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Introduction: We evaluate the accuracy of postnatal biochemical and lung function tests performed within 3 h from birth for predicting surfactant need in preterm infants ≤34 weeks’ gestation receiving noninvasive respiratory support for respiratory distress syndrome (RDS). Methods: We systematically searched MEDLINE, Embase, The Cochrane Library, PROSPERO, and clinicaltrials.gov databases for studies published from 2000 to November 10, 2021, cross-referencing relevant literature and contacting experts. We included diagnostic accuracy studies and systematic reviews of biochemical or lung function tests identifying the need for surfactant in preterm neonates ≤34 weeks’ with RDS not intubated at birth. The authors individually assessed the risk of bias following a tailored QUADAS-2 tool. Results: Eight studies, including 810 infants, met the inclusion criteria. Four tests were included: the click test, the stable microbubble test, the lamellar body count on gastric aspirates, and the forced oscillation technique. The reference standards were transparent criteria for distinguishing the infants according to oxygen requirement, which reflected the current criteria for surfactant therapy. The risk of bias was judged high because of the population selection and exclusion of participants from the analysis. There were no serious concerns regarding blinding and applicability. The individual study sensitivity and specificity range from 0.60 to 1 and from 0.51 to 0.91, respectively. It was not appropriate to combine the accuracy estimates in a meta-analysis because of the heterogeneity of the study characteristics. Conclusions: Current evidence is insufficient to recommend biochemical and lung function tests for tailoring surfactant therapy.

The forced oscillation technique can identify a surrogate of closing volume (CVFOT). We investigated its relationship with the one measured by single-breath washout (CVSBW). CVFOT weakly correlates with CVSBW. The respective closing capacities were correlated, but their increases after methacholine challenge in asthmatics did not. Our results suggest that CVFOT is less sensitive than CVSBW to few flow-limited/closed airways but more specific in detecting increases in flow-limited/closed airways involving the majority of the lung.

Background Self-reported exercise-induced dyspnea (EID) is common among adolescents. Possible underlying pathologies are exercise-induced bronchoconstriction (EIB) and laryngeal obstruction (EILO). The forced oscillation technique (FOT) may evaluate exercise-induced changes in airway caliber. Aim To investigate in adolescents the relationship between EID, EIB (post-exercise fall in forced expiratory volume in 1s (FEV1)>= 10%), EILO, and post-exercise challenge changes in FOT parameters. Methods One hundred and forty-three subjects (97 with EID) of 13-15 years old underwent a standardized exercise challenge with FOT measurement and spirometry repeatedly performed between 2 and 30 min post-exercise. EILO was studied in a subset of 123 adolescents. Subjects showing greater changes than the healthy subgroup in the modulus of the inspiratory impedance were considered FOT responders. Results EID-nonEIB subjects presented similar post-exercise changes in all FOT parameters to nonEID-nonEIB adolescents. Changes in all FOT parameters correlated with FEV1 fall. 45 of 97 EID subjects responded neither by FEV1 nor FOT to exercise. 19 and 18 subjects responded only by FEV1 (onlyFEV(1)responders) or FOT (onlyFOTresponders), respectively. Only a lower baseline forced vital capacity (FVC)%predicted and a higher FEV1/FVC distinguished the onlyFEV(1)responders from onlyFOTresponders. FOT parameters did not present specific post-exercise patterns in EILO subjects. Conclusion FOT can be used to identify post-exercise changes in lower airway function. However, EID has a modest relation with both FEV1 and FOT responses, highlighting the need for objective testing. More research is needed to understand whether onlyFEV(1)responders and onlyFOTresponders represent different endotypes.

To identify short-term repeatability of forced oscillation technique (FOT) measurement of lung function, assess the lung function response to bronchodilators (BDs) by FOT, and prove the concept that only some very preterm infants manifest a change in lung mechanics in response to BD.We retrospectively analyzed respiratory system resistance and respiratory system reactance measured by FOT (Fabian HFOi). The measurement short-term repeatability was assessed in 43 patients on 60 occasions; BD responsiveness was assessed using a different data set, including 38 measurements in 18 infants. The coefficient of repeatability was calculated as twice the SD of differences between measurements performed 15 minutes apart. We assessed BD responsiveness by measuring respiratory system resistance and respiratory system reactance before and 15 minutes after administering 200 mcg/kg of nebulized salbutamol. A positive response was defined as an improvement in respiratory system resistance or respiratory system reactance greater than the identified coefficient of repeatability.The coefficient of repeatability was 7.5 cmHWe identified a threshold to assess BD responsiveness by FOT in preterm infants. We speculate that FOT could be used to assess and personalize treatment with BD.

Objective. To examine the influence of the endotracheal tube (ETT) on respiratory reactance (Xrs) measured with the forced oscillation technique (FOT) and develop a correction method for it. Approach. In a bench study, the reactance of ETTs (Xtube) with different dimensions was measured on a breathing test lung in various respiratory settings. Main results. Xtube can be accurately predicted by a fitted formula, with an R2 of 0.97, with negligible effects due to changes in respiratory pattern and lung volume. Significance. The developed formula offers the ability to measure ETT-independent Xrs values of patients, improving the potential of FOT for lung function testing in mechanically ventilated newborns.

Objective: The objective of the study was to develop an automatic quantitative approach to identify infants with abnormal movements of the limbs at term equivalent age (TEA) compared with general movement assessment (GMA).Methods: GMA was performed at TEA by a trained operator in neonates with neurological risk. GMs were classified as normal (N) or abnormal (Ab), which included poor repertoire and cramped synchronized movements. The signals from four micro-accelerometers placed on all limbs were recorded for 10 min simultaneously. A global index (KC_index), quantifying the characteristics of individual limb movements and the coordination among the limbs, was obtained by adding normalized kurtosis of the distribution of the first principal component of the acceleration signals to the cross-correlation of the jerk for the upper and lower limbs.Results: Sixty-eight infants were studied. A KC_index cut-off of 201.5 (95% CI: 199.9–205.0) provided specificity = 0.86 and sensitivity = 0.88 in identifying infants with Ab movements.Conclusions: KC_index provides an automatic and quantitative measure that may allow the identification of infants who require further neurological evaluation.

The distribution of ventilation during high-frequency ventilation (HFV) is asynchronous, nonhomogeneous, and frequency dependent. We hypothesized that differences in the regional distribution of ventilation at different oscillatory frequencies may affect gas exchange efficiency. We studied 15 newborn infants with a median gestational age of 28.9 (26.4–30.3) wk and body weight of 1.0 (0.8–1.4) kg. Five ventilation frequencies (5, 8, 10, 12, and 15 Hz) were tested, keeping carbon dioxide diffusion coefficient constant. The displacements of 24 passive markers placed on the infant’s chest wall were measured by optoelectronic plethysmography. We evaluated the amplitude and phase shift of displacements of single markers placed along the midline and the regional displacements of the chest wall surface. Blood gases were unaffected by frequency. Chest wall volume changes decreased from 1.6 (0.4) ml/kg at 5 Hz to 0.7 ml/kg at 15 Hz. At all frequencies, the abdomen (AB) oscillated more markedly than the ribcage (RC). The mean (SD) AB/RC ratio was 1. 95 (0.7) at 5 Hz, increased to 2.1 (1.3) at 10 Hz, and then decreased to 1.1 (0.5) at 15 Hz ( P < 0.05 vs. 10 Hz). Volume changes in the AB lagged the RC and this phase shift increased with frequency. The AB oscillated more than the RC at all frequencies. Regional oscillations were highly inhomogeneous up to 10 Hz, and they became progressively more asynchronous with increasing frequency. When the carbon dioxide diffusion coefficient is held constant, such differences in regional chest wall expansion do not affect gas exchange. NEW & NOTEWORTHY We characterized the regional distribution of chest wall displacements in infants receiving high-frequency oscillatory ventilation at different frequencies. When carbon dioxide diffusion coefficient is held constant, there is no combination of frequency and tidal volume that optimizes gas exchange. The relative displacement between different chest wall compartments is not affected by frequency. However, at high frequencies, chest wall displacements are lower, with the potential to reduce total and regional overdistension without affecting gas exchange.

Background: Current criteria for surfactant administration assume that hypoxia is a direct marker of lung-volume de-recruitment. Objectives: To evaluate whether lung reactance (Xrs) assessment by FOT within 2h of birth identifies infants who would need surfactant within 24h; to eventually determine Xrs performance and a cut-off value for early detection of infants requiring surfactant. Methods: We conducted a prospective, observational, non-randomized study in our tertiary NICU in Milan. Eligible infants were born between 27+0 and 34+6 weeks' gestation presenting respiratory distress after birth. Exclusion criteria: endotracheal intubation at birth, major malformations. We assessed Xrs during nasal CPAP at 5cmH2O at 10Hz within 2h of life, recording flow and pressure tracing through a Fabian Ventilator for off-line analysis. Clinicians were blinded to FOT results. Results: We enrolled 61 infants, with a median[IQR] gestational age of 31.9[30.3; 32.9]weeks and birth weight 1490[1230; 1816]g. 14/59 infants received surfactant within 24h. Xrs predicted surfactant need with a cut-off -33.4 cmH2O*s/L and AUC-ROC=0.86 (0.76-0.96), with sensitivity 0.85 and specificity 0.83. An Xrs cut-off value of -23.3 cmH2O*s/L identified infants needing surfactant or respiratory support >28 days with AUC-ROC=0.89 (0.81-0.97), sensitivity 0.86 and specificity 0.77. Interestingly, 12 infants with Xrs

Objective We aimed to measure lung mechanics at birth by the forced oscillation technique (FOT) for assessment of the initial degree of lung aeration and the short-term aeration changes after applying different respiratory support strategies. Methods Eighteen preterm infants (gestational age = 29-36 week) were randomized to receive either continuous positive airway pressure (CPAP) at 5 cmH2 O only or combined with a sustained inflation (SI; 15 seconds at 25 cmH2 O after 5 seconds of CPAP) at birth. We assessed the respiratory system reactance at 5 Hz (X5; increases with lung volume recruitment at a given distending pressure) at 2, 40, and 150 seconds after initiation of CPAP. k-Means clustering of the initial X5 value (X5,i ) stratified newborn into either infants with lower (lowerX5,i ; X5 -240 cmH2 O*s/L) initial degree of lung volume recruitment. Results Initial values were highly heterogeneous. In the LowerX5,i group, X5 increased with time, with SI-patients showing significantly higher values at 150 seconds than the non-SI group (X5 = -89 ± 27 cmH2 O vs -274 ± 58 cmH2 O). In the higherX5,i group, X5 did not improve with time, regardless of the respiratory strategy, suggesting a lack of lung recruitment. Moreover, 75% of infants receiving SI in the higherX5,i group experienced a transient loss of aeration after the maneuver. Conclusions Preterm newborns present initially with highly heterogeneous lung aeration at birth that significantly impacts the effectiveness of the subsequent lung volume recruitment strategy. FOT may represent a valuable tool for individualizing a respiratory resuscitation at birth as it is noninvasive and may be applied simultaneously to respiratory support.

Objective Despite technical specifications of neonatal mechanical ventilators (MVs) guarantee clinically irrelevant discrepancies between the set and the delivered values of ventilation parameters, previous studies reported large deviations. Most studies characterized performances of a given model/brand by studying a single device, disregarding possible intramodel differences, and leaving the accuracy of the ventilation parameters effectively delivered in clinical settings unknown. The aim of this study was to evaluate the real-life accuracy of pressure and volume parameters delivered by neonatal ventilators ready to be used on patients in neonatal intensive care units (NICUs). Study design In vitro study. Subjects selection Neonatal ventilators (n = 33 of 8 different models) available in four European NICUs. Methodology The MVs were connected to a test lung (resistance = 50 cmH2 O*s/L, compliance = 0.35 mL/cmH2 O) provided with pressure and flow sensors. MVs were tested over two different ventilation modes randomly: (a) pressure controlled (PC) with a peak inspiratory pressure (PIP) of 22 cmH2 O, and (b) PC with volume targeted ventilation (VTV) with a tidal volume (VT ) of 6 mL. In all tests, positive end-expiratory pressure (PEEP) was set to 6 cmH2 O, respiratory rate to 45 breaths/min, inspiratory time to 0.33 seconds, and oxygen fraction to 0.3. Results During PC the median (min-max) values delivered were: PEEP = 5.84(4.95-6.48) cmH2 O, PIP = 21.63(20.04-22.62) cmH2 O. During VTV, VT was 5.94(4.63-8.01) mL. VT was considerably variable, ranging from -22% to +33% of the set and displayed values. Differences in accuracy among devices of the same model were comparable to those found among different models. Conclusions Our findings suggest that loss of accuracy in ventilation variables is likely related to daily use of the devices rather than weakness in the design or manufacturing process, urging the improvement of maintenance and quality control procedures to preserve the performances of neonatal MVs during their entire lifespan.

Background Oscillatory pressure (ΔP) measurement during high frequency oscillatory ventilation (HFOV) is technically challenging and influenced by all the components of the measurement system. Objectives To evaluate the differences between the ΔP delivered at the inlet of the endotracheal tube and those displayed by commercial neonatal mechanical ventilators and monitoring devices and to characterize how the ventilator circuit and the flowmeter proximal to the patient affect these differences. Methods Six devices were evaluated while ventilating three mechanical analogues representing the newborn respiratory system in different disease states. ΔP measured at different points of the ventilator circuit were compared. Results ΔP accuracy is highly variable and decreases with increasing oscillation frequency and amplitude, independently of the mean airway pressure. At 15 Hz, a ΔP displayed by ventilators of 40 cmH2 O resulted in a ΔP effectively delivered at the tracheal tube ranging from 22 to 49 cmH2 O, depending on the ventilator model, the ventilator circuit, and the patient condition. At these settings, the errors exclusively due to the ventilator circuit and the presence of the flowmeter ranged from 6 to 9 cmH2 O and from 1 to 6 cmH2 O, respectively. Conclusions The ventilator model, the breathing circuit, the flowmeter, and the patient condition severely impacts ΔP measurement accuracy during HFOV, leading to highly variable performances. This prevents the possibility of using the ΔP required to normalize gas exchange as an indicator of patients' condition, complicates comparison of ventilators performances, and adds a significant element of complexity in clinical management of HFOV.

Background The forced oscillation technique (FOT) allows non-invasive lung function testing during quiet breathing even without expert guidance. However, it still relies on an operator for excluding breaths with artefacts such as swallowing, glottis closure and coughing. This manual selection is operator-dependent and time-consuming. We evaluated supervised machine learning methods to exclude breaths with artefacts from data analysis automatically. Methods We collected 932 FOT measurements (Resmon Pro Full, Restech) from 155 patients (6–87 years) following the European Respiratory Society (ERS) technical standards. Patients were randomly assigned to either a training (70%) or test set. For each breath, we computed 71 features (including anthropometric, pressure stimulus, breathing pattern, and oscillometry data). Univariate filter, multivariate filter and wrapper methods for feature selection combined with several classification models were considered. Results Trained operators identified 4333 breaths with- and 10244 without artefacts. Features selection performed by a wrapper method combined with an AdaBoost tree model provided the best performance metrics on the test set: Balanced Accuracy = 85%; Sensitivity = 79%; Specificity = 91%; AUC-ROC = 0.93. Differences in FOT parameters computed after manual or automatic breath selection was less than ∼0.25 cmH2O*s/L for 95% of cases. Conclusion Supervised machine-learning techniques allow reliable artefact detection in FOT diagnostic tests. Automating this process is fundamental for enabling FOT for home monitoring, telemedicine, and point-of-care diagnostic applications and opens new scenarios for respiratory and community medicine.

Surfactant improves lung mechanics and the success of non-invasive respiratory support in preterm infants. The lack of non-invasive bedside tools for monitoring lung mechanics makes current guidelines for surfactant therapy based on O2 requirements, which may be not specific for this application. Objective: To assess feasibility and role of early, non-invasive evaluation of respiratory mechanics by FOT in non-intubated preterm infants for stratifying the severity of respiratory disease. Eligibility: 28-34wk gestation, no need of early intubation after birth. FOT at 10Hz was applied by a modified ventilator (Fabian, Acutronic) and a face-mask during CPAP=5cmH2O. Measurements were performed at 2 and 24h of life. FiO2 was titrated and surfactant given as in Sweet (2016). 4 groups (n=45) were considered: Patients not requiring respiratory support (SB); receiving CPAP for less than (CPAP-S) or more than 28d (CPAP-L) but who never received surfactant and patients who received surfactant (Surf). Xrs in Surf and CPAP-L was significantly lower at 2h compared to SB and CPAP-S (fig 1). After receiving surfactant patients improved, leaving CPAP-L only showing significantly lower Xrs at 24h. Xrs stratifies patients according to the degree of respiratory disease. CPAP-L infants presented poor Xrs at 2h, did not match clinical criteria for surfactant but had a long respiratory support dependence.

Ventilatory settings are critical in mechanically ventilated extremely preterm newborn infants due to the risk of ventilation induced lung injury (VILI) and subsequent development of bronchopulmonary dysplasia (BPD) [1]. The positive end-expiratory pressure (PEEP) settings usually rely on blood gases, oxygen requirement, lung auscultation, evaluation of chest radiograph, and assessment of pressure-volume curves provided by the ventilators. Studies of optimal PEEP settings in the surfactant treated preterm infant in need of mechanical ventilation are limited and evidence based clinical guidelines are sparse [2, 3]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Wallstrom has nothing to disclose. Conflict of interest: Dr. Veneroni reports and My institution (Politecnico di Milano University) received research grants from Chiesi Farmaceutici Conflict of interest: Dr. Zannin has nothing to disclose. Conflict of interest: Dr. Dellaca’ reports grants from Acutronic, outside the submitted work; In addition, Dr. Dellaca’ has a patent on the detection of EFL by FOT with royalties paid to Philips Respironics and Restech srl, a patent on monitoring lung volume recruitment by FOT with royalties paid to Vyaire, and a patent on early detection of exacerbations by home monitoring of FOT with royalties paid to Restech. Conflict of interest: Dr. Sindelar has nothing to disclose.

OBJECTIVE: To provide a non-invasive approach to monitoring lung function in spontaneously breathing lambs, from birth to five months of life, by the forced oscillation technique (FOT). This report describes the experimental set-up, data processing, and identification of normal predicted values of resistance (Rrs) and reactance (Xrs) of the respiratory system, along with normal bronchodilator response for bronchial reversibility testing. APPROACH: Rrs and Xrs at 5, 11, and 19 Hz were measured monthly for five months in 20 normal term lambs that breathed spontaneously. In seven lambs, repeated measurements also were made within the first month of life (at 3, 7, 14, and 21 d of life). We determined the repeatability and reproducibility of the measurements and characterized the relationship between lung mechanics and age, sex, and body dimensions, using regression analysis, and measured changes in lung mechanics in response to inhaled bronchodilator. MAIN RESULTS: The measurements provided repeatable and reproducible data. Rrs decreased, whereas Xrs increased, with growth from birth through the first two months of life, after which no statistically significant differences were detected. We identified normal value equations for Rrs and Xrs and for each of the measured anthropometric variables. Respiratory system mechanics were not affected by the bronchodilator. SIGNIFICANCE: The FOT provides reliable non-invasive measurement of respiratory system mechanics in spontaneously breathing term lambs from birth to five months of age. The methods and normal reference values defined in this study will facilitate testing of the pathophysiological consequences of preterm birth and prolonged respiratory support on respiratory system mechanics.

Respiratory management during extracorporeal membrane oxygenation (ECMO) is complex. Assessment of lung mechanics might support a patient-tailored ventilatory strategy. We report, for the first time, the use of the forced oscillation technique (FOT) to evaluate lung function during neonatal ECMO to improve the individualization of respiratory support. The patient was a formerly preterm infant at a corrected age of 40 weeks (gestational age 32 weeks) undergoing veno-arterial ECMO for refractory respiratory failure secondary to influenza A (H1N1) pneumonia. We used the FOT as a bedside non-invasive tool for daily monitoring of lung mechanics, from ECMO day 6 (E6) until decannulation. A small-amplitude, 5-Hz oscillatory pressure was overimposed on the ventilation waveform at the airway opening during positive end-expiratory pressure (PEEP) trials. From E6 to E9, lung mechanics changes with PEEP indicated a largely de-recruited and easily over-distendable lung that was not recruitable by applying lung-protective PEEP values. After surfactant and steroid administration, oscillatory reactance (Xrs) values began improving, suggesting a more recruited and pressure-recruitable lung. On E11, despite the lack of improvement in the radiographic appearance of the thorax, the FOT measurements showed a more recruited lung. Weaning from ECMO was started, and the patient was extubated within 48 h. The decannulation was successful, and the patient was extubated within 48 h after ECMO weaning. First-year respiratory and neurodevelopmental follow-up evaluation was unremarkable. This report suggests the potential usefulness of the FOT for monitoring the lung mechanics of ventilated newborns during ECMO to achieve individualized respiratory management. Such tailoring might improve neonatal outcomes and support clinicians with the establishment of a timely and safer weaning approach. These findings need to be verified on a larger population.

Background: SLI at birth has been shown to promote lung aeration in intubated preterm lambs (Tingay et al PedRes 2014). The effectiveness of applying SLI by full-face mask might be impaired by leaks, glottis closure, and accumulation of air in the stomach. Aim: To compare timing and magnitude of lung aeration at birth in preterm lambs receiving non-invasive resuscitation with and without the application of SLI. Methods: Preterm lambs (128d; ~28w in humans) were randomly assigned to receive SLI at birth (SLI group, n=7) or not (noSLI group, n=6). SLI group received two SLIs of 35s at 30cmH2O separated by 55s of nIPPV. All lambs received surfactant and were maintained with nIPPV (PEEP=8cmH2O, RR=60). PIP and FiO2 were adjusted to maintain PaCO2 at 35-55 mmHg and PaO2 at 60-80 mmHg up to 3h of life in both groups. Lung aeration was assessed as changes in lung reactance (Xrs) at 5Hz (Dellaca’ et al, ICM2011) measured by the forced oscillation technique. Data reported as median (IQR). Results: In both groups, Xrs increased with time (Figure). Xrs was significantly greater in SLI group at the end of each SLI and more variable in noSLI group. At 3h, Xrs stabilized at similar values for both groups. Conclusions: SLI applied non-invasively improved lung aeration and a more homogenous response in preterm lambs at birth. However, the improvements compared to CPAP disappear within few minutes.

Background: Ventilated preterm infants may have respiratory morbidities early in life and later at school age and adulthood (Clemm HH, 2014). Modeling with large animals is needed to identify mechanisms Aim: Use a new former preterm (FPT) lamb model to evaluate lung mechanics, airway reactivity, and airway smooth muscle (ASM) thickness. Methods: 6 preterm lambs (128d; term ~150d; ~28w gestation in humans) were resuscitated and supported by mechanical ventilation for 3-6d before weaning from respiratory support (FPT lambs). They lived for ~6m (~5m corrected postnatal age; ≈6y in humans). Control lambs (n=20), born at term, lived 5m. We measured respiratory mechanics monthly by forced oscillation technique (FOT; 11Hz) and airway reactivity by changes in FOT variables after increased doses of nebulized methacholine (MCh; 0.06-4.00 mg; ATS guideline, 1999). We used quantitative histology to measure ASM thickness in terminal bronchioles. Results: FPT lambs had increased airway reactivity during the first 2m of life (figure). ASM thickness was significantly greater in FPT lambs (6.7±1.1vs 3.1±0.5 mm control lambs). Conclusions: The new FPT lamb model recapitulates altered lung mechanics and airway reactivity in FPT humans. Interestingly, airway muscularization persists at 5m when lung mechanics and airway reactivity are no longer impaired. This model provides opportunity to identify pathogenic mechanisms.

We aimed to evaluate if lung mechanics measured by forced oscillatory technique (FOT) during the first day of life help identify extremely low gestational age newborns (ELGANs) at risk of prolonged mechanical ventilation (MV) and oxygen dependency.Positive end-expiratory pressure (PEEP) was increased 2 cmHTwenty-two newborns (24FOT can be applied bedside in ELGANs, where early changes in lung mechanics with PEEP improve clinical prediction of respiratory outcomes.

Objectives In preterm infants, the application of nasal Continuous Positive Airway Pressure (nCPAP) improves lung function through several mechanisms and may interact with the control of breathing. Our aim was to evaluate the effect of increasing/decreasing nCPAP on gas exchange, breathing pattern, and its variability in preterm infants. Methods Fifeteen infants with mild to moderate respiratory distress syndrome (RDS) were studied on the first day of life. Infants had a mean (SD) gestational age of 30 + 4 (3 + 4) weeks + day and body weight of 1405 (606) g. nCPAP was increased every 10 min stepwise (0-4-8-10 cmH2 O) and then decreased every 20 min (8-6-4-2 cmH2 O). At each step, vital parameters, oxygenation, and chest wall volume changes (optoelectronic plethysmography) were evaluated. Tidal volume (VT ), inter-breath interval (IBI), end-expiratory lung volume (EELV) changes, and other breathing pattern parameters were computed breath-by-breath. The correlation properties of VT , IBI, and EELV were quantified by detrended fluctuation analysis, computing the scaling exponent α. Results During nCPAP, oxygenation improved and VT decreased significantly compared with no nCPAP. No significant changes in breathing pattern were observed between nCPAP levels. α of EELV was significantly higher off nCPAP than during nCPAP, suggesting that nCPAP helps stabilize EELV control mechanisms. Conclusions In our population of preterm infants with mild to moderate RDS, in the first day of life, nCPAP improved gas exchange, VT , and EELV stability independent of nCPAP level.

Even if the accuracy of mechanical ventilators (MV) stated by manufacturers are largely within clinically relevant ranges, Govoni et al. (2012) found large deviations from original specifications in adult MV during real life usage, especially on volume-related parameters. This loss of accuracy can be extremely critical in neonatal MV, where the recent spreading of the volume guarantee (VG) modality made flow measurements more critical. The aim of this study was to evaluate the real life performances of MV used in neonatal intensive care unit (NICU). A test lung (TL) equipped with pressure and flow sensors mimicking a mild RDS (R=50cmH2O*s/l, C=0.35ml/cmH2O) baby was connected to the MVs ready to be used on patients (n=20) available in 3 NICUs. MVs were tested in both pressure controlled (PC, peak inspiratory pressure PIP=22cmH2O) and PC with VG (tidal volume VT=6ml) modalities in random order. In all tests, positive end-expiratory pressure (PEEP) was 6cmH2O, respiratory rate 45breaths/min, inspiratory time 0.33s, oxygen fraction 30%. The values of PEEP, PIP (during PC) and VT (during VG) delivered by MVs are reported in Figure. In several MVs, the ventilation delivered was considerably different from the set one with actual VT ranging from 5.3 to 8.0ml, urging the need of improving quality control procedures for preserving the performances of MVs with usage.

This review addresses how the combination of physiology, medicine and engineering principles contributed to the development and advancement of mechanical ventilation, emphasising the most urgent needs for improvement and the most promising directions of future development. Several aspects of mechanical ventilation are introduced, highlighting on one side the importance of interdisciplinary research for further development and, on the other, the importance of training physicians sufficiently on the technological aspects of modern devices to exploit properly the great complexity and potentials of this treatment. Educational aims To learn how mechanical ventilation developed in recent decades and to provide a better understanding of the actual technology and practice. To learn how and why interdisciplinary research and competences are necessary for providing the best ventilation treatment to patients. To understand which are the most relevant technical limitations in modern mechanical ventilators that can affect their performance in delivery of the treatment. To better understand and classify ventilation modes. To learn the classification, benefits, drawbacks and future perspectives of automatic ventilation tailoring algorithms., Physiology, medicine and engineering principles have contributed to the advancement of mechanical ventilation http://ow.ly/Fjlb30bFpLl

Summary Background The role of prone position in preterm infants has not been completely clarified. We investigated prone versus supine posture-related changes in respiratory system resistance (Rrs) and reactance (Xrs) measured by the Forced Oscillation Technique (FOT) in mechanically ventilated preterm newborns. Methods Patients were studied in the supine versus prone positions in random order. Oxygen saturation, transcutaneous partial pressure of oxygen (ptcO2), carbon dioxide (ptcCO2), Rrs and Xrs were measured in each position. Results Nine patients with respiratory distress syndrome (RDS) and nine with evolving broncho-pulmonary dysplasia (BPD) were studied. Rrs was, on average, 9.8 (1.3, 18.3 as 95%CI) cmH2O*s/l lower in the prone compared to the supine position (P = 0.02), while no differences in Xrs, ptcO2, ptcCO2, and breathing pattern were observed between postures. Only patients with evolving BPD showed a significant reduction of Rrs from 69.0 ± 27.4 to 53.0 ± 16.7 cmH2O*s/l, P = 0.01. No significant correlations were found between changes in lung mechanics and ptcO2, ptcCO2, or breathing pattern. Conclusions On short-term basis, prone positioning does not offer significant advantages in lung mechanics in mechanically ventilated infants with RDS, while it is associated with lower Rrs values in patients with evolving BPD. Pediatr Pulmonol. 2015; 50:798–804. © 2014 Wiley Periodicals, Inc.

BACKGROUND: Nitrogen (N2) single breath washout (SBW) and Forced Oscillation Technique (FOT) are sensitive to airway closures and choke points by different physical mechanisms. AIM: to characterize SBW and FOT in healthy and asthmatics pre and post methacholine challenge (Mch) and to compare the information provided by the two approaches. METHODS: Lung function was evaluated in 13 healthy subjects (9F/4M, 46±13years) and 12 stable asthmatics (7F/3M, 37±13years) by SBW and within-breath FOT at 5, 11 and 19Hz. Closing volume (CV N2 ) and the slope of phaseIII (SIII) from SBW were identified by a blinded expert. Resistance (R 5 ), reactance (X 5 ) and frequency dependence of resistance (R 5 -R 19 ) were measured during quiet breathing and during a slow vital capacity maneuver (SVC). CV FOT was defined as the volume corresponding to X 5 =-7 cmH2O*s/l during SVC. Asthmatics were studied also post Mch at 20% fall in FEV 1 . RESULTS: No differences in FOT and SBW parameters were found between healthy and asthmatics pre-Mch. However, all of them changed significantly in asthmatics after Mch, with CV FOT showing the biggest change for all the patients (minimal change=103% vs -3% in CV N2 ; 8% in SIII; 22% in R 5 ; 48% in X 5 and 75% in R 5 -R 19 ). pIII N2 correlates with all FOT parameters while CV N2 showed only a weak correlation with CV FOT (Spearman, p=0.04). CONCLUSION: CV FOT might be useful to assess in a more accurate and sensitive way the response to bronchial challenge.

Importance Heated, humidified high-flow nasal cannula (HHHFNC) has gained increasing popularity as respiratory support for newborn infants thanks to ease of use and improved patient comfort. However, its role as primary therapy for respiratory distress syndrome (RDS) of prematurity needs to be further elucidated by large, randomized clinical trials. Objective To determine whether HHHFNC provides respiratory support noninferior to nasal continuous positive airway pressure (nCPAP) or bilevel nCPAP (BiPAP) as a primary approach to RDS in infants older than 28 weeks’ gestational age (GA). Design, Setting, and Participants An unblinded, monocentric, randomized clinical noninferiority trial at a tertiary neonatal intensive care unit. Inborn infants at 29 weeks 0 days to 36 weeks 6 days of GA were eligible if presenting with mild to moderate RDS requiring noninvasive respiratory support. Criteria for starting noninvasive respiratory support were a Silverman score of 5 or higher or a fraction of inspired oxygen higher than 0.3 for a target saturation of peripheral oxygen of 88% to 93%. Infants were ineligible if they had major congenital anomalies or severe RDS requiring early intubation. Infants were enrolled between January 5, 2012, and June 28, 2014. Interventions Randomization to either HHHFNC at 4 to 6 L/min or nCPAP/BiPAP at 4 to 6 cm H 2 O. Main Outcomes and Measures Need for mechanical ventilation within 72 hours from the beginning of respiratory support. The absolute risk difference in the primary outcome and its 95% confidence interval were calculated to determine noninferiority (noninferiority margin, 10%). An intention-to-treat analysis was performed. Results A total of 316 infants were enrolled in the study: 158 in the HHHFNC group (mean [SD] GA, 33.1 [1.9] weeks; 52.5% female) and 158 in the nCPAP/BiPAP group (mean [SD] GA, 33.0 [2.1] weeks; 47.5% female). The use of HHHFNC was noninferior to nCPAP with regard to the primary outcome: failure occurred in 10.8% vs 9.5% of infants, respectively (95% CI of risk difference, −6.0% to 8.6% [within the noninferiority margin]; P = .71). Significant between-group differences in secondary outcomes were not found between the HHHFNC and nCPAP/BiPAP groups, including duration of respiratory support (median [interquartile range], 4.0 [2.0 to 6.0] vs 4.0 [2.0 to 7.0] days; 95% CI of difference in medians, −1.0 to 0.5; P = .45), need for surfactant (44.3% vs 46.2%; 95% CI of risk difference, −9.8 to 13.5; P = .73), air leaks (1.9% vs 2.5%; 95% CI of risk difference, −3.3 to 4.5; P = .70), and bronchopulmonary dysplasia (4.4% vs 5.1%; 95% CI of risk difference, −3.9 to 7.2; P = .79). Conclusions and Relevance In this study, HHHFNC showed efficacy and safety similar to those of nCPAP/BiPAP when applied as a primary approach to mild to moderate RDS in preterm infants older than 28 weeks’ GA. Trial Registration clinicaltrials.gov Identifier:NCT02570217

Objective To compare the effect of heated, humidified, high-flow nasal cannula (HHHFNC) and nasal continuous positive airways pressure (NCPAP) on lung function and mechanics in preterm infants with respiratory distress syndrome (RDS) at the same level of retropharyngeal pressure (P rp ). Design Randomised crossover trial. Setting Neonatal intensive care unit, Ospedale Maggiore Policlinico, Milan, Italy. Patients 20 preterm infants (gestational age: 31±1 wks) with mild-moderate RDS requiring non-invasive respiratory support within 96 h after birth. Interventions Infants were exposed to a randomised sequence of NCPAP and HHHFNC at different settings (2, 4 and 6 cmH 2 O for NCPAP and 2, 4, 6 L/min for HHHFNC) to enable comparison at the same level of P rp . Main outcome measures Tidal volume by respiratory inductance plethysmography, pleural pressure estimated by oesophageal pressure, and gas exchange were evaluated at each setting and used to compute breathing pattern parameters, lung mechanics and work of breathing (WOB). Results A poor linear regression between flow and P rp was found during HHHFNC (P rp =0.3+0.7*flow; r 2 =0.37). Only in 15 out of 20 infants it was possible to compare HHHFNC and NCPAP at a P rp of 2 and 4 cmH 2 O. No statistically significant differences were found in breathing pattern, gas exchange, lung mechanics and total WOB. Resistive WOB in the upper airways was slightly but significantly higher during HHHFNC (0.65 (0.49;1.09) vs 1.57 (0.85;2.09) cmH 2 O median (IQR)). Conclusions Despite differing mechanisms for generating positive airway pressure, when compared at the same P rp , NCPAP and HHHFNC provide similar effects on all the outcomes explored.

To evaluate the feasibility of forced oscillation technique (FOT) measurements at the bedside and to describe the relationship between positive end-expiration pressure (PEEP) and lung mechanics in different groups of ventilated infants.Twenty-eight infants were studied: 5 controls, 16 newborns with respiratory distress syndrome (RDS) and 7 chronically ventilated newborns that developed bronchopulmonary dysplasia. An incremental/decremental PEEP trial was performed by changing PEEP in 1-min steps of 1 cmH(2)O between 2 and 10 cmH(2)O. Forced oscillations at 5 Hz were superimposed on the ventilator waveform. Pressure and flow, measured at the inlet of the ETT, were used to compute resistance (Rrs) and reactance (Xrs).In controls Rrs and Xrs were on average 41 ± 21 and -22 ± 6 cmH(2)O s/l respectively and were almost unaffected by PEEP. RDS infants presented similar Rrs (48 ± 25 cmH(2)O s/l) and reduced Xrs (-71 ± 19 cmH(2)O s/l) at the beginning of the trial. Two behaviours were observed as PEEP was increased: in extremely low birth weight infants Xrs decreased with PEEP with marked hysteresis; in very low and low birth weight infants Xrs and Rrs were less PEEP dependent. Chronically ventilated infants had very high Rrs and very negative Xrs values at very low PEEPs (121 ± 41 and -95 ± 13 cmH(2)O s/l at PEEP = 2 cmH(2)O) that markedly changed as PEEP exceeded 3-4 cmH(2)O.Rrs and Xrs measurement in preterm newborns is feasible, and data are representative of the lung mechanics and very sensitive to its changes with PEEP, making FOT a promising technique for the non-invasive bedside titration of mechanical ventilation in preterm newborns.

The assessment of respiratory system mechanics in mechanically ventilated newborns would help in tailoring the ventilatory settings. The Forced Oscillations Technique (FOT) is a non-invasive method for the measurement of the mechanical properties of the respiratory system. The aim of the present work was to develop a measurement set-up suitable to apply FOT in mechanically ventilated newborns. Forced oscillations were generated by a servo-controlled linear motor connected to the inspiratory line of the ventilator. Pressure and flow were measured at the inlet of the tracheal tube and used to compute impedance. The set-up was tested on a mechanical analog of the infant's respiratory system showing good agreement with a traditional FOT set-up. The performance of the system was not influenced by the positive pressures generated by the ventilator. Finally, the system was well tolerated by 5 preterm babies and the measurements allowed to track changes in respiratory mechanics associated to changes in the pressure delivered by the ventilator.

Background and aim: Optoelectronic plethysmography (OEP) allows the measurement of lung volume changes through the assessment of chest wall surface motion. It has been shown that it provides an accurate estimation of total and compartmental (rib cage and abdomen) lung volume changes in adults during spontaneous breathing and mechanical ventilation and in spontaneously breathing infants (REF). The aim of the present study is to evaluate the accuracy of OEP in infants during continuous positive airways pressure (CPAP). Methods: 5 infants (GA=27.9±3.6, PNA=3.8±3.6, BW=1077±461) were studied for ∼ 2 minutes at CPAP 0, 4 and 8 cmH2O. Flow was measured at the inlet of a full-face mask by a mesh-type pneumotacograph connected to a differential pressure transducer. Chest wall volume changes were measured by OEP (DVOEP) and compared with lung volume changes obtained by integrating the flow signal (DVPNT). Results: We analysed a total of 602 breaths at 0 cmH2O, 523 at 4 cmH2O, and 150 at 8 cmH2O. The mean difference between DVOEP and DVPNT for all newborns was -0.45±3.92% of Vt at 0 cm H2O, -4.25±9.04% at 4 cmH2O and -8.31±3.87% at 8 cmH2O. Pooling data points from all infants and all pressure levels, Bland-Altman and linear regression analysis showed good agreement between the two measurement techniques (see Fig). Conclusions: OEP can be used to assess lung volume changes and breathing pattern noninvasively in newborns supported by CPAP.