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 Table of Contents  
Year : 2017  |  Volume : 6  |  Issue : 3  |  Page : 135-143

Noninvasive ventilation: Systematic approach and new perspectives for preterm infants

1 Neonatal Intensive Care Unit, Matern-fetal Department, University Hospital “Ospedali Riuniti” of Foggia, Italy
2 Division of Neonatology, Department for the Protection of Women's Health and the Nascent Life, Child and Adolescent, Policlinico A. Gemelli, Rome, Italy

Date of Web Publication11-Jul-2017

Correspondence Address:
Gianfranco Maffei
Unit Therapy Intensive Neonatal, A.O.U “Ospedali Riuniti”, No. 1, Luigi Pinto Street, 71122 Foggia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.JCN_121_16

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Noninvasive ventilation (NIV) refers to the delivery of ventilatory support through nasal prongs/mask. NIV, associated with nasal continuous positive airway pressure, representing the main method to improve the functional residual capacity in the newborn (at term or preterm) avoiding invasive actions such as tracheal intubation.

Keywords: Nasal continuous positive airway pressure, nasal intermittent positive pressure ventilation, noninvasive ventilation, preterm infants

How to cite this article:
Maffei G, Gorgoglione S, Vento G. Noninvasive ventilation: Systematic approach and new perspectives for preterm infants. J Clin Neonatol 2017;6:135-43

How to cite this URL:
Maffei G, Gorgoglione S, Vento G. Noninvasive ventilation: Systematic approach and new perspectives for preterm infants. J Clin Neonatol [serial online] 2017 [cited 2018 Aug 15];6:135-43. Available from: http://www.jcnonweb.com/text.asp?2017/6/3/135/210134

  Introduction Top

The use of noninvasive ventilation (NIV) in neonatal intensive care has been increasing in recent decades as a means to reduce ventilator-induced lung injury(VILI).[1],[2],[3],[4],[5],[6],[7] Nasal continuous positive airway pressure (nCPAP), bilevel (or biphasic) nCPAP, nasal intermittent positive airway pressure (NIPPV), and heated humidified high flow nasal cannula (HHHFNC) are the most common and available modes of NIV. In this article, we present the logic for the use of various modes of NIV, review the existing evidence, and highlight key knowledge gaps that warrant further investigation.

  Physiopathological Background Top

The respiratory system consists of several branched tubes which bring the fresh gas from the environment to the terminal airspace allowing metabolic wastes to flow from the alveoli out into the air.

During inspiration, the diaphragm contracts, creating a sort of mouth-alveoli gradient and producing an inward flow of gases. This movement is opposed by a growing intra-abdominal pressure increase until stopping the same flow of gases.

The energy, stored during the expansion of the lungs, is flowed out at the end of the inspiration, leading the lungs to return to their status quo.

Increased work of breathing (WOB) requires the intervention of the intercostals and abdominal accessory muscles both during inspiration and expiration.

The quantity of pulmonary gas, present at the end of the elastic return, when the inspiration begins, is called functional residual capacity (FRC).

Respiratory muscles in infants are more susceptible to exertion effort than those of the adults.[1]

The neurochemical control of breathing of the newborn is not well known. Central neural control is not completely developed, for this reason, it is more subject to the failure (apnea), as well as the response of chemoreceptors to hypoxemia.[2],[3],[4]

Although tidal volume (Vt) and volume per minute (Vt × respiratory rate [RR]) change with growth, the relation between anatomic dead space and tidal volume (VD/Vt) remains almost constant (approximately 0.3) for a lifetime and is called the physiological dead space.[5] Lung volume influences the lung compliance, meaning that the smaller lung volumes, the smaller their compliance; nevertheless, the relation between lung compliance and FRC (specific compliance) remains almost constant for a lifetime.

The general aim of the cardiorespiratory system is to supply the necessary oxygen quantity (DO2) to the tissues, to satisfy the oxygen consumption (VO2).

The quantity of oxygen supplied to the tissues (DO2) depends on cardiac output (stroke volume × heart rate) and on the quantity of oxygen in arterial blood (in turn depending on the hemoglobin quantity, on O2 saturation and on the quantity of dissolved oxygen).

There are conditions where the oxygen supply is not able to satisfy the tissue consumption, for example.:

  1. V/Q mismatch
  2. Reduced cardiac output due to ventricular dysfunction
  3. Reduced cardiac output due to anemia
  4. Altered mitochondrial O2 consumption due to sepsis.

Under these preconditions, it is possible to understand how the preterm infants need, at the time of their birth, a ventilation support with the risks that can arise: Problems of cardiovascular system, ventilator-induced lung injury (VILI), edema, and secretions in the airway with increase in airway resistance.

  Noninvasive Ventilation Support Top

Low-flow oxygen therapy

The simplest way to achieve an adequate oxygenation is the increase of fraction of inspired oxygen (FiO2). Since oxygen is recognized drug, it can cause side effects such as retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD)[6],[7] and for these reasons, its concentration, saturation, and tension in the arterial blood have to be frequently checked, avoiding hyperoxia, and hypoxia and the lactic acid production resulting from an increased anaerobic metabolism.[8]

New approaches about the controlled oxygen delivery, depending on values deriving from oximetry (CLiO by AVEA ®), seem to be promising, aimed at avoiding lung oxidative stress. The employment of helium as a means of administering oxygen (Heliox) is also rather recent [5],[9],[10] and it has now been demonstrated that helium plays a key role in the first phases of acute lung injury inasmuch it reduces the resistive WOB and can attenuate lung inflammatory response.

Continuous positive airway pressure

Although it was introduced 44 years ago, its specific effects on lungs have not been completely understood because such effects change in relation to clinical situations and to different type of nasal continuous positive airway pressure (NCPAP): continuous or variable flow.

Continuous positive airway pressure (CPAP) increases lung volume (such as FRC) through an increased average airway pressure which, if stimulated in a particular way, can influence also the average intrathoracic pressure causing cardiac complications.

Indeed, not only invasive ventilation but also noninvasive ventilation (NIV), to a smaller extent, can have consequences on:

  1. Right ventricle: The increase of average intrathoracic pressure increases the left atrial pressure which leads to a decrease of ventricular preload. With regard to afterload, it functions in a different manner: At low lung volumes, afterload expands collapsed units, dilating extra-alveolar vessels, and reducing pulmonary vascular resistance (PVR), consequently ventricular afterload decreases

    On the contrary, at high lung volume, the excessive lung expansion compresses alveolar capillaries with an increase of PVR and of right ventricular preload. Therefore, PVR varies in relation to lung volumes [Figure 1]. PVR variation is evident in particular during invasive ventilation

  2. Left ventricle: During invasive ventilation, the increase in intrathoracic pressure, facilitates venous return to the left atrium, compressing lung vessels, and increasing the ventricular preload. This approach is no longer followed inasmuch intrathoracic pressures are very high with a risk of acute lung injury (VILI). The increase of average intrathoracic pressure decreases ventricular afterload with a potential improvement in the global left ventricular function

    During spontaneous breathing the intrathoracic pressure is negative (−30 mmHg), so the left ventricle needs to reach a transmural pressure of 130 mmHg to get a systemic systolic pressure of 100 mmHg. On the contrary, when the patient is subject to ventilation, the average intrathoracic pressure is positive (+ 30 mmHg), and the left ventricle will have to reach a pressure of only 70 mmHg to reach the same systemic systolic pressure of 100 mmHg [Figure 2].
Figure 1: Pulmonary vascular resistance and lung volumes[11]

Click here to view
Figure 2: Heart-lungs interaction: intrathoracic pressure effects on the left ventricular afterload[11]

Click here to view

As FRC increases with the application of NCPAP, gas exchange improves, PaO2 increases, and PCO2 decreases. When NCPAP pressure is too high, lung over-expands, PaO2 remains high, and PCO2 begins to increase. At the same time, current lung volume begins to decrease and consequently anatomic dead space (VD/Vt) increases with a risk of air leaks.[12]

Cardiac consequences caused by high NCPAP levels have been amply discussed; we can mention the possible impact on lung perfusion and the increase in ventilation/perfusion mismatch resulting in a PaO2 decrease.[13],[14] PVR can be increased or decreased according to the applied CPAP level and to lung compliance in that moment (greater compliance = greater high blood pressure effects).

Other possible effects of CPAP are:

  1. The regulation of breathing pattern in the preterm infant through the stabilization of the thoracic wall [15]
  2. To decrease obstructive apnea [16]
  3. To increase inspiratory and expiratory time
  4. To increase the release of surfactant in respiratory distress syndrome (RDS)
  5. To increase intracranial pressure (if lung compliance is normal) increasing the risk of intracranial hemorrhages [8]
  6. To decrease glomerular filtration and diuresis [17]
  7. To increase aldosterone and antidiuretic hormone.[18]

At this point, we might ask: can CPAP be used to treat all premature babies, and especially, those born at <28 weeks (i.e., extremely low gestational age [GA] neonates) in the delivery room?

The main four CPAP trials (COIN, SUPPORT, CURPAP, and VON DRM) have shown that in the delivery room the NCPAP is just as effective in the treatment of premature infants born at <29 weeks as a routine intubation although its failure is quite common, especially in premature babies born at <26 weeks.[19],[20],[21],[22]

There is an on-going multicenter randomized clinical trial aimed to compare the application of a recruitment maneuver using the high-frequency oscillatory ventilation (HFOV) modality just before the surfactant administration followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate: IN-REC-SUR-E) with INtubate, SURfactant, Extubate (INSURE) alone in spontaneously breathing extremely low GA infants requiring NCPAP as initial respiratory support and reaching predefined CPAP failure criteria.[23] Even though the main outcome of this study is to demonstrate a major surfactant efficacy in a previously well-recruited lung, local experience with CPAP/NIV in the smallest patients, and type of CPAP applied seem to play an important role on outcome because it is well known that failure to CPAP therapy is multifactorial. Based on the results of a recent survey on neonatal respiratory support strategies in the Italian neonatal Intensive Care Units (NICUs),[24] NCPAP is the most commonly used noninvasive mode of respiratory support, both in the acute and postextubation phase of RDS and all the 37 NICUs involved in the present study have a great experience with noninvasive respiratory support. Moreover, both the management with CPAP in the delivery room and the criteria of CPAP failure before surfactant administration and before starting mechanical ventilation (MV) in the NICU are clearly defined in this study, offering in this way the opportunity to evaluate the different efficacy (if any) of all the NIV strategies (CPAP, nasal intermittent positive pressure ventilation [NIPPV], nasal HFOV [nHFOV]) adopted in the several centers.

Recently, we noted a renovated interest in bubble CPAP because several experimental studies speculate that this method can mimic high-frequency ventilation by tracheal intubation [25] even if tidal volume (Vt) and ventilation per minute are lower than HFOV used with noninvasive support through the nose.

However, bubble CPAP can increase PaO2 and decrease WOB.[26]

Clinical indications

  1. Apnea of prematurity: Apnea frequency is reduced thanks to rib cage stabilization, oxygenation improvement, and supraglottic resistances decrease.[27] It prevents obstructive apnea attack thanks to its effect on airway patency [28]
  2. Ventilatory assistance after extubation: This increases extubation success limiting the effects of apnea and postextubation atelectasis. NCPAP is more efficacious if used at 5 cm H2O and if extubation is performed within the first 14 days of life [29],[30]
  3. RDS: During the last decade, several randomized and controlled trials have been conducted [21],[22],[23],[31] to define the role of NCPAP as first form of ventilator assistance of RDS in preterm infants. The outcomes of these studies demonstrate that the early NCPAP, already in the delivery room, offers to neonates of GA <30 weeks significant benefits without specific side effects in the short-term. Moreover, it prevents or reduces the need of MV and the incidence of a combined outcome of death or BPD at 36 weeks of correct GA [32] and does not increase the risk of long-term negative outcomes
  4. Transient tachypnea of the newborn, tracheobronchomalacia, chronic lung disease, and bronchiolitis.[33]

Advised parameters

Starting with CPAP at about 6 cm H2O, thereafter, the CPAP level has to be adapted according to clinical condition, oxygenation, and perfusion.

Flow: 8–12 L/min; an high flow leads a greater stability of blood pressure during respiratory cycle and a decrease in WOB. FiO2: To maintain PaO2 values between 50 and 60 mmHg and O2 saturation levels between 90% and 95%.[30]

Nasal continuous positive airway pressure failure criteria

When there are these criteria, it is recommended to administer surfactant and/or MV:[30]

  • Increase in oxygen needs (FiO2 >0.35–0.40), especially when there are signs of increased WOB (worsening tachypnea)
  • Respiratory acidosis (PCO2 >65 mmHg and pH <7.20 of arterial blood or arterialized capillary blood)
  • Apnea crisis needing manual ventilation.

Side effects

Nasal lesions and increased Gram-negative colonization.[34]

Increased incidence of early nosocomial bacterial sepsis in neonates of GA <28 weeks or birth weight (BW) <1000 g treated with this procedure.[35]

Effects related to high pressures:

  • Cardiovascular effects: Decreased cardiac venous return and decreased cardiac output, hypotension, increase in intracranial venous pressure, decrease in cerebral, and renal blood flow and decrease in glomerular filtration [36],[37]
  • Gastrointestinal effects: Decrease in blood flow at gastroenteric level, abdominal distension (CPAP Belly syndrome) lead to gastrointestinal perforation [38]
  • Pulmonary effects: A higher incidence of pneumothorax in neonates treated with NCPAP approaching 8 cm H2O was reported.[39],[40]

Noninvasive mechanical ventilation

Noninvasive mechanical ventilation (NIMV) is the alternative method to maintain FRC through the increase average pressure in the airway compared to the simple NCPAP.

At the beginning, this method has been emphasized for its ability to avoid extubation failure compared with the simple NCPAP.[41]

Later, this method created interest inasmuch it can avoid intubation and MV in preterm infants with moderate-severe respiratory failure [42] and to exercise better control on apnea in preterm infants compared to simple NCPAP.[43]

Side effects such as pneumothorax and gastric distension in NIMV have not been observed.[44],[45],[46]

Several studies [47],[48] demonstrated that NIMV is effective in initial RDS treatment and can decrease BPD incidence compared with NCPAP.

Compared with NCPAP, NIMV improves CO2 washout of the upper airway by increasing its average pressure and increases the respiratory drive in preterm infants.

It has been shown that NIMV does not increase tidal volume and decreases the WOB compared with nonsynchronized form but to decrease considerably WOB,[49] in spite of objective difficulties to synchronize nasal ventilation due to open ventilation system and very low pressure in preterm infants: from the initial Graseby capsule to the esophageal feeding tube during neurally adjusted ventilatory assist (NAVA) or to the flow sensor by GINEVRI ®.

At present, the better possibility of synchronization is offered by NAVA that is ventilation assistance through the Maquet “Servo-i”® which is very precise and works with different modalities of noninvasive assistance; on the other hand, it has the disadvantage to be very expensive and to be a “partially noninvasive system.”

We should consider also that, using esophageal feeding tube in preterm infants, the combination “diaphragm contraction/glottis opening” is out of phase in 60% of cases because the glottis opening does not follow immediately diaphragm contraction and for this reason, ventilation flow could find the glottis closed although diaphragm starts to move downward.

Clinical indications

  1. Apnea of prematurity: NIPPV increases positive effects on preterm infants suffering from frequent or severe apnea. Moreover, certain authors consider synchronized NIPPV (SNIPPV) more effective than NCPAP in the treatment of apnea of prematurity [41],[50]
  2. Ventilatory assistance after extubation: SNIPPV increases extubation success compared to NCPAP (RR: 0.21 [0.1, 0.45], number needed to treat = 3), without the evidence of gastrointestinal side effects. Extubation is associated with a reduction of apnea episodes, BPD, and ROP stage 2.[45],[50] Similar advantages have been observed with the use of NIPPV.[51] A NIPPV trial can be considered in neonates who did not tolerate NCPAP after extubation [30]
  3. RDS of prematurity: Mild/moderate RDS: NIPPV proves to be more effective than NCPAP to reduce the need of MV when it is used as first respiratory support for RDS in preterm infants.[52] Nevertheless, a recent meta-analysis demonstrated that this strategy does not decrease BPD incidence;[48] Moderate/severe RDS in combination with exogenous surfactant: NIPPV/INSURE compared to with NCPAP/INSURE proved to be more effective in decreasing MV need in neonates of GA = 28–34 weeks.[53],[54]

Advised parameters

Initial peak inspiratory pressure (PIP) at 10 cm H2O above CPAP or 2 cm H2O above PIP which was earlier applied during MV. Adjust PIP in the course of ventilation depending on chest expansion and desired PCO2 values until a maximum of 22 cm H2O.

Positive end-expiratory pressure (PEEP) of 4–6 cm H2O or identical to PEEP during MV with Inspiratory Time (Ti) = 0.30-0.45 s. In synchronized mode, it is more advisable to reach Ti <0.4 s. In the aim to avoid an asynchrony phase,[55] on the contrary in nonsynchronized mode, it is better to choose long Ti (0.5–0.6 s).

The respiratory rate (RR) should be set at 10-40 breaths/min.

Flow 8–12 L/min (a high flow guarantees a rapid pressure increase in the first airway with the crushing of soft palate toward the tongue and the seal of the oral cavity).

Adjust FiO2 necessary to maintain SpO2 between 90% and 94%.[56]

Side effects

Lesions of nasal mucosa, gastric distension, and pneumothorax.

Nasal bilevel positive airway pressure

This technique consists of two levels of positive pressure in the airway, so the neonate can breathe spontaneously, and it has been proposed as an alternative method to increase mean airway pressure without reaching peak values typical of positive pressure ventilation [Figure 3].[57],[58]
Figure 3: Waveform pressure/time during bilevel positive airway pressure. TIPAP - Time inspiratory positive airway pressure; IPAP - Inspiratory positive airway pressure; EPAP - Expiratory positive airway pressure[24]

Click here to view

The action on respiratory mechanics depends on the following factors:

  1. ΔP produced by the ventilator creates a switch from FRC level to another one, then generating volume
  2. Derived changes in FRC improves alveolar ventilation
  3. Vt depends on both ΔP and lung compliance values of the patient based on the formula ([Phigh − Pmin] × C)
  4. Vmin depends on spontaneous breathing, ΔP, and established rate (Σ of the different components).[59]

There are three kinds of interfaces applicable during NIV and CPAP between device and newborn:

  1. Short binasal prongs
  2. Hypopharyngeal tube
  3. Nasal mask.

Several authors [60],[61] agreed that short binasal prongs are more effective than a hypopharyngeal tube to decrease reintubation rate and to treat infants during the early phase of RDS. Our experience allows us to affirm that short binasal prongs represent the better interface for both the comfort of the patient (they adapt correctly and with minimal injury) and the success of the technique (lower flow resistance).

Clinical indications

  1. Assistance after extubation in neonates of GA <30 weeks, however, a recent clinical trial demonstrated that nasal bilevel positive airway pressure (NBiPAP) use after extubation does not determine significant advantages compared with NCPAP in neonates of BW <1250 g [62]
  2. First choice of ventilatory assistance in preterm infants suffering from mild/moderate RDS. NBiPAP, compared with NCPAP, decreased the duration of ventilatory support, O2 dependence, and hospital stay [57]
  3. Ventilatory assistance in preterm infants suffering from moderate/severe RDS associated with exogenous surfactant. The NBiPAP/INSURE approach, compared with SNIPPV/INSURE approach, does not determine significant advantages [58]
  4. Rescue strategy in newborns who do not tolerate INSURE before MV.[59]

Advised parameters

  1. Level of low airway pressure: 4–6 cm H2O
  2. Level of high airway pressure: 8–10 cm H2O
  3. Time of high airway pressure (Ti): 0.7–1”
  4. Rate 20–40/min
  5. FiO2 needed to address SpO2 90%–94%; if FiO2 >0.40 and RDS is worsening, it is necessary to give surfactant and/or use MV.

Side effects

They are the same as for NCPAP.

Oxygen therapy with heated humidified high flow through nasal cannula

Oxygen therapy is a treatment which provides gas mixture through a nasal cannula whose flow is higher than the normal inspiratory flow rate in the newborn (>2 L/min). It is a common opinion that with flow between 2 and 8 L/min, in relation to the weight of the newborn, his mouth opening, etc., positive pressure in airway can vary from 2 to 6 cm H2O. The main mechanisms of action are:

  1. Washout of nasopharyngeal dead space
  2. Reduction of respiratory resistance
  3. Continuous distending pressure increase
  4. Respiratory gas conditioning.

It is a comfortable system for the newborn and easily manageable for the nursing staff; the only side effects can be nasal injuries and risk of naris occlusion.

Clinical indications

Clinical indications include apnea of prematurity, postextubation care, and treatment of mild/moderate RDS as first choice action.[63],[64],[65]

Promising outcomes have been achieved in the treatment of bronchiolitis.

Advised parameters

  1. Initial flow rate: 3–6 L/min in neonates of weight <1 kg; on the contrary in neonates of weight >1 kg, it is possible to increase the flow rate until 8 L/min
  2. Temperature: 34°C–35°C for flows <5 L/min and 36°C–37°C for flows >5 L/min
  3. Diameter of nasal cannula: should not exceed 50%–60% of the naris diameter
  4. Alternative modalities of ventilatory assistance have to be considered if it is necessary to deliver FiO2 >0.5 to neonates or if it is possible to observe signs of hypercapnia, acidosis or apnea.

Side effects

Lesions of skin and nasal mucosa caused by the use of high-flow nasal cannula are less frequent than NCPAP.[66] A number of cases of Pneumothorax (PNX) due to the use High Flow Nasal Cannula (HFNC) have been reported in literature.[67]

Nasal pressure support ventilation and nasal high-frequency oscillatory ventilation

Few works on the use of nasal pressure support ventilation in neonates have been published; they are cited for completeness.[68],[69],[70],[71] CPAP stabilizes the surfactant-deficient alveoli and improves oxygenation, but does not necessarily improve alveolar ventilation or PCO2 elimination. The use of nHFOV in very low BW infants with respiratory failure, using nasopharyngeal tube has been demonstrated to be able in lowering PCO2 levels.[70] No randomized controlled trials have directly evaluated the efficacy of nHFOV versus NCPAP with the use of nasal prongs in extremely low BW. A multicenter, randomized controlled trial is under way, and its findings seem promising.[72] Nevertheless, further studies are needed to demonstrate the real effectiveness and certainty of these strategies in neonates with respiratory insufficiency.

Weaning from noninvasive ventilation

Parameters to define stability, as well as the better weaning strategy, have still to be established before attempting NIV weaning.

Inappropriate weaning can cause an increase in WOB, that is the deterioration of respiratory function which extends the duration of ventilation support, increases the oxygen needs and prolongs the duration of convalescence. Moreover, it results anguishing for the family and depressing for intensivist doctors.

Many factors influence the weaning process during NCPAP, such as BW, GA and days of life, the presence of chorioamnionitis, intubation in the delivery room, steroid prophylaxis, surfactant therapy, patent ductus arteriosus, anemia, sepsis, intraventricular hemorrhage, etc. Pickerd,[73] using inductive plethysmography, demonstrated that serial measurements of Vt can help the clinicians during NCPAP weaning. There are few NICUs which begin a weaning process from CPAP taking into account BW or corrected GA. Most of them stop NCPAP when FiO2 reaches 21% in an arbitrary way. Moreover, parameters of CPAP weaning failure are not well standardized. The only reference, whose values parameters are shown in [Table 1] and [Table 2], belongs to Todd (2012).[74]
Table 1: Stability criteria (presence of all 8 criteria >12 h) to start continuous positive airway pressure

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Table 2: Criteria for failure trial without continuous positive airway pressure (at least 2 of the following)

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Strategies to stop NIV are even more undefined, most literature referring to weaning from the CPAP. The available approaches are listed below:

  1. Total interruption of NCPAP independently of level of airway pressure
  2. Reduction of NCPAP to reach a predefined pressure so NCPAP can be interrupted
  3. Daily interruption of NCPAP for hours which increases gradually
  4. Stop NCPAP and start low flow oxygen therapy
  5. Combination of strategies here above with other cointerventions (e.g., methylxanthines, especially if administered during the first 3 days of life).

Weaning from NIPPV, synchronized NIPPV, or bilevel positive airway pressure is usually effected through a passage to NCPAP as soon as clinical conditions improve. In our experience, in NIPPV, we prefer to decrease gradually PIP rather than rate to avoid diaphragmatic strain and can train respiratory muscles.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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