Pulmonary stretch receptor activity during partial liquid ventilation with different pressure waveforms.

BACKGROUND: The aim of the present study was to investigate pulmonary stretch receptor activity (PSR) under different peak inspiratory pressures (PIPs) and inspiratory pressure waveforms during partial liquid (PLV) and gas ventilation (GV). METHODS: PSR instantaneous impulse frequency (PSRfimp) was recorded from single fibers in the vagal nerve during PLV and GV in young cats. PIPs were set at 1.2/1.8/2.2/2.7 kPa, and square and sinusoidal pressure waveforms were applied. RESULTS: PSRfimp at the start of inspiration increased with increasing PIPs, and was steeper and higher with square than with sinusoidal waveforms (p < 0.05). Total number of impulses, peak and mean PSRfimp were lower during PLV than GV at the lowest and highest PIPs (p < 0.025). Time to peak PSRfimp was shorter with square than with sinusoidal waveforms at all pressures and ventilations (p < 0.005). Irrespective of waveform, lower PIPs yielded lower ventilation during PLV. CONCLUSION: As assessed by PSRfimp, increased PIPs do not expose the lungs to more stretching during PLV than during GV, with only minor differences between square and sinusoidal waveforms.

The receptor for hyaluronan-mediated motility (RHAMM) expression in neonatal bronchiolar epithelium correlates negatively with lung air content.

INTRODUCTION: Hyaluronan (HA) and the receptor for hyaluronan-mediated motility (RHAMM) may play an important role in lung development. We examined the expression of HA content and RHAMM during postnatal lung development by analyzing human lung specimens from newborn infants with a variety of lung diseases at different gestational (GA) and postnatal (PNA) ages. MATERIALS AND METHODS: Ninety-four patients were evaluated. Immunohistochemical RHAMM expression was studied with digital image analysis, followed by hierarchical cluster analysis of both these data and clinical data to define subgroups. The air content of the lung was determined by computerized analysis. HA content was estimated by radiometric assay. RESULTS: Cluster analysis defined six distinct patient groups (Group 1-2: 34-41 weeks GA; Group 3-5: 23-27 weeks GA; Group 6: mixed population). Group 1-5 showed individual patterns in RHAMM expression and HA content (Group 1: high RHAMM/low HA; Group 2: low RHAMM/low HA; Group 3: low RHAMM/low HA; Group 4: low RHAMM/high HA; Group 5: high RHAMM/high HA). HA content decreased with increasing PNA independently of GA. Negative correlation was observed between air content and RHAMM expression in the bronchiolar epithelium irrespective of clustered groups. Lung hypoplasia appeared in two distinctive groups, with significant differences in lung development and RHAMM expression. CONCLUSIONS: RHAMM expression may show dynamic changes during pathological processes in the neonatal lung. The distribution of RHAMM in the lung tissue is heterogeneous with a predominance to the bronchiolar epithelium. We found a negative correlation between lung air content and RHAMM expression in bronchiolar epithelium.

Impact at age 11 years of major neonatal morbidities in children born extremely preterm.

BACKGROUND: Uncertainty continues regarding the extent to which neonatal morbidities predict poor long-term outcome and functional abilities in extremely preterm infants. OBJECTIVE: The goal of this study was to determine the impact of bronchopulmonary dysplasia (BPD), ultrasonographic signs of brain injury, and severe retinopathy of prematurity (ROP) on 11-year outcomes in infants born at <26 weeks' gestation. METHODS: A total of 247 infants were born alive before 26 completed weeks of gestation from 1990 through 1992 in all of Sweden, and 98 (40%) survived to a postmenstrual age of 36 weeks. Main outcome measures were (1) poor outcome, defined as combined end point of death after 36 weeks' postmenstrual age or survival with at least 1 major disability at 11 years, and (2) consequences of chronic conditions in the survivors according to a validated instrument administered to parents. RESULTS: Brain injury and severe ROP but not BPD correlated independently with poor outcome at 11 years of age. Among children who were free from BPD, brain injury, and severe ROP, 10% had a poor outcome. Corresponding rates with any 1, any 2, and all 3 neonatal morbidities were 19%, 58%, and 80%, respectively. Multivariate analysis revealed that brain injury and severe ROP were associated with high rates of consequences of chronic conditions. CONCLUSIONS: In infants born extremely preterm who survive to a postmenstrual age of 36 weeks, severe ROP and brain injury separately predict the risk of death or major disability at 11 years of age. Thus, continued research to determine how to prevent these complications of prematurity is critical.

Antenatal Corticosteroids and Postnatal Fluid Restriction Produce Differential Effects on AQP3 Expression, Water Handling, and Barrier Function in Perinatal Rat Epidermis.

Loss of water through the immature skin can lead to hypothermia and dehydration in preterm infants. The water and glycerol channel aquaglyceroporin-3 (AQP3) is abundant in fetal epidermis and might influence epidermal water handling and transepidermal water flux around birth. To investigate the role of AQP3 in immature skin, we measured in vivo transepidermal water transport and AQP3 expression in rat pups exposed to clinically relevant fluid homeostasis perturbations. Preterm (E18) rat pups were studied after antenatal corticosteroid exposure (ANS), and neonatal (P1) rat pups after an 18 h fast. Transepidermal water loss (TEWL) and skin hydration were determined, AQP3 mRNA was quantified by RT-PCR, and in-situ hybridization and immunocytochemistry were applied to map AQP3 expression. ANS resulted in an improved skin barrier (lower TEWL and skin hydration), while AQP3 mRNA and protein increased. Fasting led to loss of barrier integrity along with an increase in skin hydration. These alterations were not paralleled by any changes in AQP3. To conclude, antenatal corticosteroids and early postnatal fluid restriction produce differential effects on skin barrier function and epidermal AQP3 expression in the rat. In perinatal rats, AQP3 does not directly determine net water transport through the skin.

Bronchopulmonary C-fibers modulate the breathing pattern in surfactant-depleted juvenile cats.

The aim of this study was to investigate the influence of nonmyelinated C-fibers on the breathing pattern by cooling the vagal nerves to temperatures at which myelinated nerve transmission from pulmonary stretch receptors is blocked (+7 degrees C) and further at which nonmyelinated fiber input is blocked (0 degrees C), in anaesthetized spontaneously breathing juvenile cats with normal (L(N)), surfactant-depleted (L(D)) and surfactant-treated (L(T)) lungs. In L(N), vagal cooling from +7 to 0 degrees C decreased respiratory frequency (f(R); -8%; p < 0.01), and increased tidal volume (V(T); +40%; p < 0.01). In the presence of shallow fast breathing in L(D), f(R) decreased (+38 to +7 degrees C: -26%; p < 0.015 and +7 to 0 degrees C: -24%; p < 0.001) and V(T) increased (+37%; p < 0.049 and +88%; p < 0.016). In L(T), f(R) decreased (+7 to 0 degrees C: -21%; p < 0.001), whereas V(T) remained the same at 0 degrees C (+12%; NS). These findings show for the first time that the activity of bronchopulmonary C-fibers have a prominent role in modulating the breathing pattern in juvenile cats with surfactant-depleted lungs.

Mental health and social competencies of 10- to 12-year-old children born at 23 to 25 weeks of gestation in the 1990s: a Swedish national prospective follow-up study.

OBJECTIVE: We investigated a national cohort of extremely immature children with respect to behavioral and emotional problems and social competencies, from the perspectives of parents, teachers, and children themselves. METHODS: We examined 11-year-old children who were born before 26 completed weeks of gestation in Sweden between 1990 and 1992. All had been evaluated at a corrected age of 36 months. At 11 years of age, 86 of 89 survivors were studied and compared with an equal number of control subjects, matched with respect to age and gender. Behavioral and emotional problems, social competencies, and adaptive functioning at school were evaluated with standardized, well-validated instruments, including parent and teacher report questionnaires and a child self-report, administered by mail. RESULTS: Compared with control subjects, parents of extremely immature children reported significantly more problems with internalizing behaviors (anxiety/depression, withdrawn, and somatic problems) and attention, thought, and social problems. Teachers reported a similar pattern. Reports from children showed a trend toward increased depression symptoms compared with control subjects. Multivariate analysis of covariance of parent-reported behavioral problems revealed no interactions, but significant main effects emerged for group status (extremely immature versus control), family function, social risk, and presence of a chronic medical condition, with all effect sizes being medium and accounting for 8% to 12% of the variance. Multivariate analysis of covariance of teacher-reported behavioral problems showed significant effects for group status and gender but not for the covariates mentioned above. According to the teachers' ratings, extremely immature children were less well adjusted to the school environment than were control subjects. However, a majority of extremely immature children (85%) were functioning in mainstream schools without major adjustment problems. CONCLUSIONS: Despite favorable outcomes for many children born at the limit of viability, these children are at risk for mental health problems, with poorer school results.

School level at 10 years of age in children who required neonatal intensive care in 1980-1989.

UNLABELLED: School level at age 10 was studied in two cohorts of children who had required neonatal intensive care (NIC): cohort 1, children born 1980-1985 (n=310); and cohort 2, children born 1986-1989 (n=245); and two control groups. More than 80% of all NIC children of both cohorts attended the appropriate mainstream grade 3 or 4; 12.9% of cohort 1 and 6.8% of cohort 2 were in mainstream grade 2. Six per cent of both cohorts received special education. Among very preterm children (23-31 gestational weeks), 73.5% of cohort 1 and 80.3% of cohort 2 attended grades 3 and 4, while 22.9% and 12.1%, respectively, were in grade 2. Assistance (remedial teaching, personal assistant or special teaching group) was given to 42.4% of cohort 1 in the mainstream (grades 2, 3 and 4) and to 38.2% of cohort 2 in the mainstream. In cohort 2, more very preterm girls than matched controls received assistance (p<0.05); no corresponding difference was found in very preterm boys. Most children with congenital malformations received assistance in mainstream education or received special education. CONCLUSION: Most NIC children are in mainstream school classes at age 10. Twelve to 23% of very preterm children are 1 y behind. Many NIC children in the school mainstream need assistance at school, but the proportion of children in mainstream education increases markedly with time.

Growth in 10- to 12-year-old children born at 23 to 25 weeks' gestation in the 1990s: a Swedish national prospective follow-up study.

BACKGROUND: Knowledge of long-term growth of extremely preterm infants in relation to gestational age is incomplete, and there are concerns regarding their poor growth in early childhood. As part of a longitudinal study of a national cohort of infants born at <26 weeks' gestation (extremely immature), growth development from birth to the age of 11 years was examined, and correlates of growth attainment were analyzed. METHODS: Two hundred forty-seven extremely immature children were born alive from April 1990 through March 1992 in the whole of Sweden, and 89 (36%) survived. Growth and neurosensory outcomes of all extremely immature survivors were evaluated at 36 months of age. Eighty-six (97%) extremely immature children were identified and assessed at 11 years of age. In this growth study, 83 extremely immature infants (mean [SD]: birth weight, 772 g [110 g]; gestational age, 24.6 weeks [0.6 weeks]) without severe motor disability were followed up prospectively from birth to 11 years old and compared with a matched group of 83 children born at term. z scores for weight, height, head circumference, and BMI were computed for all children. We also examined gender-specific longitudinal growth measures. Predictors of 11-year growth were studied by multivariate analyses. RESULTS: Extremely immature children were significantly smaller in all 3 growth parameters than the controls at 11 years. Extremely immature children showed a sharp decline in weight and height z scores up to 3 months' corrected age, followed by catch-up growth in both weight and height up to 11 years. In contrast to weight and height, extremely immature children did not exhibit catch-up growth in head circumference after the first 6 months of life. The mean BMI z scores increased significantly from 1 to 11 years in both groups. The mean BMI change between 1 and 11 years of age was significantly larger in extremely immature than in control participants. Extremely immature girls showed a faster weight increase than extremely immature boys, whereas catch-up growth in height and head circumference was similar in these groups. Multiple-regression analyses revealed that preterm birth and parental height were significant predictors of 11-year height, and group status (prematurity) correlated strongly with head circumference. CONCLUSIONS: Children born at the limit of viability attain poor growth in early childhood, followed by catch-up growth to age 11 years, but remain smaller than their term-born peers. Strategies that improve early growth might improve the outcome.

Chronic conditions, functional limitations, and special health care needs in 10- to 12-year-old children born at 23 to 25 weeks' gestation in the 1990s: a Swedish national prospective follow-up study.

BACKGROUND: Children born extremely immature (gestational age < 26 weeks' gestation) increasingly reach school age. Information on their overall functioning and special health care needs is necessary to plan for their medical and educational services. This study was undertaken to examine neurosensory, medical, and developmental conditions together with functional limitations and special health care needs of extremely immature children compared with control subjects born at term. METHODS: We studied 11-year-old children born before 26 completed weeks of gestation in all of Sweden from 1990 through 1992. All had been evaluated at 36 months' corrected age. Identification of children with chronic conditions lasting > or = 12 months was based on a questionnaire administered to parents. Neurosensory impairments were identified by reviewing health records. Information regarding other specific medical diagnoses and developmental disabilities was obtained by standard parent and teacher questionnaires. RESULTS: Of 89 eligible children, 86 (97%) were studied at a mean age of 11 years. An equal number of children born at term served as controls. Logistic-regression analyses adjusting for social risk factors and gender showed that significantly more extremely immature children than controls had chronic conditions, including functional limitations (64% vs 11%, respectively), compensatory dependency needs (59% vs 25%), and services above those routinely required by children (67% vs 22%). Specific diagnoses or disabilities with higher rates in extremely immature children than in controls included neurosensory impairment (15% vs 2%), asthma (20% vs 6%), poor motor skills of > 2 SDs above the mean (26% vs 3%), poor visual perception of > 2 SDs above the mean (21% vs 4%), poor learning skills of > 2 SDs above the mean (27% vs 3%), poor adaptive functioning with T scores of < 40 (42% vs 9%), and poor academic performance with T score < 40 (49% vs 7%). CONCLUSIONS: Children born extremely immature have significantly greater health problems and special health care needs at 11 years of age. However, few children have severe impairments that curtail major activities of daily living.

Ambient humidity influences the rate of skin barrier maturation in extremely preterm infants.

OBJECTIVES: To test the hypothesis that the level of relative humidity (RH) in which preterm infants are nursed might influence their postnatal skin maturation. STUDY DESIGN: In 22 preterm infants (GA 23-27 weeks), transepidermal water loss (TEWL) was determined at postnatal ages (PNA) of 0, 3, 7, 14, and 28 days. At a PNA of 7 days, the infants were randomized to care at either 50% or 75% RH. RESULTS: TEWL decreased at a slower rate in infants nursed at the higher RH. At a PNA of 28 days, TEWL was about twice as high in infants nursed at 75% RH (22 +/- 2 g/m2 h) than in those nursed at 50% RH (13 +/- 1 g/m2 h; P < .001). CONCLUSIONS: The results indicate that the level of RH influences skin barrier development, with more rapid barrier formation in infants nursed at a lower RH. The findings have an impact on strategies for promoting skin barrier integrity in extremely preterm infants.

Maintained inspiratory activity during proportional assist ventilation in surfactant-depleted cats early after surfactant instillation: phrenic nerve and pulmonary stretch receptor activity.

BACKGROUND: Inspiratory activity is a prerequisite for successful application of patient triggered ventilation such as proportional assist ventilation (PAV). It has recently been reported that surfactant instillation increases the activity of slowly adapting pulmonary stretch receptors (PSRs) followed by a shorter inspiratory time (Sindelar et al, J Appl Physiol, 2005 [Epub ahead of print]). Changes in lung mechanics, as observed in preterm infants with respiratory distress syndrome and after surfactant treatment, might therefore influence the inspiratory activity when applying PAV early after surfactant treatment. OBJECTIVE: To investigate the regulation of breathing and ventilatory response in surfactant-depleted young cats during PAV and during continuous positive airway pressure (CPAP) early after surfactant instillation in relation to phrenic nerve activity (PNA) and the activity of PSRs. METHODS: Seven anesthetized, endotracheally intubated young cats were exposed to periods of CPAP and PAV with the same end-expiratory pressure (0.2-0.5 kPa) before and after lung lavage and after surfactant instillation. PAV was set to compensate for 75% of the lung elastic recoil. RESULTS: Tidal volume and respiratory rate were higher with lower PaCO2 and higher PaO2 during PAV than during CPAP both before and after surfactant instillation (p < 0.05; both conditions). As an indicator of breathing effort, esophageal deflection pressure and PNA were lower during PAV than during CPAP in both conditions (p < 0.02). Peak PSR activity was higher and occurred earlier during PAV than during CPAP (p < 0.01), and correlated linearly with PNA duration in all conditions studied (p < 0.001). The inspiratory time decreased as tidal volume increased when CPAP was changed to PAV, with the highest correlation observed after surfactant instillation (r = -0.769). No apneic periods could be observed. CONCLUSION: PSR activity and the control of breathing are maintained during PAV in surfactant-depleted cats early after surfactant instillation, with a higher ventilatory response and a lower breathing effort than during CPAP.

Water and heat--the priority for the newborn infant.

Maintaining fluid and heat balance is of vital importance to the newborn infant. At birth, the infant is exposed to a cold and dry environment, and preterm neonates in particular, are then at risk of dehydration and hypothermia. These conditions may have serious consequences and significantly influence mortality and morbidity. Preterm neonates have a high rate of water and heat loss mainly as a consequence of their immature skin. The care environment influences the magnitude of water and heat exchange and needs to be individually tailored on the basis of the infant's clinical status, maturity at birth and postnatal age. This paper reviews data obtained from series of studies on neonatal water and heat exchange using non-invasive measurements of insensible water loss and calculations of different modes of heat exchange. These studies have influenced the way in which newborn infants are being nursed today.

Surfactant replacement partially restores the activity of pulmonary stretch receptors in surfactant-depleted cats.

Single units of slowly adapting pulmonary stretch receptors (PSRs) were investigated in anesthetized cats during spontaneous breathing on continuous positive airway pressure (2-5 cmH2O), before and after lung lavage and then after instillation of surfactant to determine the PSR response to surfactant replacement. PSRs were classified as high threshold (HT) and low threshold (LT), and their instantaneous impulse frequency (f imp) was related to transpulmonary pressure (Ptp) and tidal volume (Vt). Both the total number of impulses and maximal f imp of HT and LT PSRs decreased after lung lavage (55 and 45%, respectively) in the presence of increased Ptp and decreased Vt. While Ptp decreased markedly and Vt remained unchanged after surfactant instillation, all except one PSR responded with increased total number of impulses and maximal f imp (42 and 26%, respectively). Some HT PSRs ceased to discharge after lung lavage but recovered after surfactant instillation. The end-expiratory activity of LT PSRs increased or was regained after surfactant instillation. After instillation of surfactant, respiratory rate increased further with a shorter inspiratory time, resulting in a lower inspiratory-to-expiratory time ratio. Arterial pH decreased (7.31 +/- 0.04 vs. 7.22 +/- 0.06) and Pco2 increased (5.5 +/- 0.7 vs. 7.2 +/- 1.3 kPa) after lung lavage, but they were the same after as before instillation of surfactant (pH = 7.21 +/- 0.08 and Pco2 = 7.6 +/- 1.4 kPa) during spontaneous breathing. In conclusion, surfactant instillation increased lung compliance, which, in turn, increased the activity of both HT and LT PSRs. A further increase in respiratory rate due to a shorter inspiratory time after surfactant instillation suggests that the partially restored PSR activity after surfactant instillation affected the breathing pattern.

Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls.

Preterm birth might induce permanent changes in vascular structure and function as well as in blood pressure. To elucidate this hypothesis and underlying mechanisms in girls born before term, the authors correlated neonatal data, including estradiol levels, with vascular function and structure and with blood pressure after puberty. In a case-control study design, 34 girls born before term and 32 gender- and age-matched control infants born at term were included. Pulse wave analysis was used to determine aortic pressure profiles and overall arterial compliance. Stiffness of the carotid artery and abdominal aorta was measured with ultrasonography. Pulse wave velocity in the forearm was measured with photoplethysmography. A laser Doppler technique was used to determine skin perfusion before and after transdermal delivery of acetylcholine, an endothelium-dependent vasodilator. It was found that preterm girls had significantly higher brachial and aortic blood pressure, a narrower but less stiff abdominal aorta, and lower peripheral skin blood flow than did control infants. Augmentation index, carotid stiffness, pulse wave velocity, endothelium-dependent vasodilatation, and heart rate were similar in the two groups. In the preterm group, blood pressure and vascular functions showed no association with intrauterine growth retardation or neonatal estradiol levels. In conclusion, preterm girls have higher blood pressure and an increased resistance in the vascular tree after puberty. These findings may have implications for future cardiovascular risk in the growing adult population surviving preterm birth.

Inhibition of breathing after surfactant depletion is achieved at a higher arterial PCO2 during ventilation with liquid than with gas.

BACKGROUND: Inhibition of phrenic nerve activity (PNA) can be achieved when alveolar ventilation is adequate and when stretching of lung tissue stimulates mechanoreceptors to inhibit inspiratory activity. During mechanical ventilation under different lung conditions, inhibition of PNA can provide a physiological setting at which ventilatory parameters can be compared and related to arterial blood gases and pH. OBJECTIVE: To study lung mechanics and gas exchange at inhibition of PNA during controlled gas ventilation (GV) and during partial liquid ventilation (PLV) before and after lung lavage. METHODS: Nine anaesthetised, mechanically ventilated young cats (age 3.8 +/- 0.5 months, weight 2.3 +/- 0.1 kg) (mean +/- SD) were studied with stepwise increases in peak inspiratory pressure (PIP) until total inhibition of PNA was attained before lavage (with GV) and after lavage (GV and PLV). Tidal volume (Vt), PIP, oesophageal pressure and arterial blood gases were measured at inhibition of PNA. One way repeated measures analysis of variance and Student Newman Keuls-tests were used for statistical analysis. RESULTS: During GV, inhibition of PNA occurred at lower PIP, transpulmonary pressure (Ptp) and Vt before than after lung lavage. After lavage, inhibition of inspiratory activity was achieved at the same PIP, Ptp and Vt during GV and PLV, but occurred at a higher PaCO2 during PLV. After lavage compliance at inhibition was almost the same during GV and PLV and resistance was lower during GV than during PLV. CONCLUSION: Inhibition of inspiratory activity occurs at a higher PaCO2 during PLV than during GV in cats with surfactant-depleted lungs. This could indicate that PLV induces better recruitment of mechanoreceptors than GV.

Pulmonary stretch receptor activity during Partial Liquid Ventilation in Cats with Healthy Lungs.

AIM: To study whether pulmonary stretch receptor (PSR) activity in mechanically ventilated young cats with healthy lungs during partial liquid ventilation (PLV) is different from that during gas ventilation (GV). METHODS: In 10 young cats (4.4 +/- 0.4 months, 2.3 +/- 0.3 kg; mean +/- SD), PSR instantaneous impulse frequency (PSR fimp) was recorded from single fibres in the vagal nerve during GV and PLV with perfluorocarbon (30 ml/kg) at increasing positive inspiratory pressures (PIP; 1.2, 1.8, 2.2 and 2.7 kPa), and at a positive end-expiratory pressure of 0.5 kPa. RESULTS: All PSRs studied during GV maintained their phasic character with increased impulse frequency during inspiration during PLV. Peak PSRfimp was lower at PIP 1.2 kPa (p < 0.05) and at PIP 2.7 kPa (p = 0.10) during PLV than during GV, giving a lower number of PSR impulses at these two settings during PLV (p < 0.05). CONCLUSION: The phasic character of PSR activity is similar during GV and PLV. PSR activity is not higher during PLV than during GV in cats with healthy lungs, indicating no extensive stretching of the lung during PLV.

Inhaled nitric oxide therapy in neonates and children: reaching a European consensus.

Inhaled nitric oxide (iNO) was first used in neonatal practice in 1992 and has subsequently been used extensively in the management of neonates and children with cardiorespiratory failure. This paper assesses evidence for the use of iNO in this population as presented to a consensus meeting jointly organised by the European Society of Paediatric and Neonatal Intensive Care, the European Society of Paediatric Research and the European Society of Neonatology. Consensus Guidelines on the Use of iNO in Neonates and Children were produced following discussion of the evidence at the consensus meeting.