung function, surfactant distribution and pulmonary blood flow distribution in lung lavaged rabbits.

OBJECTIVE: Surfactant nebulisation is a promising alternative to surfactant instillation in newborns with the respiratory distress syndrome. Although less surfactant is deposited in the lung, it improves gas exchange, probably due to a superior distribution. We hypothesize that a more uniform distribution of nebulised surfactant results in a more uniform pulmonary blood flow and consequently a more efficient gas exchange. We asked whether the pulmonary blood flow changes after surfactant replacement, and to what extent pulmonary blood flow is influenced by the amount of surfactant deposition. Furthermore, we investigated whether sufficient nebulised surfactant is deposited in the lungs to achieve a sustained improvement in lung function. INTERVENTIONS: Surfactant was nebulised or instilled, or saline was nebulised, in 18 lung-lavaged rabbits. After 2 h the rabbits were weaned from mechanical ventilation to continuous positive airway pressure, 40% oxygen. We measured blood gasses, dynamic lung compliance, surfactant distribution using 99m technetium nanocoll label, and the pulmonary blood flow distribution, using microspheres. RESULTS: Partial pressure of oxygen in arterial blood and lung compliance were significantly higher after surfactant nebulisation than after saline nebulisation. Surfactant instillation gave a superior effect with respect to these variables. Nebulised surfactant was distributed more uniformly over the lungs than instilled surfactant. Although pulmonary blood flow changed over time, it remained uniformly distributed following both modes of surfactant treatment. Surfactant deposition was neither strongly related to pulmonary blood flow nor strongly related to the change in blood flow. CONCLUSIONS: Although nebulised surfactant is uniformly distributed, we can provide no evidence that this results in a more uniform pulmonary blood flow distribution. Therefore, other than a superior surfactant distribution, no additional reason was found for the efficient gas exchange after nebulisation.

Surfactant nebulisation prevents the adverse effects of surfactant therapy on blood pressure and cerebral blood flow in rabbits with severe respiratory failure.

OBJECTIVE: Surfactant replacement therapy for the neonatal respiratory distress syndrome has shown beneficial effects on lung function and survival. Recently, rapid fluctuations of haemodynamics and cerebral perfusion following surfactant instillation have been described and an association with the development of intraventricular haemorrhage has been proposed. Therefore, alternative methods of surfactant therapy that reduce the effects on cerebral perfusion have to be explored. Does instillation of surfactant influence blood pressure and cerebral blood flow in rabbits with severe respiratory failure? Can nebulisation of surfactant prevent these adverse effects on blood pressure and cerebral blood flow? INTERVENTIONS: Surfactant (Alveofact, 100 mg/kg body weight) was nebulised using the MiniNEB nebuliser, or instilled, in 12 rabbits with severe respiratory failure induced by lung lavage. Assessed were blood gasses, mean arterial blood pressure (MABP) and cerebral blood flow over the left carotid artery, using ultrasonic transit-time flow probes. RESULTS: Partial pressure of oxygen in arterial blood increased quickly after instillation, from 8.7 +/- 1.3 to 24.9 +/- 6.4 kPa after 15 min, and increased gradually during nebulisation from 8.0 +/- 0.5 to 24.5 +/- 4.6 after 120 min. After instillation, MABP decreased 22 +/- 5% (in 8 min) and cerebral blood flow dropped even more: 64 +/- 9% within 8 min. During nebulisation, MABP did not change significantly and cerebral blood flow decreased gradually, 31 +/- 14% over 90 min. CONCLUSIONS: Surfactant instillation was followed by a rapid decrease in MABP and an even more pronounced drop in cerebral blood flow, while during nebulisation MABP did not change and cerebral blood flow decreased less and more gradually.

Surfactant nebulisation: safety, efficiency and influence on surface lowering properties and biochemical composition.

OBJECTIVE: The objectives of this study were, to select a nebuliser first, that operates safely in a neonatal ventilator setting and, second, that is most efficient. Thirdly, we studied the particle sizes of the surfactant aerosol. Fourthly, we studied where the nebulised surfactant is deposited in the tubing system of the ventilator. Finally, we studied whether nebulisation influences the composition and biophysical properties of surfactant. MEASUREMENTS AND RESULTS: Safety was assessed by measuring "mean airway pressures" in a test lung before, during and after surfactant nebulisation, for three jet nebulisers. The MiniNEB did not alter these pressures, and is thus safe, whereas the other two nebulisers (Intersurgical and Flo-Thru) increased these pressures. The efficiency of nebulisation was assessed by measuring the amount of phospholipid deposited in the test lung. The MiniNEB showed the highest efficiency: 10% versus 1-3% of the other two nebulisers. The particle sizes of surfactant aerosol were assessed by the laser diffraction method. Seventy percent of the particles were 1-5 microns. The deposition of surfactant aerosol in the tubing system was assessed by nebulising surfactant that was labelled with 99mTc Nanocoll. Afterwards the tubing system was imaged using a gamma camera. The majority of surfactant was deposited in the expiratory hose (28%), nebuliser (20%), Y-piece (16%) and expiratory filter (12%). Finally the phospholipid composition, spreading velocity, static and dynamic surface tensions were assessed for the nebulised surfactant and compared to the stock surfactant. In addition, nebulised surfactant was instilled in premature rabbits and tidal volumes were measured to assess the dose-response relation. We found that neither the composition nor biophysical properties had been altered by nebulisation. CONCLUSIONS: The MiniNEB nebulised surfactant safely in a neonatal ventilator setting with respect to airway pressures. The efficiency of nebulisation is low: the majority of the surfactant aerosol is deposited in the expiratory tubing. The surfactant composition and function is not altered by nebulisation. Therefore the nebulisation of surfactant is feasible, but efforts should be made to improve the efficiency of this procedure.

Usefulness of the bilirubin/albumin ratio for predicting bilirubin-induced neurotoxicity in premature infants.

Unconjugated hyperbilirubinaemia occurs in almost all premature infants and is potentially neurotoxic. Treatment is based on total serum bilirubin (TSB), but treatment thresholds are not evidence based. Free bilirubin (Bf)-that is, not bound to albumin, seems a better parameter for bilirubin neurotoxicity, but measurements of Bf are not available in clinical practice. The bilirubin/albumin (B/A) ratio is considered a surrogate parameter for Bf and an interesting additional parameter in the management of hyperbilirubinaemia. This paper reviewed the evidence supporting the use of B/A ratios for predicting bilirubin-induced neurological dysfunction (BIND) including neurodevelopmental delay in jaundiced premature infants (gestational age less than 32 weeks). A literature search was performed and six publications reviewed regarding B/A ratios in the management and outcome of jaundiced premature infants. No prospective clinical trials had been undertaken to show whether bilirubin-induced neurotoxicity is reduced or whether unnecessary treatment is avoided by using the B/A ratio in addition to TSB. Recently, a randomised controlled trial evaluating the effect of the additional use of the B/A ratio on neurodevelopmental outcome in jaundiced premature infants has been initiated. Based on the prevailing evidence many authorities suggest that the additional use of the B/A ratio may be valuable when evaluating jaundiced premature infants.

A comparison of the hemodynamic and respiratory effects of surfactant instillation during interrupted ventilation versus noninterrupted ventilation in rabbits with severe respiratory failure.

The purpose of this study was to evaluate whether avoiding interruption of ventilation during surfactant instillation improves the effects on lung function and surfactant distribution and whether it prevents the adverse effects on blood pressure and cerebral blood flow. The study was performed using rabbits with severe respiratory failure induced by lung lavages. These rabbits were randomized to 99mTc-Nanocoll labeled surfactant instillation through a side lumen of the endotracheal tube without interrupting ventilation or instillation during a short interruption of ventilation. After surfactant instillation with interruption of ventilation, PaO2 rose from 8.7+/-1.3 to 24.9+/-6.4 kPa (mean+/-SEM). Without interruption, PaO2 rose from 8.4+/-0.8 to 32.4+/-4.3 kPa. PaCO2 decreased with interruption from 4.69+/-0.51 to 3.61+/-0.26 kPa and without interruption from 5.06+/-0.41 to 4.13+/-0.23 kPa. Dynamic and static compliance indices were not statistically different after both procedures. Surfactant distribution tended to be less nonuniform after instillation without interrupting ventilation. In contrast, avoidance of interruption of ventilation resulted in less uniform lobar distribution and less peripheral deposition of surfactant. By instillation with interruption, blood pressure increased quickly (28+/-6.6%), followed by a 22+/-5.3% decrease. Blood pressure increased quickly (16+/-4.2%), followed by a 40+/-10% decrease by surfactant instillation without interruption. Cerebral blood flow, measured by an ultrasonic transit time flow probe on the carotid artery, increased quickly (45+/-14%), followed by a 64+/-11% decrease with interruption, whereas it increased 15+/-4.9% (p = 0.06 versus with interruption) and decreased 61+/-13% without interruption of ventilation. Therefore, avoiding interruption of ventilation during surfactant instillation tends to prevent the potential adverse effects of a rapid rise in cerebral blood flow, and furthermore, tends to improve uniformity of surfactant distribution, whereas having no detrimental effect on respiratory function.

Surfactant nebulization versus instillation during high frequency ventilation in surfactant-deficient rabbits.

Surfactant nebulization improves lung function at low alveolar doses of surfactant. However, efficiency of nebulization is low, and lung deposition seems to depend on lung aeration. High frequency ventilation (HFV) has been shown to improve lung aeration. We hypothesize that the combination of HFV and surfactant nebulization may benefit lung deposition of surfactant and consequently, lung function. The aim of this study was to compare the effect of surfactant nebulization versus instillation during HFV on lung function, surfactant distribution, and cerebral blood flow. Therefore, severe respiratory failure was induced by lung lavages in 18 rabbits. HFV was applied: frequency = 8 Hz, mean airway pressure = 12 cm H2O, amplitude = 100%, fraction of inspired O2 = 1.0. Technetium-99m-labeled surfactant (Alveofact, 100 mg/kg of BW) was nebulized or instilled (n = 6 each). Six other rabbits did not receive surfactant (control, HFV only). We found that after instillation partial arterial O2 tension increased from 7.0 kPa (95% confidence interval, 6.3-8.0 kPa) to 34 kPa (16-51 kPa), and during nebulization from 7.0 kPa (6.0-9.0 kPa) to 46 kPa (27-58 kPa). Partial arterial CO2 tension decreased after instillation from 6.1 kPa (5.3-7.1 kPa) to 4.8 kPa (3.9-5.6 kPa), and during nebulization, after an initial rise, it decreased from 6.3 kPa (5.3-7.4 kPa) to 4.9 kPa (4.4-5.6 kPa). Both treatments resulted in nonuniform distribution. Surfactant deposition after nebulization was 9.8%. Instillation resulted in a drop of mean arterial blood pressure of 17% (8-31%), and an even more pronounced drop in cerebral blood flow of 39% (18-57%). Nebulization did not affect blood pressure. Cerebral blood flow decreased with a maximum of 27% (10-37%). We conclude that surfactant nebulization during HFV improves lung function in rabbits with severe respiratory failure, without improving distribution, but with less effects on blood pressure and cerebral blood flow, when compared with surfactant instillation.

Quality improvement of patient care: some preliminary results of a hospital-wide quality-assurance project at the University Hospital of Maastricht.

Dutch hospitals have to design their quality-assessment programmes within the boundaries set by "indirect government legislation". At the University hospital of Maastricht a five-stage project was started in 1985 to construct a hospital-wide quality-assurance organisation that includes regular review of the quality of professional performance. This paper will describe intermediate results of the first stage and will discuss the results of different subsurveys undertaken to assess the current level of quality of care and several key-issues conditional to the implementation of such a hospital-wide structure in the existing organisation of a University hospital. Finally the results of the first stage will be contrasted with external legislative standards and internal needs of the University hospital recognised during assessment of the current situation.