Oxytocin levels in the saliva of preterm infant twins during Kangaroo care.

BACKGROUND AND PURPOSE: To investigate whether Kangaroo care (KC) influences the salivary oxytocin (OT) concentration in preterm infants, and which correlates affect the OT response. METHODS: Eleven twin pairs participated in a study in which we collected saliva using cotton swabs twice a day, once during KC and once during baseline conditions (lying in bed or incubator). The total study duration was five days. The saliva of twin siblings were pooled to obtain vials with sufficient volumes of either saliva collected during KC or at baseline. OT levels were measured using a radio-immuno assay. The infants' state of comfort and parent-infant interaction were examined using previously developed Likert-scales, amongst other correlates such as the KC duration, gestational age and birth weight. RESULTS: During KC, OT was lower compared to baseline (mean 1.39 pg/ml (SD 0.58 pg/ml) versus 2.40 pg/ml (SD 1.64 pg/ml), p =  0.03). Comfort at baseline and parent-infant interaction seemed to influence OT responses. CONCLUSION: The OT concentration in the pooled saliva of preterm infant twins decreased during KC. This response of the OT system might be explained by stress during baseline.

Pilot study demonstrates that salivary oxytocin can be measured unobtrusively in preterm infants.

AIM: This study assessed the feasibility and obtrusiveness of measuring salivary oxytocin in preterm infants receiving Kangaroo care, because this is a period of maximal bonding or co-regulation. We also analysed possible influential determinants, including maternal oxytocin. METHODS: The saliva of preterm infants and their mothers was collected prior to, and during, Kangaroo care using cotton swabs and pooled into vials until sufficient volumes were obtained to measure oxytocin levels using a radioimmunoassay. The obtrusiveness of the infants' collections was measured with a Likert scale. RESULTS: Saliva was collected unobtrusively prior to, and during, 30 Kangaroo care sessions in 21 preterm infants. This resulted in three vials with sufficient volumes of before-Kangaroo care saliva and three with during-Kangaroo care saliva. Oxytocin was detectable in all six vials. The Kangaroo care duration and the intensity of the mother-infant interaction before and during Kangaroo care seemed to be the most important determinants, and these should preferably be standardised in any future trials. CONCLUSION: Oxytocin was measured unobtrusively in the pooled saliva of preterm infants both before and during Kangaroo care and could therefore be investigated as a biomarker in future studies.

Suboptimal bonding impairs hormonal, epigenetic and neuronal development in preterm infants, but these impairments can be reversed.

UNLABELLED: This review aimed to raise awareness of the consequences of suboptimal bonding caused by prematurity. In addition to hypoxia-ischaemia, infection and malnutrition, suboptimal bonding is one of the many unnatural stimuli that preterm infants are exposed to, compromising their physiological development. However, the physiological consequences of suboptimal bonding are less frequently addressed in the literature than those of other threatening unnatural stimuli. CONCLUSION: This review found that suboptimal bonding significantly impaired hormonal, epigenetic and neuronal development, but these impairments could be reversed by bonding interventions. This suggests that neonatal intensive care units should focus more on interventions that optimise bonding.

Design of a breathing mattress based on the respiratory movement of kangaroo mother care for the development of neonates.

Kangaroo mother care (KMC) benefits the development of neonates. This paper focuses on the design and implementing the extension of KMC for infants at Neonatal Intensive Care Units (NICU). A breathing mattress is proposed to comfort infants and stimulate them to breathe regularly by mimicking the movement of the parent's chest during KMC. The incubator mattress simulates the breathing of the parent's chest with embedded electronics and pneumatic technology for mattress motion actuating systems. The stakeholders, including the child, parents and NICU staff, were directly involved during the concept development, prototyping and evaluation.

Rapid target allopurinol concentrations in the hypoxic fetus after maternal administration during labour.

OBJECTIVE: Perinatal hypoxia-induced free radical formation is an important cause of hypoxic-ischaemic encephalopathy and subsequent neurodevelopmental disabilities. Allopurinol reduces the formation of free radicals, which potentially limits hypoxia-induced brain damage. We investigated placental transfer and safety of allopurinol after maternal allopurinol treatment during labour to evaluate its potential role as a neuroprotective agent in suspected fetal hypoxia. DESIGN: We used data from a randomised, double-blind multicentre trial comparing maternal allopurinol versus placebo in case of imminent fetal hypoxia (NCT00189007). PATIENTS: We studied 58 women in labour at term, with suspected fetal hypoxia prompting immediate delivery, in the intervention arm of the study. SETTING: Delivery rooms of 11 Dutch hospitals. INTERVENTION: 500 mg allopurinol, intravenously to the mother, immediately prior to delivery. MAIN OUTCOME MEASURES: Drug disposition (maternal plasma concentrations, cord blood concentrations) and drug safety (maternal and fetal adverse events). RESULTS: Within 5 min after the end of maternal allopurinol infusion, target plasma concentrations of allopurinol of ≥2 mg/L were present in cord blood. Of all analysed cord blood samples, 95% (52/55) had a target allopurinol plasma concentration at the moment of delivery. No adverse events were observed in the neonates. Two mothers had a red and/or painful arm during infusion. CONCLUSIONS: A dose of 500 mg intravenous allopurinol rapidly crosses the placenta and provides target concentrations in 95% of the fetuses at the moment of delivery, which makes it potentially useful as a neuroprotective agent in perinatology with very little side effects. TRIAL REGISTRATION: The study is registered in the Dutch Trial Register (NTR1383) and the Clinical Trials protocol registration system (NCT00189007).

Quantitative analysis of maturational changes in EEG background activity in very preterm infants with a normal neurodevelopment at 1 year of age.

BACKGROUND: The electroencephalographic (EEG) background pattern of preterm infants changes with postmenstrual age (PMA) from discontinuous activity to continuous activity. However, changes in discontinuity have been investigated by visual analysis only. AIM: To investigate the maturational changes in EEG discontinuity in healthy preterm infants using an automated EEG detection algorithm. STUDY DESIGN: Weekly 4h EEG recordings were performed in preterm infants with a gestational age (GA)<32weeks and normal neurological follow-up at 1year. The channel C3-C4 was analyzed using an algorithm which automatically detects periods of EEG inactivity (interburst intervals). The interburst-burst ratio (IBR, percentage of EEG inactivity during a moving time window of 600s) and mean length of the interburst intervals were calculated. Using the IBR, discontinuous background activity (periods with high IBR) and continuous background activity (periods with low IBR) were automatically detected and their mean length during each recording was calculated. Data were analyzed with regression and multivariate analysis. RESULTS: 79 recordings were performed in 18 infants. All recordings showed a cyclical pattern in EEG discontinuity. With advancing PMA, IBR (R(2)=0.64; p<0.001), interburst interval length (R(2)=0.43; p<0.001) and length of discontinuous activity (R(2)=0.38; p<0.001) decreased, while continuous activity increased (R(2)=0.50; p<0.001). Multivariate analysis showed that all EEG discontinuity parameters were equally influenced by GA and postnatal age. CONCLUSION: Analyzing EEG background activity in preterm infants is feasible with an automated algorithm and shows maturational changes of several EEG derived parameters. The cyclical pattern in IBR suggests brain organisation in preterm infant.

Quantitative analysis of amplitude-integrated electroencephalogram patterns in stable preterm infants, with normal neurological development at one year.

BACKGROUND: The amplitude-integrated EEG (aEEG) is feasible for monitoring cerebral activity in preterm infants. However, quantitative data on normal patterns in these infants are limited. OBJECTIVE: To study maturational aEEG changes in a cohort of stable preterm infants by automated quantification. METHODS: In a cohort of stable preterm infants with gestational age (GA) <32 weeks and normal neurological follow-up at 1 year, weekly 4 h EEG recordings were performed. aEEG traces were obtained from channel C(3)-C(4). The upper margin amplitude (UMA), lower margin amplitude (LMA) and bandwidth (BW) were quantitatively calculated using an expert software system. In addition, the relative duration of discontinuous background pattern (discontinuous background defined as activity with LMA <5 microV, expressed as DC-%) was calculated. RESULTS: 79 aEEG recordings (4-6 recordings/infant) were obtained in 18 infants. Analysis of the first week recordings demonstrated a strong positive correlation between GA and LMA, while DC-% decreased significantly. Longitudinally, all infants showed increase of LMA. Multivariate analysis showed that GA and postnatal age (PA) both contributed independently and equally to LMA and DC-%. We found a strong correlation between postmenstrual age (GA + PA) and LMA and DC-%, respectively. CONCLUSION: To our knowledge, this is the first study where aEEG development was studied by automated quantification of aEEG characteristics in a cohort of stable preterm infants with a normal neurological development at 1 year of age. LMA and DC-% are simple quantitative measures of neurophysiologic development and may be used to evaluate neurodevelopment in infants.

Systemic air embolism after cardiopulmonary resuscitation in a preterm infant.

UNLABELLED: We report a preterm infant with extensive systemic air embolism after cardiopulmonary resuscitation for cardiac arrest due to an occluding thrombus in the inferior vena cava. After excluding other potential causes (air infusion, necrotizing enterocolitis or pulmonary leakage syndrome), we postulate that the pressure gradient needed for air embolism to occur is related to the resuscitation procedure. An important clue of air embolism was noted on the chest X-ray taken before death showing intracardial air. CONCLUSION: Systemic air embolism may occur as a very rare complication after cardiopulmonary resuscitation.

The long-term outcome of antenatal hydronephrosis up to 15 millimetres justifies a noninvasive postnatal follow-up.

AIM: To assess the incidence of urinary tract infections (UTIs) and surgery in infants with different grades of antenatal hydronephrosis (ANH) and to evaluate incidence, severity and course of underlying vesicoureteral reflux (VUR). METHODS: Retrospective data of 125 infants with ANH were collected. The patients were divided into two groups according to the anterior-posterior pelvis diameter: group I, 5-14 mm and group II, > or =15 mm. RESULTS: UTIs developed in 4 of 106 infants from group I and 5 of 19 infants from group II. Surgical interventions were performed on 1 of 106 patients of group I and 7 of 19 patients of group II. These differences were statistically significant (p-values 0.004 and <0.001, respectively). In group I, 6 of 106 patients had VUR; none of them required surgical intervention and only two developed a UTI (one of whom also had contralateral ureteropelvic junction obstruction). Five of 19 infants in group II had underlying VUR, four of them with associated anomalies, 1 infant required surgical correction and 4 developed UTIs. CONCLUSION: Infants with ANH up to 15 mm have a low incidence of UTIs and surgery and a low incidence and benign course of underlying VUR. Therefore, noninvasive postnatal follow-up is justified and standard voiding cystourethrography should not be performed, but only in cases of ureteric dilatation.

Amplitude-integrated electroencephalographic changes in a newborn induced by overdose of morphine and corrected with naloxone.

UNLABELLED: The amplitude-integrated electroencephalogram (aEEG) is a useful tool to assess brain function after perinatal asphyxia in term infants. We report a full-term newborn with moderate perinatal asphyxia, who accidentally received an overdose of morphine (5000 microg/kg). The overdose of morphine resulted in a clear and immediate change of aEEG background activity from a continuous (C) to discontinuous (DC) background pattern. After administration of naloxone, the background activity restored immediately to continuous background pattern. The aEEG was used to monitor the stepwise reduction in continuous naloxone infusion. CONCLUSION: An overdose of morphine leads to clear and immediate changes in aEEG which restore after naloxone treatment. The aEEG can be used to monitor naloxone infusion.

An algorithm for the automatic detection of seizures in neonatal amplitude-integrated EEG.

AIM: To develop and evaluate an algorithm for the automatic screening of electrographic neonatal seizures (ENS) in amplitude-integrated electroencephalography (aEEG) signals. METHODS: CFM recordings were recorded in asphyxiated (near)term newborns. ENS of at least 60 sec were detected based on their characteristic pattern in the aEEG signal, an increase of its lower boundary. The algorithm was trained using five CFM recordings (training set) annotated by a neurophysiologist, observer1. The evaluation of the algorithm was based on eight different CFM recordings annotated by observer1 (test set observer 1) and an independent neurophysiologist, observer2 (test set observer 2). RESULTS: The interobserver agreement between observer1 and 2 in interpreting ENS from the CFM recordings was high (G coefficient: 0.82). After dividing the eight CFM recordings into 1-min segments and classification in ENS or non-ENS, the intraclass correlation coefficient showed high correlations of the algorithm with both test sets (respectively, 0.95 and 0.85 with observer1 and 2). The algorithm showed in five recordings a sensitivity > or = 90% and approximately 1 false positive ENS per hour. However, the algorithm showed in three recordings much lower sensitivities: one recording showed ENSs of extremely high amplitude that were incorrectly classified by the algorithm as artefacts and two recordings suffered from low interobserver agreement. CONCLUSION: This study shows the feasibility of automatic ENS screening based on aEEG signals and may facilitate in the bed-side interpretation of aEEG signals in clinical practice.

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.

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 treatment before reperfusion improves the immediate function of lung transplants in rats.

An impaired function of alveolar surfactant can cause lung transplant dysfunction early after reperfusion. In this study it was investigated whether treatment with surfactant before reperfusion improves the immediate function of lung transplants and whether an improved transplant function was associated with an increase in alveolar surfactant components. Left lungs with 6-h (n = 8) or prolonged 20-h ischemia (n = 10) were transplanted syngeneically in rats. In both ischemia groups half of the lung transplants were treated with surfactant just before reperfusion. Lung function was measured during reperfusion for 1 h. Thereafter, the rats were killed and bronchoalveolar lavage was performed to measure alveolar surfactant components. We found that surfactant treatment improved the immediate function of lung transplants in parallel with a higher amount of total surfactant phospholipids, a higher percentage of the heavy subtype of surfactant, a normalized percentage of phosphatidylcholine, and a higher amount of endogenous surfactant protein A (SP-A). We conclude that surfactant treatment before reperfusion does improve the immediate lung transplant function in rats in association with an increase in alveolar surfactant components. More particularly, the amount of (endogenous) SP-A is thought to be crucial for the efficacy of surfactant treatment after lung transplantation.

Distribution of exogenous surfactant in rabbits with severe respiratory failure: the effect of volume.

The transient effect of surfactant therapy that is observed in some patients might, at least in part, be explained by a nonhomogeneous distribution. Therefore, we investigated the distribution of a surfactant preparation (Alvofact, 45 g/L) that is used clinically. Rabbits with severe respiratory failure were treated with this surfactant at a dose of 100 mg/kg body weight, and the distribution of surfactant was determined by the use of 141Ce-labeled microspheres that were mixed with the surfactant. Fifteen min after surfactant administration, the rabbits were killed, and the lungs were removed and divided into 200 pieces. The radioactivity per mg lung tissue was determined in each piece. We found that the endotracheal instillation of this surfactant preparation results in a nonhomogeneous distribution. However, a significantly improved distribution was obtained when this dose of surfactant (100 mg/kg body weight) was diluted with normal saline to a concentration of 6.25 g/L. The consequence of the administration of this dose was an intratracheal fluid administration of 16.0 mL/kg body weight. The distribution was also nonhomogeneous after the administration of a small-volume (2.4 mL/kg body weight), low-concentration surfactant preparation (6.25 g/L). We conclude that a surfactant preparation with clinical application is distributed nonhomogeneously in the lungs after endotracheal administration. The distribution can be significantly improved by increasing the fluid volume in which the surfactant is suspended.

Immune response after surfactant treatment of newborn infants with respiratory distress syndrome.

We examined the sera of 68 newborn infants with respiratory distress syndrome; 49 were treated with a natural porcine-derived surfactant preparation and 19 were controls. Serum of the patients was collected before, 3 weeks and 3 months after surfactant treatment. To detect any antibody that had been raised, we applied diluted serum of the babies in an indirect immunoperoxidase staining technique on frozen pig lung tissue specimens. With light microscopy an immune response could be appreciated as a brown reddish deposit in the porcine lung tissue specimens in 4 out of the 49 surfactant-treated and not in the control babies.

Asymmetrical pulmonary changes in premature infants with surgical closure of a persistent ductus arteriosus.

The chest radiographs of 57 premature infants admitted consecutively with hyaline membrane disease and receiving respirator therapy were reviewed, comparing right and left pulmonary abnormalities. Fifteen infants (Group I) did not develop a persistent ductus arteriosus (PDA). Forty-two infants developed a PDA, which was successfully treated with indomethacin in 17 infants (Group II), while in 25 infants (Group III) the ductus was closed surgically. Analysis of the three groups showed that infants who had undergone surgical closure of their PDA developed significantly more asymmetrical broncho-pulmonary damage. Statistically significant fewer radiological findings of broncho-pulmonary damage were found on the left side in comparison with the right side in the group treated surgically.