Peter H. Dijk

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.

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.

Pharmacokinetics and pharmacodynamics of medication in asphyxiated newborns during controlled hypothermia. The PharmaCool multicenter study

BackgroundIn the Netherlands, perinatal asphyxia (severe perinatal oxygen shortage) necessitating newborn resuscitation occurs in at least 200 of the 180–185.000 newly born infants per year. International randomized controlled trials have demonstrated an improved neurological outcome with therapeutic hypothermia. During hypothermia neonates receive sedative, analgesic, anti-epileptic and antibiotic drugs. So far little information is available how the pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs are influenced by post resuscitation multi organ failure and the metabolic effects of the cooling treatment itself. As a result, evidence based dosing guidelines are lacking. This multicenter observational cohort study was designed to answer the question how hypothermia influences the distribution, metabolism and elimination of commonly used drugs in neonatal intensive care.Methods/DesignMulticenter cohort study. All term neonates treated with hypothermia for Hypoxic Ischemic Encephalopathy (HIE) resulting from perinatal asphyxia in all ten Dutch Neonatal Intensive Care Units (NICUs) will be eligible for this study. During hypothermia and rewarming blood samples will be taken from indwelling catheters to investigate blood concentrations of several antibiotics, analgesics, sedatives and anti-epileptic drugs. For each individual drug the population PK will be characterized using Nonlinear Mixed Effects Modelling (NONMEM). It will be investigated how clearance and volume of distribution are influenced by hypothermia also taking maturation of neonate into account. Similarly, integrated PK-PD models will be developed relating the time course of drug concentration to pharmacodynamic parameters such as successful seizure treatment; pain assessment and infection clearance.DiscussionOn basis of the derived population PK-PD models dosing guidelines will be developed for the application of drugs during neonatal hypothermia treatment. The results of this study will lead to an evidence based drug treatment of hypothermic neonatal patients. Results will be published in a national web based evidence based paediatric formulary, peer reviewed journals and international paediatric drug references.Trial registrationNTR2529.

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 μm. 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.

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 99 m 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.

Systemic hydrocortisone to prevent bronchopulmonary dysplasia in preterm infants (the SToP-BPD study); a multicenter randomized placebo controlled trial

BackgroundRandomized controlled trials have shown that treatment of chronically ventilated preterm infants after the first week of life with dexamethasone reduces the incidence of the combined outcome death or bronchopulmonary dysplasia (BPD). However, there are concerns that dexamethasone may increase the risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. So far no randomized controlled trial has investigated its efficacy when administered after the first week of life to ventilated preterm infants.Methods/DesignThe SToP-BPD trial is a randomized double blind placebo controlled multicenter study including 400 very low birth weight infants (gestational age < 30 weeks and/or birth weight < 1250 grams), who are ventilator dependent at a postnatal age of 7 - 14 days. Hydrocortisone (cumulative dose 72.5 mg/kg) or placebo is administered during a 22 day tapering schedule. Primary outcome measure is the combined outcome mortality or BPD at 36 weeks postmenstrual age. Secondary outcomes are short term effects on the pulmonary condition, adverse effects during hospitalization, and long-term neurodevelopmental sequelae assessed at 2 years corrected gestational age. Analysis will be on an intention to treat basis.DiscussionThis trial will determine the efficacy and safety of postnatal hydrocortisone administration at a moderately early postnatal onset compared to placebo for the reduction of the combined outcome mortality and BPD at 36 weeks postmenstrual age in ventilator dependent preterm infants.Trial registration numberNetherlands Trial Register (NTR): NTR2768

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.

Cerebral oxygenation is associated with neurodevelopmental outcome of preterm children at age 2 to 3 years

The aim of the study was to determine whether regional cerebral tissue oxygen saturation (rcSO2) and fractional tissue oxygen extraction (FTOE), using near‐infrared spectroscopy, are associated with neurodevelopmental outcome of preterm infants.

Severe Neonatal Hyperbilirubinemia in the Netherlands

Background: The occurrence of severe neonatal hyperbilirubinemia (SH) is partly attributed to nonhospitalized perinatal care. The Netherlands have a high frequency of home births and nonhospitalized perinatal care, and the incidence of SH is unknown. Objective: To assess the effects of home births and early hospital discharge on the incidence of SH in term-born infants in the Netherlands. Methods: In this nationwide prospective surveillance study between 2005 and 2009, infants (≥37 weeks GA) were included if total serum bilirubin (TSB) was ≥500 µmol/l or if they received an exchange transfusion when TSB was ≥340 µmol/l. Results: Seventy-one infants had SH (incidence 10.4/100,000); 43 had a TSB ≥500 μmol/l (incidence 6.3/100,000) and 45 (63%) underwent an exchange transfusion. 26% of the infants with SH were born at home, which is similar to 22% of all term infants who are born at home in the Netherlands (p = 0.41). Maximum TSB levels were similar in infants born at home (523 ± 114 μmol/l) and infants born in hospital (510 ± 123 μmol/l; p = 0.70). Of the 51 infants born in hospital, 33 were discharged and readmitted with SH, with maximal TSB levels (567 ± 114 μmol/l), which were higher than in infants who remained hospitalized (406 ± 47 μmol/l; p = 0.0001). Conclusion: The incidence of severe hyperbilirubinemia in term-born infants in the Netherlands is 10.4 per 100,000, which is similar to other developed countries. Home birth and early hospital discharge do not necessarily lead to a higher incidence of SH, provided that perinatal home care is well organized.

Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia

AIM(S) Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic−ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients METHODS Demographic, clinical and laboratory data of patients included in a multicentre prospective observational cohort study (the ‘PharmaCool Study’) were collected. A non-linear mixed-effects regression analysis (nonmem®) was performed to describe the population PK of gentamicin. The most optimal dosing regimen was evaluated based on simulations of the final model. RESULTS A total of 47 patients receiving gentamicin were included in the analysis. The PK were best described by an allometric two compartment model with gestational age (GA) as a covariate on clearance (CL). During hypothermia the CL of a typical patient (3 kg, GA 40 weeks, 2 days post-natal age (PNA)) was 0.06 l kg−1 h−1 (inter-individual variability (IIV) 26.6%) and volume of distribution of the central compartment (Vc) was 0.46 l kg−1 (IIV 40.8%). CL was constant during hypothermia and rewarming, but increased by 29% after reaching normothermia (>96 h PNA). CONCLUSIONS This study describes the PK of gentamicin in neonates undergoing controlled hypothermia. The 29% higher CL in the normothermic phase compared with the preceding phases suggests a delay in normalization of CL after rewarming has occurred. Based on simulations we recommend an empiric dose of 5 mg kg−1 every 36 h or every 24 h for patients with GA 36–40 weeks and GA 42 weeks, respectively.