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Cochrane Neonatal is withdrawing the protocol because it is out of date and does not meet the current methodological standards of Cochrane

Supplemental Digital Content is available in the text., OBJECTIVES: Clinicians have little guidance on the time needed before assessing the effect of a mean airway pressure change during high-frequency oscillatory ventilation. We aimed to determine: 1) time to stable lung volume after a mean airway pressure change during high-frequency oscillatory ventilation and 2) the relationship between time to volume stability and the volume state of the lung. DESIGN: Prospective observational study. SETTING: Regional quaternary teaching hospital neonatal ICU. PATIENTS: Thirteen term or near-term infants receiving high-frequency oscillatory ventilation and muscle relaxants. INTERVENTIONS: One to two cm H2O mean airway pressure changes every 10 minutes as part of an open lung strategy based on oxygen response. MEASUREMENTS AND MAIN RESULTS: Continuous lung volume measurements (respiratory inductive plethysmography) were made during the mean airway pressure changes. Volume signals were analyzed with a biexponential model to calculate the time to stable lung volume if the model R2 was greater than 0.6. If volume stability did not occur within 10 minutes, the model was extrapolated to maximum 3,600 s. One-hundred ninety-six mean airway pressure changes were made, with no volume change in 33 occurrences (17%). One-hundred twenty-five volume signals met modeling criteria for inclusion; median (interquartile range) R2, 0.96 (0.91–0.98). The time to stable lung volume was 1,131 seconds (718–1,959 s) (mean airway pressure increases) and 647 seconds (439–1,309 s) (mean airway pressure decreases), with only 17 (14%) occurring within 10 minutes and time to stability being longer when the lung was atelectatic. CONCLUSIONS: During high-frequency oscillatory ventilation, the time to stable lung volume after a mean airway pressure change is variable, often requires more than 10 minutes, and is dependent on the preceding volume state.

This article highlights the feasibility of creating water-in-oil lecithin microcapsules, at predetermined sizes, at large-scale quantities (~80 kg/h) using the Controlled Deformation Dynamic Mixer (CDDM) mixer. The aim of this work was to create capsules with the exterior properties of oil and the fat content of water, with the impact being the replacement of oil in food formulations with water-in-oil capsules. Benchmark trials were performed using ultrasonic mixers and bench-top high-shear mixers, and the capsules created compared to those produced using CDDM technology. This work highlights that the CDDM is capable of both matching the ultrasonic mixer for capsule formulation, and can create capsules of varying size; dependent on the processing parameters used. Oil content of the capsules was reduced by over 85% resulting in water capsules with ~13% oil covering the shell, enabling the capsules to maintain the exterior properties of oil but with minimal fat.

ObjectivesClinicians have little guidance on the time needed before assessing the effect of a mean airway pressure (PAW) change during high-frequency oscillatory ventilation (HFOV). We aimed to determine 1) time to stable lung volume after a PAW change during HFOV and, 2) the relationship between time to volume stability and the volume state of the lung.MethodsContinuous lung volume measurements (respiratory inductive plethysmography) after 1-2 cmH2O PAW changes made every 10 minutes during an open lung strategy (n=13 infants) were analysed with a bi-exponential model. Time to stable lung volume (extrapolated to maximum 3600s) was calculated if the model R2 was >0.6.Results196 PAW changes were made, with no volume change in 33 (17%) occurrences. 125 volume signals met modelling criteria for inclusion; median (IQR) R2 0.96 (0.91, 0.98). The time to stable lung volume was 1131 (718, 1959)s (PAW increases) and 647 (439, 1309)s (PAW decreases), with only 17 (14%) occurring within 10 minutes and time to stability being longer when the lung was atelectatic.ConclusionsDuring HFOV, the time to stable lung volume after a PAW change is variable, often requires more than 10 minutes and is dependent on the preceding volume state.Impact StatementIn infants without preterm respiratory distress syndrome the time to achieve lung volume stability after a PAW change during HFOV is usually greater than 10 minutes.The volume state of the lung at the time of PAW change influences the time required to achieve a stable new lung volume; being shorter when the lung is well recruited and longer when the lung is already atelectatic.Clinicians should be aware that it may require least 10 minutes before assessing the clinical response to a change in PAW during HFOV

This protocol describes a method for measuring the metabolism in Drosophila melanogaster larval and adult brains. Quantifying metabolism in whole organs provides a tissue-level understanding of energy utilization that cannot be captured when analyzing primary cells and cell lines. While this analysis is ex vivo, it allows for the measurement from a number of specialized cells working together to perform a function in one tissue and more closely models the in vivo organ. Metabolic reprogramming has been observed in many neurological diseases, including neoplasia, and neurodegenerative diseases. This protocol was developed to assist the D. melanogaster community's investigation of metabolism in neurological disease models using a commercially available metabolic analyzer. Measuring metabolism of whole brains in the metabolic analyzer is challenging due to the geometry of the brain. This analyzer requires samples to remain at the bottom of a 96-well plate. Cell samples and tissue punches can adhere to the surface of the cell plate or utilize spheroid plates, respectively. However, the spherical, three-dimensional shape of D. melanogaster brains prevents the tissue from adhering to the plate. This protocol requires a specially designed and manufactured micro-tissue restraint that circumvents this problem by preventing any movement of the brain while still allowing metabolic measurements from the analyzer's two solid-state sensor probes. Oxygen consumption and extracellular acidification rates are reproducible and sensitive to a treatment with metabolic inhibitors. With a minor optimization, this protocol can be adapted for use with any whole tissue and/or model system, provided that the sample size does not exceed the chamber generated by the restraint. While basal metabolic measurements and an analysis after a treatment with mitochondrial inhibitors are described within this protocol, countless experimental conditions, such as energy source preference and rearing environment, could be interrogated.

This protocol describes a method for measuring the metabolism in Drosophila melanogaster larval and adult brains. Quantifying metabolism in whole organs provides a tissue-level understanding of energy utilization that cannot be captured when analyzing primary cells and cell lines. While this analysis is ex vivo, it allows for the measurement from a number of specialized cells working together to perform a function in one tissue and more closely models the in vivo organ. Metabolic reprogramming has been observed in many neurological diseases, including neoplasia, and neurodegenerative diseases. This protocol was developed to assist the D. melanogaster community's investigation of metabolism in neurological disease models using a commercially available metabolic analyzer. Measuring metabolism of whole brains in the metabolic analyzer is challenging due to the geometry of the brain. This analyzer requires samples to remain at the bottom of a 96-well plate. Cell samples and tissue punches can adhere to the surface of the cell plate or utilize spheroid plates, respectively. However, the spherical, three-dimensional shape of D. melanogaster brains prevents the tissue from adhering to the plate. This protocol requires a specially designed and manufactured micro-tissue restraint that circumvents this problem by preventing any movement of the brain while still allowing metabolic measurements from the analyzer's two solid-state sensor probes. Oxygen consumption and extracellular acidification rates are reproducible and sensitive to a treatment with metabolic inhibitors. With a minor optimization, this protocol can be adapted for use with any whole tissue and/or model system, provided that the sample size does not exceed the chamber generated by the restraint. While basal metabolic measurements and an analysis after a treatment with mitochondrial inhibitors are described within this protocol, countless experimental conditions, such as energy source preference and rearing environment, could be interrogated.

Background: The mode of waveform generation and circuit characteristics differ between high-frequency oscillators. It is unknown if this influences performance. Objectives: To describe the relationships between set and delivered pressure amplitude (ΔP), and the interaction with frequency and endotracheal tube (ETT) diameter, in eight high-frequency oscillators. Methods: Oscillators were evaluated using a 70-ml test lung at 1.0 and 2.0 ml/cm H2O compliance, with mean airway pressures (PAW) of 10 and 20 cm H2O, frequencies of 5, 10 and 15 Hz, and an ETT diameter of 2.5 and 3.5 mm. At each permutation of PAW, frequency and ETT, the set ΔP was sequentially increased from 15 to 50 cm H2O, or from 20 to 100% maximum amplitude (10% increments) depending on the oscillator design. The ΔP at the ventilator (ΔPVENT), airway opening (ΔPAO) and within the test lung (ΔPTRACH), and tidal volume (VT) at the airway opening were determined at each set ΔP. Results: In two oscillators the relationships between set and delivered ΔP were non-linear, with a plateau in ΔP thresholds noted at all frequencies (Dräger Babylog 8000) or ≥10 Hz (Dräger VN500). In all other devices there was a linear relationship between ΔPVENT, ΔPAO and ΔPTRACH (all r2 >0.93), with differing attenuation of the pressure wave. Delivered VT at the different settings tested varied between devices, with some unable to deliver VT >3 ml at 15 Hz, and others generating VT >20 ml at 5 Hz and a 1:1 inspiratory-to-expiratory time ratio. Conclusions: Clinicians should be aware that modern high-frequency oscillators exhibit important differences in the delivered ΔP and VT.

Background Many neuronal and glial diseases have been associated with changes in metabolism. Therefore, metabolic reprogramming has become an important area of research to better understand disease at the cellular level, as well as to identify targets for treatment. Model systems are ideal for interrogating metabolic questions in a tissue dependent context. However, while new tools have been developed to study metabolism in cultured cells there has been less progress towards studies in vivo and ex vivo. New method We have developed a method using newly designed tissue restraints to adapt the Agilent XFe96 metabolic analyzer for whole brain analysis. These restraints create a chamber for Drosophila brains and other small model system tissues to reside undisrupted, while still remaining in the zone for measurements by sensor probes. Results This method generates reproducible oxygen consumption and extracellular acidification rate data for Drosophila larval and adult brains. Single brains are effectively treated with inhibitors and expected metabolic readings are observed. Measuring metabolic changes, such as glycolytic rate, in transgenic larval brains demonstrates the potential for studying how genotype affects metabolism. Comparison with existing methods and conclusions Current methodology either utilizes whole animal chambers to measure respiration, not allowing for targeted tissue analysis, or uses technically challenging MRI technology for in vivo analysis that is not suitable for smaller model systems. This new method allows for novel metabolic investigation of intact brains and other tissues ex vivo in a quick, and simplistic way with the potential for large-scale studies.

OBJECTIVES:: During high-frequency oscillatory ventilation, an understanding of the relationship between lung volume and lung mechanics may help clinicians better apply ventilation. The objectives of this study were: 1) to describe the relationship between lung volume and lung function parameters during mapping of the deflation limb of the pressure-volume relationship in infants receiving high-frequency oscillatory ventilation, and 2) to determine whether these parameters might be useful in targeting an optimal volume to apply ventilation. DESIGN:: Observational physiological study. SETTING:: Tertiary neonatal intensive care unit in a pediatric hospital. PATIENTS:: Fifteen infants receiving high-frequency oscillatory ventilation and muscle relaxants. INTERVENTIONS:: The deflation limb of the pressure-volume relationship was mapped in each infant, after recruitment to total lung capacity, using stepwise airway pressure decrements. Total lung capacity and closing volume were defined by oxygenation response. MEASUREMENTS AND MAIN RESULTS:: Lung volume (respiratory inductive plethysmography), oxygen saturation, transcutaneous carbon dioxide, and indicators of lung mechanics were recorded at each pressure. A distinct bell-shaped relationship between lung volume and carbon dioxide, minute ventilation, and tidal volume (both at airway opening and by inductive plethysmography) could be identified on the deflation limb, with an improvement of 21.6 mm Hg (CO2), 168 mL/sec (minute ventilation), 0.25 mL/kg (airway opening tidal volume), and 13.7% (plethysmography tidal volume) compared with total lung capacity levels. The mean (SD) optimal volumes and pressures for these parameters were significantly lower than total lung capacity, occurring at volumes between 38.6 (39.8)% and 62.8 (31.1)% of total lung capacity, and 28 (36.3)% and 41.3 (38.7)% of pressure at total lung capacity (p < 0.05; Bonferroni post-test). These coincided with the lowest pressure and volumes that maintained the oxygenation benefit of recruitment. CONCLUSIONS:: Transcutaneous carbon dioxide, tidal volume, and minute ventilation may assist in refining strategies to identify optimal lung volume. © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

Objective To assess (1) agreement between the ultrasonic cardiac output monitor (USCOM) 1A device for measurement of cardiac output in newborn infants and conventional echocardiography (ECHO), (2) repeatability of USCOM measurements and (3) agreement between novice and expert users of the USCOM. Design A prospective observational study. Setting The Neonatal Unit at the Royal Children9s Hospital, Melbourne, Australia. Patients 56 term and near-term infants, with no evidence of structural or functional cardiovascular disease, or haemodynamic shunts. Measurements Agreement between ECHO and USCOM was assessed by paired measurements of ventricular outputs by a single experienced user. Repeatability was assessed using five repeated measurements in 10 infants. Agreement between five novices and one expert user was assessed by paired USCOM measurements over 30 training measurements. Results Agreement between USCOM and ECHO for left ventricular output (LVO) was (bias, ±limits of agreement, mean % error): 14, ±108 ml/kg/min, 43%, and for right ventricular output (RVO): −59, ±160, ml/kg/min, 57%. Intra-observer repeatability was 6.7% for USCOM LVO and 3.6% for ECHO LVO. After five training measurements, the mean difference between USCOM measures of LVO by novice and expert users was less than 50 ml/kg/min, but with variability. Conclusions Repeatability of USCOM measures is high in newborn infants. New users can be trained quickly, but with high inter-user variability. Agreement between USCOM and conventional ECHO is broad, and worse for RVO and LVO. Further studies are required to assess the ability of the device to detect clinically significant changes in infant cardiac output.

We aimed to identify the effect of suction pressure and catheter size on change in lung volume during open and closed endotracheal suction. Anesthetized piglets (n = 12) were intubated with a 4.0-mm endotracheal tube. Lung injury was induced with saline lavage. Three suction methods (open, closed in-line, and closed with a side-port adaptor) were performed in random order using 6, 7, and 8 French gauge (FG) catheters, at vacuum pressures of 80, 140, and 200 mm Hg. Lung volume change was measured with respiratory inductive plethysmography. Overall, open suction resulted in greater lung volume loss during and at 60-s postsuction than either closed method (p < 0.001). When open and closed methods were analyzed separately, volume change was independent of catheter size and suction pressure with open suction. With closed suction, volume loss increased with larger catheter sizes and higher suction pressures (p < 0.001). With an 8-FG catheter and suction pressure of 140 or 200 mm Hg, volume loss was equivalent with open and closed suction. Lung volume changes are influenced by catheter size and suction pressure, as well as suction method. With commonly used suction pressures and catheter sizes, closed suction has no advantage in preventing loss of volume in this animal model.

To compare the effectiveness of open and closed endotracheal suction in recovering thin and thick secretions in normal and injured lungs during conventional and high frequency ventilation.Randomised study in a paediatric intensive care model in the animal research laboratory of a tertiary paediatric hospital.16 New Zealand White rabbits.Anaesthetised animals were intubated with a 3.5-mm endotracheal tube. Simulated thin and thick secretions (iopamidol 2 ml, a watery radio-opaque fluid, and fluorescent mucin 1 ml) were instilled in turn 1 cm below the tube tip through a catheter placed via a tracheostomy. Open or closed suction, randomly assigned, was applied for 6s at -140 mmHg using a 6-F gauge catheter. Following lung injury with repeated saline lavage the procedure was repeated on conventional and high frequency ventilation.Iopamidol recovery was determined by digitally subtracting the post-contrast and post-suction radiographic images. Mucin recovery was determined by fluorescence assay of the aspirate. In the normal lung similar amounts were recovered by both suction methods. In the lavaged lung closed suction recovered less iopamidol during conventional (22 +/- 7.5%) and high frequency ventilation (11 +/- 2.4%) than open suction (36 +/- 2% and 22 +/- 8.1%, respectively). Mucin recovery was less with closed suction during conventional 32 +/- 28 microl) and high frequency ventilation (30 +/- 31 microl) than with open suction (382 +/- 235 microl and 24 +/- 153 microl).In the injured lung closed suction was less effective than open suction at recovering thin and thick simulated secretions, irrespective of ventilation mode.

Aim: To examine the use of high frequency ventilation (HFV) to treat newborn infants in Australia and New Zealand and the associated complications and outcomes. Methods: Data for all infants receiving HFV were collected from the 28 neonatal intensive care units contributing to the Australian and New Zealand Neonatal Network database between 1996 and 2003, inclusive. For comparison, the same data were gathered on all infants who received conventional mechanical ventilation (CMV) and nasal continuous positive airway pressure. Results: HFV was used to treat 3270 infants (10.1% of all ventilated infants) between 1996 and 2003; uptake doubled during this period from 5.9% to 12.6% of ventilated infants per year. HFV was most frequently applied in the context of extreme prematurity (29.9% of ventilated infants

The importance of applying high-frequency oscillatory ventilation with a high lung volume strategy in infants is well established. Currently, a lack of reliable methods for assessing lung volume limits clinicians' ability to achieve the optimum volume range.To map the pressure-volume relationship of the lung during high-frequency oscillatory ventilation in infants, to determine at what point ventilation is being applied clinically, and to describe the relationship between airway pressure, lung volume, and oxygenation.In 12 infants, a partial inflation limb and the deflation limb of the pressure-volume relationship were mapped using a quasi-static lung volume optimization maneuver. This involved stepwise airway pressure increments to total lung capacity, followed by decrements until the closing pressure of the lung was identified.Lung volume and oxygen saturation were recorded at each airway pressure. Lung volume was measured using respiratory inductive plethysmography. A distinct deflation limb could be mapped in each infant. Overall, oxygenation and lung volume were improved by applying ventilation on the deflation limb. Maximal lung volume and oxygenation occurred on the deflation limb at a mean airway pressure of 3 and 5 cm H(2)O below the airway pressure approximating total lung capacity, respectively.Using current ventilation strategies, all infants were being ventilated near the inflation limb. It is possible to delineate the deflation limb in infants receiving high-frequency oscillatory ventilation; in doing so, greater lung volume and oxygenation can be achieved, often at lower airway pressures.

PurposeTo investigate in an empirical situation the resources that drive organizational performance, considering as resources HR practices, human competencies and other tangible resources and evaluating performance according to the balanced scorecard (BSC) model.Design/methodology/approachAfter literature review, a case study in a Brazilian water company was chosen. Methodology consisted of in‐depth interviews with managers; collection of information from company's database and questionnaires; factor analysis to identify underlying factors that explain the majority of variance for each BSC perspective; regression analysis to find association between factors and resources.FindingsIn general, resources seemed to be correlated to performance, but further details appeared: employee competency presented no correlation with performance; environmental factors related to demand seemed to be the strongest performance determinant; employee satisfaction showed association with all BSC perspective.Research limitations/implicationsThe research circumstances are quite particular and should not be generalized to other organizations. Future research should focus on more knowledge intensive firms and use a longitudinal research design.Practical implicationsThe results for practitioners, especially those in the investigated company, included the need to review part of their indicators, choosing formulae that are better connected to business results.Originality/valueThis paper helps to understand how resources and competencies convert into performance and proposes a methodology to be used under particular conditions of organizations with multiple and comparable business units.

Meconium aspiration syndrome (MAS) is an important cause of respiratory distress in the term infant. Therapy for the disease remains problematic, and newer treatments such as high-frequency ventilation and inhaled nitric oxide are being applied with increasing frequency. There is a significant disturbance of the pulmonary surfactant system in MAS, with a wealth of experimental data indicating that inhibition of surfactant function in the alveolar space is an important element of the pathophysiology of the disease. This inhibition may be mediated by meconium, plasma proteins, haemoglobin and oedema fluid, and, at least in vitro, can be overcome by increasing surfactant phospholipid concentration. These observations have served as the rationale for administration of exogenous surfactant preparations in MAS, initially as standard bolus therapy and, more recently, in association with therapeutic lung lavage. Bolus surfactant therapy in ventilated infants with MAS has been found to improve oxygenation in most studies, although there are a significant proportion of nonresponders and in many cases the effect is transient. Pooled data from randomised controlled trials of surfactant therapy suggest a benefit in terms of a reduction in the requirement for extracorporeal membrane oxygenation (relative risk 0.48 in surfactant-treated infants) but no diminution of air leak or ventilator days. Current evidence would support the use of bolus surfactant therapy on a case by case basis in nurseries with a relatively high mortality associated with MAS, or the lack of availability of other forms of respiratory support such as high-frequency ventilation or nitric oxide. If used, bolus surfactant should be administered as early as practicable to infants who exhibit significant parenchymal disease, at a phospholipid dose of at least 100 mg/kg, rapidly instilled into the trachea. Natural surfactant or a third-generation synthetic surfactant should be used and the dosage repeated every 6 hours until oxygenation has improved. Lung lavage with dilute surfactant has recently emerged as an alternative to bolus therapy in MAS, which has the advantage of removing surfactant inhibitors from the alveolar space in addition to augmenting surfactant phospholipid concentration. Combined animal and human data suggest that lung lavage can remove significant amounts of meconium and alveolar debris, and thereby improve oxygenation and pulmonary mechanics. Arterial oxygen saturation inevitably falls during lavage but has been noted to recover relatively rapidly, even in infants with severe disease. Several randomised controlled trials of surfactant lavage in MAS are underway, and until the results are known, lavage must be considered an unproven and experimental therapy.

During the 1990s the “information age” spawned a new breed of enterprises devising business models unheard of previously. One aspect of this changing business environment has been the trend in disintermediation observed in many industries. Where many recent papers see disintermediation as a phenomenon related to online transactions, this paper defines it more broadly as the removal or a weakening of an intermediary within a supply chain. This paper attempts to explain why disintermediation of distributors/import agents often occurs at the growth phase of a product's lifecycle, highlighting possible opportunities and outcomes for distributors threatened by disintermediation. The paper uses a downturn in a company's fortune to illustrate the case and to provide a potentially generic analytical tool for small distributors that will almost inevitably face a conflict of interests with their suppliers, which leads to disintermediation pressure.

Neonatal upper cervical spinal cord injury is associated with rotational forceps delivery and presents with quadriparesis and diaphragmatic paralysis. The underlying pathology determines neurologic outcome but is difficult to assess clinically or with simple radiographic techniques. We report 4 cases in which early magnetic resonance imaging demonstrated the extent and severity of the injury and guided management.

The recently developed technique of fibre optic respiratory plethysmography (FORP) has been modified to monitor the rapid, small amplitude movements of the chest wall during high-frequency oscillatory ventilation (HFOV). The FORP sensor is an expandable belt encircling the chest, in which is housed a fibre optic loop that alters its radius of curvature as a function of chest perimeter. These curvature changes cause variations in macrobending losses of light transmitted through the fibre, which are proportional to the chest perimeter. Dynamic measurement of transmitted light intensity can hence be used to monitor chest wall motion (CWM). For application to HFOV, the design of the FORP belt was altered to increase sensitivity and the materials were chosen to maximise macrobending effects induced by the CWM. FORP was tested in four piglets ventilated with HFOV, both in the normal and surfactant-deficient lung. Measurement of CWM was possible over the full range of tidal volumes and ventilation frequencies used during HFOV. In all cases, the measured frequency of the CWM fell within 3% of the applied ventilation frequency. In addition, the technique was sufficiently sensitive to detect changes in the amplitude of CWM in response to changes in applied tidal volume. It is anticipated that application of this new non-invasive measurement device will lead to an increased understanding of the dynamics of chest and abdominal wall motion during HFOV.

Summary Aim This study presents the clinicopathological features in three patients with acinar dysplasia, a very rare developmental abnormality of the lungs, to expand on the spectrum of the disease. Methods The clinical and histological features in the biopsies and autopsies were reviewed and compared with those reported in literature and in other diffuse lung diseases in neonates. Results All three patients presented at birth with severe respiratory distress. Two were siblings, with autopsy in both, and sequential lung biopsies in one. Histology showed spaces lined by ciliated columnar epithelium and separated by mesenchyme, with minimal saccule-like structures. The changes seemed considerably less severe in the biopsy than at autopsy. Both died, one at 6 hours and the other at 24 days with no improvement following ventilation and steroids. The third had a previous sibling who died at a few hours of age following severe respiratory distress. She was given ventilation and extracorporeal membranous oxygenation. Her biopsy showed changes similar to although less uniform than those in the biopsy of the previous patient. She improved slowly and was discharged at 4 months. At 18 months she was without tachypnoea and weaned off supplemental oxygen. Conclusions Acinar dysplasia may show more variation in the degree of involvement and clinical outcome than previously recognised, even within families, sometimes compatible with survival.

Lung lavage using two aliquots of 15 mL/kg of dilute surfactant was performed in 30 ventilated infants with severe meconium aspiration syndrome (MAS). Mean recovery of instilled lavage fluid was 46%, with greater fluid return associated with lower mean airway pressure at 24 h and a shorter duration of respiratory support. Conclusion: Recovery of instilled lavage fluid is paramount in effective lung lavage in MAS and must be afforded priority in the lavage technique.

Chromaffin cells have been shown to release a combination of pain-reducing neuroactive compounds including catecholamines and opioid peptides. The allogeneic transplantation of chromaffin cells in the subarachnoid space has been shown to alleviate pain in various rodent models and possibly in terminal cancer patients. Because of the shortage of human cadaver donor tissue, we are investigating the possibility of transplanting xenogeneic cells in polymer capsules. In this technique, cells are surrounded by a permselective synthetic membrane whose pores are suitably sized to allow diffusion of nutrients, neurotransmitters and growth factors, but restrict the diffusion of the large molecules of the immune system and prevent contact with immunocompetent cells. The encapsulation technique therefore allows transplantation of xenogeneic tissue between species as well as retrieval of transplanted cells. Previously we have reported that encapsulated bovine chromaffin cells survive and alleviate pain in various rodent models. The purpose of the present study was to assess the feasibility of implanting a human sized device in a large animal model. Adrenals from 5 calves were surgically removed; chromaffin cells were isolated from these glands using a collagenase-based digestion-filtration technique. Cells were loaded into acrylic-based tubular (5 cm long, 920 μm wide) permselective capsules attached to silicone tethers. The capsules were maintained in vitro for at least 7 days following the encapsulation procedure. Nicotine evoked release was analyzed in a defined subgroup from each batch. One capsule was then implanted using a guiding cannula system in the lumbar subarachnoid space of each sheep for 4 (n = 5) and 8 (n = 1) wk. All capsules were retrieved intact by gentle pulling on the silicone tether. Except for one capsule, the evoked catecholamine release of the retrieved capsules was in the same range as that of other capsules from the same cohort that had been maintained in vitro. All retrieved capsules were devoid of host cell reaction. Clusters of viable cells dispersed in an alginate immobilizing matrix were observed throughout all the implanted capsules. This study demonstrates the feasibility of transplanting functional encapsulated xenogeneic chromaffin cells into the cerebrospinal fluid of a large animal model using a capsule of appropriate dimensions for human implants. We believe that these results suggest the appropriateness of human clinical trials in patients suffering from refractory terminal cancer pain.

Background: Closed endotracheal suction interferes with mechanical ventilation received by infants, but the change to ventilation may be different when ventilator modes that target expired tidal volume (VTe) are used. Objective: To measure airway pressure and tidal volume distal to the endotracheal tube (ETT) during and after closed suction in a volume-targeted ventilation mode with the Dräger Babylog 8000+, and to determine the time until VTe returns to the baseline level. Methods: In this benchtop study, closed suction was performed on 2.5- to 4.0-mm ETTs connected to a test lung. 5–8 French suction catheters were used at suction pressures of 80–200 mm Hg during tidal-volume-targeted ventilation. Results: During catheter insertion and suction, circuit inflating pressure increased and tidal volume was maintained, except when a large catheter relative to the ETT was used, in which case tidal volume decreased. End-expiratory pressure distal to the ETT was reduced during suction by up to 75 cm H2O while circuit end-expiratory pressure was unchanged. Reduction in end-expiratory pressure distal to the ETT was greatest with large catheters and high suction pressures. Following suction, circuit and tracheal inflating pressures increased and tidal volume increased before returning to baseline in 8–12 s. Conclusions: Closed endotracheal suction interferes with ventilator function in volume-targeted mode, with substantially negative intratracheal pressure during suction, and the potential for high airway pressures and tidal volumes following the procedure. These effects should be considered and pressure limits set appropriately whenever using volume-targeted ventilation.

In newborn infants, closed endotracheal tube (ETT) suction may reduce associated adverse effects, but it is not clear whether ventilation is maintained during the procedure. We aimed to determine the effect of ETT size, catheter size, and suction pressure on ventilation parameters measured distal to the ETT. Suction was performed on a test lung, ventilated with conventional (CMV) and high-frequency oscillatory ventilation (HFOV) using ETT sizes 2.5-4.0 mm, catheter sizes 5-8 French gauge (Fr), and suction pressures 80-200 mm Hg. Tracheal and circuit peak inspiratory pressure, positive end-expiratory pressure, and tracheal tidal volume (VT) were recorded for each suction episode. During both CMV and HFOV, tracheal pressures and VT were considerably reduced by suctioning; this reduction was dependent on the combination of ETT, catheter, and suction pressure. Loss of VT, inflation pressure (CMV), and pressure amplitude (HFOV) occurred primarily with insertion of the catheter, and loss of end-expiratory pressure (CMV) and mean tracheal pressure (HFOV) occurred with the application of suction. Circuit pressures were reduced to lesser degree. We conclude that airway pressures and VT are not maintained during closed endotracheal suction with either CMV or HFOV, and choice of equipment and settings will affect the degree of interruption to ventilation.

Background: In infants with pulmonary hypertension (PHT), right ventricular (RV) function may be altered and contribute to disease severity. Tissue Doppler imaging (TDI) is a new echocardiographic modality which directly measures myocardial velocities and may allow quantitative assessment of systolic and diastolic ventricular function in infants. Objective: To measure and compare RV myocardial velocities in infants with PHT and in normal control infants, using TDI. Methods: This was a prospective case-control study. Twenty-eight control infants and 15 infants with PHT, of whom 11 had congenital diaphragmatic hernia (CDH), were recruited. TDI was used to obtain systolic and diastolic myocardial velocities in the RV and interventricular septum in all infants. Results: There were significant reductions in systolic isovolumic contraction velocity (IVV; 5.3 vs. 6.6 cm/s) and systolic ejection velocity (S; 6.6 vs. 9.2 cm/s) in the PHT group compared to the control group. Early diastolic myocardial velocity, E’, was also significantly reduced in the RV in the PHT infants compared to controls (–4.3 vs. 8.6 cm/s). The same significant reductions in systolic and early diastolic TDI velocities were observed in the subgroup of CDH infants alone. Conclusions: TDI permits non-invasive assessment of RV myocardial velocities in infants. Reduced systolic and diastolic velocities in PHT may represent impaired systolic contraction and early diastolic relaxation. Therapies which target inotropic and lusitropic function may be appropriate in infants with PHT and RV dysfunction. The load-dependency of TDI measures in infants and the effects of specific therapies on RV function in PHT require further investigation.

To compare four methods of volume recruitment upon initiation of high frequency oscillatory ventilation (HFOV).Anesthetized intubated neonatal piglets (n = 10) underwent repeated saline lavage, followed by conventional mechanical ventilation (CMV). After transition to HFOV at a mean airway pressure 8 cmH2O above CMV (P(basal)), four methods of lung volume recruitment were tested in each animal in random order: Escalating--step-wise pressure increments over 6 min to a peak mean airway pressure 12 cmH2O above P(basal); Sustained dynamic inflation (DI)--a 20 s inflation to the same peak pressure; DI repeated six times for 1 s; Standard--mean airway pressure set directly at P(basal). After each recruitment method, HFOV continued at P(basal) for 15 min. Thoracic gas volume and distribution of aeration were determined by single slice computed tomography, and oxygenation by arterial blood gas sampling.Escalating recruitment resulted in the greatest thoracic gas volume 15 min post recruitment [77 +/- 3.3% of total lung capacity vs. 70 +/- 4.2% (Sustained DI), 65 +/- 3.5% (Repeated DI),63 +/- 5.1% (Standard); mean +/- SEM; P = 0.042, ANOVA]. All methods resulted in a reduction in non-aerated lung, with the greatest redistribution to normally aerated lung being with Escalating recruitment. Oxygenation 15 min post recruitment was better with the Escalating method than with Repeated DI or Standard recruitment (pO2 307 +/- 41 vs. 159 +/- 36 vs. 134 +/- 39 mmHg, respectively; P = 0.016, ANOVA).Escalating recruitment produced the greatest increase in lung volume and resolution of atelectasis, and is recommended for lung volume recruitment upon initiation of HFOV.

Background This study aimed to measure and compare right ventricular (RV) function in normal infants and those with pulmonary hypertension (PHT) using the myocardial performance index (RVMPI) and to investigate the relationship between RV function and pulmonary artery pressure. Methods A case-control study measured RVMPI in 16 infants with PHT (9 of whom had congenital diaphragmatic hernia) and 28 normal control infants. For the PHT infants, 43 paired measures of RVMPI and pulmonary artery pressure (estimated from tricuspid regurgitation jet velocity) were taken to allow investigation of the relationship between RVMPI and pulmonary artery pressure. Results The mean RVMPI for the control infants was 0.24 ± 0.09. The RVMPI was significantly elevated in the PHT group (0.55 ± 0.17; p

Objectives: To compare change in lung volume (ΔV L ), using respiratory inductive plethysmography, time to recover pre-suction lung volume (t rec ) and the cardiorespiratory disturbances associated with open suction (OS) and closed suction (CS) in ventilated infants. Design: Randomised blinded crossover trial. Setting: Neonatal intensive care unit. Patients: Thirty neonates, 20 receiving synchronised intermittent mandatory ventilation (SIMV) and 10 high-frequency oscillatory ventilation (HFOV, four receiving muscle relaxant). Interventions: OS and CS were performed, in random order, on each infant using a 6FG catheter at −19 kPa for 6 seconds and repeated after 1 minute. Outcome measures: ΔV L , oxygen saturation (Spo 2 ) and heart rate were continuously recorded from 2 minutes before until 5 minutes after suction. Lowest values were identified during the 60 seconds after suction. Results: Variations in all measures were seen during CS and OS. During SIMV no differences were found between OS and CS for maximum ΔV L or t rec ; mean (95% CI) difference of 3.5 ml/kg (−2.8 to 9.7) and 4 seconds (−5 to 13), respectively. During HFOV t rec was longer during OS by 13 seconds (0 to 27) but there was no difference in the maximum ΔV L of 0.1 mV (−0.02 to 0.22). A small reduction in SpO 2 with CS in the SIMV group mean difference 6% (2.1 to 9.8) was the only significant difference in physiological measurements. Conclusions: Both OS and CS produced transient variable reductions in heart rate and Spo 2 . During SIMV there was no difference between OS and CS in ΔV L or t rec . During HFOV there was no difference in ΔV L but a slightly longer t rec after OS.

Systemic haemodynamics in three infants with severe cardiac failure secondary to vein of Galen malformation (VGAM) were studied using two-dimensional and Doppler echocardiography. In all cases, ventricular outputs were over two times normal and superior vena caval flows up to 10 times normal reflecting high flow through the low-resistance fistula. Severe pulmonary hypertension, right heart dilatation and retrograde flow in the descending aorta were uniformly present. Systemic blood flow below the head and neck was reduced resulting in metabolic acidosis at presentation. Two infants had patent arterial ducts, in which flow was entirely right to left and on entering the aorta passed predominantly retrogradely towards the VGAM. These findings provide a basis for understanding the pathophysiology of cardiac failure in VGAM and support treatment with pulmonary and systemic vasodilating agents.

Background: Therapeutic lung lavage is an emerging treatment for meconium aspiration syndrome (MAS), but the ideal fluid volume and lavage technique remain unclear. Objective: To evaluate the impact of suction technique, chest squeeze and aliquot volume on the efficacy of lung lavage in MAS. Methods: MAS was induced in ventilated 2-week-old piglets using 4 ml/kg of 20% human meconium. Lung lavage with either two 8 ml/kg saline aliquots (n = 5) or a single 15 ml/kg aliquot (n = 6) was performed soon after meconium instillation. Lavage fluid was recovered by three methods performed in sequence: closed suction via a suction adaptor; open suction with the ventilator disconnected, and open suction with manual vibratory chest squeezing. Return fluid was collected separately with each method. Recovery of meconium and lavage fluid was determined and expressed as a proportion of the amount instilled. Results: Closed suction resulted in poor meconium and fluid returns, with recovery of meconium being only 5.2 ± (SD) 2.5% with 2 × 8 ml/kg lavage and 19 ± 11% with a single 15 ml/kg aliquot. Chest squeeze during suction increased recovery of both meconium and lavage fluid. Overall recovery of instilled meconium was greater with 15 ml/kg lavage (45 ± 17%) than with two 8 ml/kg aliquots (24 ± 4.5%, p = 0.028, repeated-measures ANOVA); the corresponding values for return of lavage fluid were 73 ± 10 and 49 ± 13%, respectively (p < 0.01). Conclusions: Open suction, vibratory chest squeezing and an aliquot volume of 15 ml/kg each improve the efficacy of lung lavage in MAS, and merit inclusion in the lavage technique in clinical trials of this therapy.

To describe the pattern and magnitude of lung volume change during open endotracheal tube (ETT) suction in infants receiving high-frequency oscillatory ventilation (HFOV).Prospective observational clinical study.Tertiary neonatal intensive care unit.Seven intubated and muscle-relaxed newborn infants receiving HFOV.Open ETT suction was performed for 6 s at -100 mmHg using a 6-F catheter passed to the ETT tip after disconnection from HFOV. The HFOV was then recommenced at the same settings as prior to ETT suction.Change in lung volume (DeltaV (L)) referenced to baseline lung volume before suction was measured with a calibrated respiratory inductive plethysmography recording from 30 s before until 60 s after ETT suction. In all infants ETT suction resulted in significant loss of lung volume. The mean DeltaV (L) during suctioning was -13 ml/kg (SD 4 ml/kg) (p0.0001 vs. baseline, repeated-measures ANOVA), with a mean 76.5% (SD 14.1%) of this volume loss being related to circuit disconnection. After recommencing HFOV lung volume was rapidly regained with mean DeltaV (L) at 60 s being 1 ml/kg (SD 4 ml/kg) below baseline (p0.05, Tukey post-test).Open ETT suction caused a significant but transient loss of lung volume in muscle-relaxed newborn infants receiving HFOV.

Background: Death remains a common event in the neonatal intensive care unit, and often involves limitation or withdrawal of life sustaining treatment. Objective: To document changes in the causes of death and its management over the last two decades. Methods: An audit of infants dying in the neonatal intensive care unit was performed during two epochs (1985-1987 and 1999-2001). The principal diagnoses of infants who died were recorded, as well as their apparent prognoses, and any decisions to limit or withdraw medical treatment. Results: In epoch 1, 132 infants died out of 1362 admissions (9.7%), and in epoch 2 there were 111 deaths out of 1776 admissions (6.2%; p,0.001). Approximately three quarters of infants died after withdrawal of life sustaining treatment in both epochs. There was a significant reduction in the proportion of deaths from chromosomal abnormalities, and from neural tube defects in epoch 2. Conclusions: There have been substantial changes in the illnesses leading to death in the neonatal intensive care unit. These may reflect the combined effects of prenatal diagnosis and changing community and medical attitudes.

BACKGROUND: The early institution of enteral feeding in the first few days of life is known to impact on the development of unconjugated hyperbilirubinaemia. However, the effect of early intravenous nutrition on neonatal jaundice remains unknown. OBJECTIVES: To determine the effect of early intravenous nutrition on neonatal jaundice. SEARCH METHODS: The standard search strategy of the Cochrane Neonatal Review Group was used including searches of the Cochrane Controlled Trials Register (Cochrane Library: Issue 3, 2002), MEDLINE (1966‐December 2002), and EMBASE (1974‐December 2002). SELECTION CRITERIA: Randomised or quasi‐randomised controlled trials evaluating the effect of early intravenous nutrition on unconjugated bilirubin. DATA COLLECTION AND ANALYSIS: The search strategy identified no eligible studies, thus no data were collected. MAIN RESULTS: No studies were identified. AUTHORS' CONCLUSIONS: Decisions regarding the institution of early intravenous nutrition must continue to be based upon factors others than its effect on neonatal jaundice.

Therapeutic lung lavage is an emerging treatment for meconium aspiration syndrome. Our objective was to investigate the type of fluid and aliquot volume most appropriate for lung lavage in this condition. Meconium injury was induced in 2-week-old piglets, followed by a 30 ml/kg lavage in two aliquots 40 minutes later. Lavage with either dilute bovine surfactant (2.5 mg/ml) or a perfluorocarbon emulsion (20% wt/vol) improved oxygenation compared with a nonlavaged control group, but only with dilute surfactant was there a sustained improvement in oxygenation (alveolar-arterial oxygen difference at 5 hours: dilute surfactant 250 mm Hg; perfluorocarbon emulsion 460 mm Hg; controls 460 mm Hg; p = 0.0031). There was histologic and biochemical evidence of decreased lung injury in the dilute surfactant group. In a further study, 30 ml/kg dilute surfactant lavage was performed 40 minutes after meconium injury using either two aliquots of 15 ml/kg, or multiple 3-ml aliquots. Aliquot volume of 15 ml/kg was associated with increased meconium removal, better post-lavage lung function, and less lung injury. Dilute surfactant lavage using two 15-ml/kg aliquots is an effective therapy in the piglet model of meconium aspiration, and should be evaluated in human infants with this condition.

Background Phototherapy is used to treat newborn infants with hyperbilirubinaemia. Fibreoptic phototherapy is a new mode of phototherapy which is reported to lower serum bilirubin (SBR) while minimising disruption of normal infant care. Objectives To evaluate the efficacy of fibreoptic phototherapy. Search methods The standard search strategy of the Cochrane Collaboration was used including searches of the Cochrane Controlled Trials Register, MEDLINE, EMBASE and discussion with experts in the field. Selection criteria Randomised or quasi-randomised controlled trials evaluating the efficacy of fibreoptic phototherapy in the management of newborn infants with hyperbilirubinaemia. Data collection and analysis Thirty-one studies were identified of which 24 met inclusion criteria. They evaluated the efficacy of fibreoptic phototherapy in a number of different clinical situations and patient populations. Main results Fibreoptic phototherapy was more effective at lowering SBR than no treatment but less effective than conventional phototherapy (percentage change in SBR after 24 hours of treatment: WMD -10.7%, 95%CI -18.14, -3.26 and WMD 3.59%, 95%CI 1.27, 5.92 respectively). Fibreoptic phototherapy was equally as effective as conventional phototherapy in preterm infants and when two fibreoptic devices were used simultaneously (change in SBR after 24 hours of treatment: WMD 1.7%, 95%CI -2.65, 6.05 and change in SBR per day over whole treatment period: WMD 2.82%, 95%CI -1.84, 7.48 respectively). A combination of fibreoptic and conventional phototherapy was more effective than conventional phototherapy alone (duration of phototherapy: WMD -12.51 hr, 95%CI -16.00, -9.02, meta-analysis affected by heterogeneity). No conclusion can be made on the superiority of one fibreoptic device over another as the two studies comparing them (one favouring BiliBlanket, the other finding no difference) did not contain a common outcome measure. Authors' conclusions Fibreoptic phototherapy has a place in the management of neonatal hyperbilirubinaemia. It is probably a safe alternative to conventional phototherapy in term infants with physiological jaundice. No trials have been identified which support the widely-held view that fibreoptic devices interfere less with infant care or impact less on parent-child bonding.

Objective To evaluate whether lung lavage with surfactant changes the duration of mechanical respiratory support or other outcomes in meconium aspiration syndrome (MAS). Study design We conducted a randomized controlled trial that enrolled ventilated infants with MAS. Infants randomized to lavage received two 15-mL/kg aliquots of dilute bovine surfactant instilled into, and recovered from, the lung. Control subjects received standard care, which in both groups included high frequency ventilation, nitric oxide, and, where available, extracorporeal membrane oxygenation (ECMO). Results Sixty-six infants were randomized, with one ineligible infant excluded from analysis. Median duration of respiratory support was similar in infants who underwent lavage and control subjects (5.5 versus 6.0 days, P = .77). Requirement for high frequency ventilation and nitric oxide did not differ between the groups. Fewer infants who underwent lavage died or required ECMO: 10% (3/30) compared with 31% (11/35) in the control group (odds ratio, 0.24; 95% confidence interval, 0.060-0.97). Lavage transiently reduced oxygen saturation without substantial heart rate or blood pressure alterations. Mean airway pressure was more rapidly weaned in the lavage group after randomization. Conclusion Lung lavage with dilute surfactant does not alter duration of respiratory support, but may reduce mortality, especially in units not offering ECMO.

Aim: To explore the effects of a large volume lung lavage procedure in ventilated infants with meconium aspiration syndrome. Methods: Infants with severe meconium aspiration requiring high-frequency ventilation underwent lung lavage using dilute bovine surfactant at a phospholipid concentration of 5 mg/mL. Lavage aliquot volumes were increased through the case series, aiming to deliver two aliquots of 15 mL/kg in rapid sequence. Physiological effects of lavage were documented, and comparison was made with a group of infants with meconium aspiration requiring high-frequency ventilation, in whom lavage was not performed. Results: Nine episodes of lavage were performed in eight infants at a median age of 23 h (range 8–83 h). Three infants underwent a lavage that was defined as potentially therapeutic (total lavage volume of at least 25 mL/kg administered before 24 h of age). Lavage was not associated with bradycardia or hypotension. Recovery of arterial oxygen saturation to above 80% was achieved within 12 min in all but one infant in whom oxygen saturation was below 80% at the outset. Mean airway pressure was significantly lower in the Therapeutic lavage group compared with non-lavaged infants in the first 48 h, with a trend towards improved oxygenation. Conclusion: Dilute surfactant lavage with aliquots of up to 15 mL/kg appears to be feasible in haemodynamically stable ventilated infants with meconium aspiration syndrome, and its efficacy deserves further investigation in a randomised controlled trial.