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Volume-targeted ventilation in newborn infants

Mechanical ventilation via an endotracheal tube remains a ‘standard of care’ for infants with severe respiratory failure. Ventilation saves lives but can also cause lung injury and evidence suggests that excessive or inadequate tidal volume delivery causes more lung injury (volutrauma) than unregulated inspiratory pressure delivery (barotrauma). Volume-targeted ventilation (VTV) has been shown to produce better short-term outcomes than pressure- targeted ventilation and is used to aim to minimise lung injury. However, data are limited with regards to medium- and long-term outcomes and there are no published data comparing efficacy and safety of different modes of VTV.

Helen Chitty1 hile non-invasive methods of surfactant deficiency or inactivation, and 4 MBBS, MRCPCH, PGCertClinEd Wrespiratory support are now structural immaturity of the lungs. Clinical Research Fellow in Neonatology commonly used,1 mechanical ventilation Surfactant, produced by type II via an endotracheal tube remains the ‘gold pneumocytes, lines the alveoli and reduces 1,2 Sunil Sinha standard’ for treatment of infants with surface tension while maintaining the MD, PhD, FRCP, FRCPCH severe respiratory failure.2 Different types functional residual capacity (FRC) of the Professor of Paediatrics and Neonatal of volume-targeted ventilation (VTV), lungs. Surfactant insufficiency leads to loss Medicine aimed at monitoring and delivering desired of FRC, collapse of the alveoli and [email protected] tidal volumes to the infant, are now being atelectasis. The infant has to make a greater 3 1Department of Neonatology, James Cook used widely. This review aims to discuss inspiratory effort to open the alveoli on University Hospital, Middlesbrough the reasons for recommending the use of inspiration, causing fatigue and further 2The University of Durham VTV and to describe commonly used atelectasis. This leads to hypoventilation Keywords modes of VTV. and hypoperfusion followed by hypoxaemia, hypercarbia and acidosis. volume-targeted ventilation; ventilation- Respiratory distress syndrome With the ensuing endothelial and epithelial induced lung injury; newborn infant; Respiratory distress syndrome (RDS) is a damage and leakage of plasma proteins respiratory distress syndrome; common cause of respiratory failure in there is further requirement for bronchopulmonary dysplasia preterm infants, although some term ventilation,4 thus becoming a part of the Key points infants are also affected. It occurs due to a pulmonary injury sequence (FIGURE 1).5 combination of factors including The diagnosis of RDS is made by a Chitty H., Sinha S. Volume-targeted ventilation in newborn infants. Infant Qualities of 2015; 11(1): 8-12. Initiation/ premature lungs 1. Volume-targeted ventilation (VTV) is a chronic which increase VILI ventilation susceptibility to VILI newer modality of ventilation designed • Surfactant deficiency to minimise ventilator-induced lung • Premature anti-oxidant injury. Inadequate lung system function • Premature lung structure 2. Systematic reviews of the evidence to • Compliant chest wall Inhibition of CLD date have shown that VTV is associated Viable premature birth alveolarisation

with improved short-term outcomes in } 23 37 neonates. Intrauterine cytokine exposure Lung development phases 3. There are several different modes of Glucocorticoid treatment Embryonic Glandular Canalicular Saccular Alveolar Microvascular VTV in clinical use but no evidence maturation (antenatal and postnatal) regarding comparison of modes. Septation and alveolarisation Insufficient nutrition 4. Neonatal staff must have a thorough process

Developmental Lung and systemic infections working knowledge of the mode used 5-7 16-17 24-26 36-38 1-2 2-3 weeks weeks weeks weeks years years Oxygen toxicity in their unit in order to ensure that VTV is delivered in an optimal and safe FIGURE 1 Mechanisms of ventilator-induced lung injury and chronic lung disease in preterm 5 manner. infants. Reprinted from Attar and Donn with permission from Elsevier. Key: VILI = ventilator- induced lung injury, CLD = chronic lung disease.

8 VOLUME 11 ISSUE 1 2015 infant CLINICAL PRACTICE composite of clinical assessment, blood gas Cause Effects analysis and radiographic changes. RDS Barotrauma Excessive inspiratory pressure Alveolar damage, pulmonary typically starts in the first few hours of life delivery oedema, pulmonary air leak and usually peaks in severity within 48 Volutrauma Excessive inspiratory tidal volume Disruption of alveolar cells and hours. Many infants recover from RDS delivery epithelial and endothelial layers without any initial clinical sequelae. However, there is evidence to show that Atelectrauma Repeated recruitment and ‘Shearing’ effect on alveoli during derecruitment of lung units due to reopening of lung units lung injury can occur even within the first inadequate PEEP and positive few ventilated breaths.6 Infants ventilated Over-expansion of some lung units pressure ventilation due to inability to deliver the for several days or weeks develop lung inspiratory volume to other closed injury due to one or a combination of lung units factors including prolonged ventilation, Biotrauma Inflammation or infection Ongoing lung inflammation oxygen toxicity and infection, on a background of structural lung immaturity. Rheotrauma Inappropriate airway flow Excessive flow: turbulence, excessive Histologically, there are fewer and larger PEEP, lung over-inflation alveoli with reduced or absent septation. Insufficient flow: air hunger, This is known as chronic lung disease increased work of breathing (CLD) or bronchopulmonary dysplasia TABLE 1 The different types of lung injury.2,5 Key: PEEP = positive end expiratory pressure. (BPD) and is defined clinically by most as oxygen dependency and/or the need for to surfactant5 in animal models. eously. Although the clinician may target a artificial respiratory support at 36 weeks’ A study published in 1989 compared particular tidal volume using a ventilator, postconceptional age.7,8 The different varying degrees of positive inspiratory this volume will not be delivered to closed mechanisms of lung injury are pressure (PIP) – 15, 30 and 45cmH2O – on lung units and therefore may lead to the summarised in TABLE 1. three different groups of rabbit models.11 over-expansion of the remaining open lung In the first group, the lungs were removed units (causing volutrauma).5 Ventilator-induced lung injury and ventilated in isolation (the lack of a Biotrauma Conventional ventilation can be divided chest wall meant that lung expansion had 9 Exposure to inflammatory mediators as a into two modalities: no external restriction). In the second result of in utero or postnatal infection, 1) pressure-targeted ventilation group, rabbits were ventilated with intact oxidative stress or mechanical ventilation 2) volume-targeted ventilation. chest walls that expanded normally during can lead to ongoing lung inflammation Ventilation can lead to complications if it is inspiration, allowing for normal lung that may contribute to BPD.2 not optimised or is prolonged. One such inflation. In the third group, rabbits were complication is ventilator-induced lung placed in thoraco-abdominal casts in order Rheotrauma injury (VILI) which is multifactorial in to prevent expansion of the chest wall It is not only the amount of tidal volume origin (FIGURE 1).5 during ventilation. The casts prevented an but also the way in which the volume flows increase in tidal volumes during lung to the lungs that also contributes to lung Barotrauma inflation despite the use of increasing PIPs. injury. Excessive gas flow causes lung over- Barotrauma was originally thought to be The researchers found that the isolated inflation and unintentional positive end the main cause of VILI.10 High-pressure lungs showed the greatest evidence of VILI expiratory pressure (PEEP), whereas ventilation can cause pulmonary oedema even at the lowest PIP level (15cmH2O). insufficient gas flow leads to air hunger and structural damage in animal models.10 The lungs of rabbits with intact chests and increased work of breathing.9 However, subsequent work has shown that showed significant evidence of damage It is likely that all four mechanisms of the majority of VILI is likely to be caused when ventilated at 30 and 45cmH O. 2 injury contribute to VILI in a preterm by excessive tidal volumes.11 However, the lungs of rabbits with tidal infant. However, volutrauma and volumes restricted by the thoraco- Volutrauma atelectrauma due to over- and under- abdominal casts showed no evidence of Volutrauma is the result of the delivery of expansion of the alveoli seem to contribute lung injury, even at the highest PIP levels. excessive inspiratory volume to the alveoli. to most of the damage. These results support the argument that This may be due to a shearing effect which it is the alveolar ‘stretch’ caused by causes disruption of the alveolar type I Evidence to support the use of VTV excessive tidal volume delivery rather than cells (which line the alveoli and are Does the importance of maintaining tidal damage due to excessive pressure delivery responsible for gas exchange) and the volume delivery within a specific range in that leads to VILI in newborn infants.7 epithelial and endothelial layers.11 The order to prevent VILI translate into compliant chest wall of preterm infants Atelectrauma improved clinical outcomes? A recent increases the risk of VILI as it allows the In contrast to volutrauma, atelectrauma is Cochrane review13 and meta-analysis14 by lungs to expand more for any given caused by under-expansion of alveoli Wheeler and colleagues, comparing VTV pressure. Excessive tidal volumes are leading to atelectasis.5 Infants with RDS with pressure-targeted ventilation, associated with low lung compliance, have unequal areas of lung expansion and combined the results from 12 and nine reduced ventilator efficacy and high collapse meaning that both volutrauma trials respectively. VTV was associated with protein leak,12 as well as reduced response and atelectrauma can occur simultan- a reduction in the combined outcomes of infant VOLUME 11 ISSUE 1 2015 9 CLINICAL PRACTICE death and CLD (number needed to treat = Ventilatory mode Mechanism of action 8) as well as reductions in the rates of pneumothoraces, duration of ventilation, Volume-controlled • Inspiratory volume set by clinician hypocarbia, and the combined outcomes of ventilation (VCV) • Flow rate set by clinician to provide continuous inspiratory flow periventricular leukomalacia (PVL) or • PIP and maximum inspiratory volume increase during, and peak grade III-IV intraventricular haemorrhage at the end of, inspiration (IVH). Another more recent meta-analysis • Inspiratory time depends on the set inspiratory volume reviewed 18 studies and reported similar and flow findings but found no difference in the • PIP varies automatically according to lung compliance incidence of death.15 These results support the use of VTV in infants in reducing Volume guarantee (VG) • Inspiratory volume, inspiratory time and maximum PIP limit set short- and medium-term complications ventilation by clinician associated with mechanical ventilation. • Inspiratory flow rate is variable and determined by the ventilator Different modes of VTV • Peak inspiratory flow occurs early in inspiration, then Volume-targeted modes of ventilation decelerates throughout the remainder of inspiration allow the clinician to control the volume of • PIP and maximum inspiratory volume peak early in inspiration gas delivered to the infant. The different • The ventilator adjusts PIP on a breath-by-breath basis to target modes deliver and maintain this volume in the set volume different ways but all share the common • The ventilator uses the VTe of the previous breath as a reference goal of aiming to deliver either a specific for adjustment of PIP volume, or a volume within a specific • The working PIP will not exceed the maximum PIP limit range, to the infant. The differences in tidal volume delivery, flow and inspiratory Pressure-regulated • Inspiratory volume and maximum PIP limit set by clinician volume controlled pressure are summarised in TABLE 2. • Inspiratory flow rate is variable and determined by the (PRVC) ventilation ventilator Volume-controlled ventilation • Peak inspiratory flow occurs early in inspiration, then When using volume-controlled ventilation decelerates throughout the remainder of inspiration (VCV) the primary aim is to keep the • Initial PIP is delivered at 10cmH2O above the set PEEP – this is expired tidal volume within a desired used as a reference to calculate the pressure needed to achieve range. The expired tidal volume is the set inspiratory volume during further breaths measured using a flow sensor situated as • Next three breaths delivered using a PIP of 75% of the close to the endotracheal tube (ETT) as calculated PIP possible. The flow sensor monitors airway • Further adjustments in PIP are made in 3cmH2O increments or pressures, tidal volumes and gas flows decrements passing between the infant and the • The working PIP will not exceed a threshold higher than ventilator.2 5cmH O below the maximum PIP limit The clinician sets a volume of gas that 2 the ventilator delivers to the infant when- Volume-assured • Relies on the infant breathing spontaneously in order to ever the infant takes a breath (or according pressure support (VAPS) ‘trigger’ the ventilator to deliver breaths to the pre-set mandatory respiratory rate if ventilation • Inspiratory volume set by the clinician the infant is apnoeic). The ventilator aims • Inspiratory flow accelerates and decelerates according to to deliver this volume irrespective of the patient effort and ventilator variables (similar to PSV) lung compliance or PIP required to deliver • When flow decelerates to a minimum value the delivered it. The gas is delivered at a constant flow volume is measured 2 rate that is also set by the clinician. • If the delivered volume exceeds the set inspiratory volume the However, not all of the set volume of gas breath is terminated and cycled into expiration (similar to PSV) that leaves the ventilator ultimately reaches • If the set inspiratory volume is not achieved flow is continued the infant’s lungs. Much of it remains and inspiratory time increased until the volume is achieved within the circuit between the ventilator (similar to VCV) and the infant and is referred to as • Working pressure may also be increased by the ventilator in 2 ‘compressible volume loss’. Some is also order to achieve the set volume lost due to the leak around the uncuffed ETT. The compressible volume loss TABLE 2 Differences between different modes of VTV.2 Key: PIP = peak inspiratory pressure, VTe increases as lung compliance decreases (the = expired tidal volume. PSV = pressure support ventilation, VCV = volume-controlled ventilation. stiffer the lungs, the smaller the volume of gas that reaches them). The clinician within a desired range and achieves within a desired range it is often not intermittently adjusts the set volume acceptable gas exchange.2 practically possible to achieve specific tidal manually on the ventilator to aim to In this mode, although the clinician can volumes with each breath. Therefore the deliver a volume to the infant’s lungs that is aim to keep the expired tidal volume volume of gas that actually reaches the

10 VOLUME 11 ISSUE 1 2015 infant CLINICAL PRACTICE infant is dependent both on lung before the desired tidal volume is achieved. pressure-limited ventilation but this was compliance, which can vary rapidly and A maximum pressure limit can be selected derived from a post hoc analysis and there frequently, and the clinician who may not above which the ventilator will not was no difference between the two modes keep up with the rapid changes in lung generate peak pressures. This is useful in in the study population as a whole. compliance. The ventilator will generate instances such as partial ETT obstruction Volume-assured pressure support whatever PIP is necessary to deliver the when an increasing peak pressure is related Pressure support ventilation (PSV) is a pre-set tidal volume (although this can be to a mechanical problem rather than poor flow-cycled, variable flow mode. Being a limited by the clinician for safety reasons) lung compliance. However, the clinician pressure type of ventilation, it does not and there is therefore an increase or needs to ensure that the limit is set high guarantee the amount of volume delivered reduction in the generated PIP as lung enough above the working PIP so that the to the infant. However VAPS is a hybrid compliance deteriorates or improves ventilator can deliver the desired tidal mode that combines aspects of PSV with respectively. However regulation of PIP is volume, particularly if lung compliance is VCV to aim to control volume delivery. not controlled by the ventilator as in the worsening. Flow accelerates rapidly at the start of case with the other volume-targeted VG is a commonly used mode of VTV 2 inspiration (acceleration is affected by the modes. but it still requires further scientific extent of the infant’s spontaneous VCV was associated with improved evaluation in clinical trials powered to inspiratory effort) and cycles into short- to medium-term clinical outcomes detect differences in long-term outcomes.21 expiration if the desired volume is reached when compared to pressure-targeted Its use has been associated with 16-19 or exceeded (similar to PSV). If it is not ventilation in previous clinical trials improvements in short-term clinical achieved, the inspiratory flow continues but has not been compared to other modes outcomes, such as (and the inspiratory time is extended) until of VTV. ■ less variability (better control) of tidal the desired volume is reached (similar to volumes22-25 Hybrid modes VCV). PIP is augmented if the volume is ■ fewer episodes of hypocarbia24-26 These modes are primarily pressure modes well below the target value.2 ■ shorter duration of ventilation27 of ventilation but aim to achieve the same There are no published neonatal trials ■ a reduction in markers of lung goal as VCV by targeting a specific volume comparing VAPS to another mode of inflammation.28,29 of gas. This is facilitated by the use of ventilation. microprocessor technology and a However, methodological limitations of servocontrolled mechanism to up- or some studies restrict the application of Differing patterns of gas flow their results to clinical practice. None of down-regulate tidal volumes. The The patterns of gas flow in VCV and the studies compare VG to a different microprocessor is contained within a flow hybrid modes of VTV are different and mode of VTV. sensor that monitors tidal volumes with they may have different effects on the each breath. It then feeds back to the Pressure-regulated volume control underlying lung mechanics. In VCV, the ventilator to enable adjustments of ventilation clinician selects a specific flow rate at pressure or flow to be made with the next PRVC is similar to VG in that it uses which the volume should be delivered so breath in order to achieve the desired tidal variable gas flow and a servocontrolled that gas flow is constant throughout 2 volume. These modes include volume mechanism to target tidal volumes. The inspiration and therefore the maximal tidal guarantee (VG), pressure-regulated volume clinician sets the desired tidal volume and a volume and PIP are reached at the end of control (PRVC), volume-assured pressure maximum pressure limit. The ventilator inspiration. In VG and PRVC the flow is support (VAPS), and newer emerging delivers the first breath using a PIP that is variable and maximal at the beginning of modes which require further evaluation. 10cmH2O above the PEEP and measures inspiration meaning that PIP and tidal Volume guarantee ventilation the actual tidal volume that is achieved in volume are achieved earlier in inspiration.2 When using VG the clinician sets the order to calculate the PIP needed to deliver When the designated PIP has been desired tidal volume. The flow sensor the desired tidal volume. It will then deliver achieved the gas flow rate decreases during measures the infant’s expired tidal volume the next three breaths using a PIP that is the remainder of inspiration. VAPS is and the ventilator uses this as a reference to 75% of that calculated. If the desired unique in that it changes the flow pattern adjust the PIP up or down over the next volume is not reached, the PIP is increased breath by breath if the machine detects 21 few breaths to aim to deliver the set tidal by 3cmH2O until it is achieved. Likewise, that the tidal volume is not going to be volume. Adjustments to the PIP are made if an excessive tidal volume is delivered the achieved – it starts in the same way as in in small increments to avoid large PIP is decreased by 3cmH2O until the VG or PRVC unless the preset tidal volume fluctuations in volume delivery. The gas desired volume is reached.2 Unlike VG, in is not achieved at which point flow flow rate is variable and occurs more which the working PIP is adjusted on a continues as it would in VCV. rapidly at the beginning of an inspired breath-by-breath basis, an average of four One area for future research is to breath. This mechanism aims to overcome breaths is used to adjust the PIP during determine whether the variable flow rate the problem of compressible volume loss.2,9 PRVC ventilation. provided by a hybrid mode of VTV or the However this mode is sensitive to ETT There are few neonatal clinical trials constant flow rate provided by VCV is leak – the higher the leak, the less reliable comparing PRVC with other modes. One more advantageous in certain clinical the technology is in accurately measuring study demonstrated a significantly shorter situations, such as in infants with early tidal volumes.20 The PIP is altered in small time to extubation in infants weighing RDS or ventilator-dependent infants with increments so it may take several breaths <1,000g30 when compared with time-cycled evolving BPD. infant VOLUME 11 ISSUE 1 2015 11 CLINICAL PRACTICE

Conclusion Manual ventilation with a few large breaths at birth up of very low birth weight infants from a neonatal compromises the therapeutic effect of subsequent volume versus pressure mechanical ventilation trial. VTV is no longer considered an surfactant replacement in immature lambs. Pediatr Arch Dis Child Fetal Neonatal Ed 2009;94:F360-62. experimental treatment and is now used Res 1997;42:348-55. 19. Hummler H.D., Engelmann A., Pohlandt F., Franz widely in neonatal intensive care units. It 7. Jobe A.H., Bancalari E. NICHD/NHLBI/ORD A.R. Volume-controlled intermittent mandatory is considered to be safe and effective and Workshop Summary: Bronchopulmonary dysplasia. ventilation in preterm infants with hypoxemic has short-term advantages such as Am J Respir Crit Care Med 2001;162:1723-29. episodes. Int Care Med 2006;32:577-84. 8. Korones S.B. Complications. In: Goldsmith J P., 20. Donn S.M., Boon W. Mechanical ventilation of the reduction in the duration of ventilation Karotkin E.H. (eds.) Assisted Ventilation of the neonate: should we target volume or pressure? and its associated complications. Data Neonate. 5th ed. St. Louis, Mo; Elsevier Saunders; Respir Care 2009;54:1236-43. regarding longer term clinical outcomes 2011. p.389-425. 21. Grover A., Field D. Volume-targeted ventilation in are lacking and large multi-centre trials 9. Donn S.M., Sinha S.K. Assisted ventilation and its the neonate: time to change? Arch Dis Child Fetal will be needed to investigate these complications. In: Martin R.J., Fanaroff A.A., Walsh Neonatal Ed 2008;93:F7-9. M.C. (eds) Fanaroff and Martin’s Neonatal-Perinatal 22. Abubakar K.M., Keszler M. Patient-ventilator outcomes. However, these trials may prove Medicine: Diseases of the Fetus and Infant. 9th ed. St. interactions in new modes of patient-triggered to be difficult to achieve because of the Louis, Mo: Elsevier Mosby; 2011. p1116-140. ventilation. Pediatr Pulmonol 2001;32:71-75. introduction of several newer devices that 10. Dreyfuss D., Saumon G. Barotrauma is volutrauma, 23. Herrera C., Gerhardt T., Claure N. et al. Effects of have not been compared in clinical trials but which volume is the one responsible? Int Care volume-guaranteed synchronized intermittent and because of the varying ventilation Med 1992;18:139-41. mandatory ventilation in preterm infants recovering strategies practised between units. In the 11. Hernandez L.A., Peevy K.J., Moise A.A., Parker J.C. from respiratory failure. Pediatrics 2002;110:529-33. Chest wall restriction limits high airway pressure- 24. Keszler M., Abubaker K. Volume guarantee: stability meantime, clinicians must familiarise induced lung injury in young rabbits. J App Physiol of tidal volume and incidence of hypocarbia. Pediatr themselves with the modes and device 1989;66:2364-68. Pulmonol 2004;38:240-45. used to deliver VTV on their unit in order 12. Wada K., Jobe A.H., Ikegami M. Tidal volume effects 25. Scopesi F., Calevo M.G., Rolfe P. et al. Volume to ensure that volume-targeting is on surfactant treatment responses with the targeted ventilation (volume guarantee) in the achieved safely and optimally. initiation of ventilation in preterm lambs. J App weaning phase of premature newborn infants. Physiol 1997;83:1054-61. Pediatr Pulmonol 2007;42:864-70. 13. Wheeler K., Klingenberg C., McCallion N. et al. 26. Cheema I., Sinha A., Kempley S., Ahluwalia J.S. References Volume-targeted versus pressure-limited ventilation Impact of volume guarantee ventilation on carbon 1. Garg S., Sinha S. Non-invasive ventilation in in the neonate. Cochrane Database of Syst Rev dioxide tension in newborn infants: a randomised premature infants: based on evidence or habit. 2010;11:CD003666. controlled trial. Early Hum Dev 2007;83:183-89. J Clin Neonatol 2013;2:155-59. 14. Wheeler K.I., Klingenberg C., Morley C.J., Davis P.G. 27. Guven S., Bozdag S., Saner H. et al. Early neonatal 2. Sinha S.K., Donn S.M. Volume-targeted ventilation. Volume-targeted versus pressure-limited ventilation outcomes of volume guaranteed ventilation in In: Goldsmith J.P., Karotkin E.H. (eds.) Assisted for preterm infants: a systematic review and meta- preterm infants with respiratory distress syndrome. Ventilation of the Neonate. 5th ed. St. Louis, Mo: analysis. Neonatology 2011;100:219-27. J Matern Fetal Neonatal Med 2013;26:396-401. Elsevier Saunders; 2011. p.186-99. 15. Peng W., Zhu H., Shi H., Liu E. Volume-targeted 28. Lista G., Colnaghi M., Castoldi F. et al. Impact of 3. Klingenberg C., Wheeler K.I., Owen L.S. et al. An ventilation is more suitable than pressure-limited targeted-volume ventilation on lung inflammatory international survey of volume-targeted neonatal ventilation for preterm infants: a systematic review response in preterm infants with respiratory ventilation. Arch Dis Child Fetal Neonatal Ed and meta-analysis. Arch Dis Child Fetal Neonatal Ed distress syndrome (RDS). Pediatr Pulmonol 2004;37: 2011;96:F146-48. 2014;99:F158-65. 510-14. 4. Hamvas A. Pathophysiology and management of 16. Sinha S.K., Donn S.M., Gavey J., McCarty M. 29. Lista G., Castoldi F., Fontana P. et al. Lung respiratory distress syndrome. In: Martin R.J., Randomised trial of volume controlled versus time inflammation in preterm infants with respiratory Fanaroff A.A., Walsh M.C. (eds.) Fanaroff and Martin’s cycled, pressure limited ventilation in preterm distress syndrome: effects of ventilation with Neonatal-Perinatal Medicine. Diseases of the Fetus infants with respiratory distress syndrome. Arch Dis different tidal volumes. Pediatr Pulmonol and Infant. 9th ed. St. Louis, Mo: Elsevier Mosby; Child 1997;77:F202-05. 2006;41:357-63. 2011. p.1106-16. 17. Singh J., Sinha S.K., Clarke P. et al. Mechanical 30. Piotrowski A., Sobala W., Kawczy´nski P. Patient- 5. Attar M.A., Donn S.M. Mechanisms of ventilator- ventilation of very low birth weight infants: is initiated, pressure-regulated, volume-controlled induced lung injury in premature infants. Semin volume or pressure a better target variable? J Peds ventilation compared with intermittent mandatory Neonatol 2002;7:353-60. 2006;149:308-13. ventilation in neonates: a prospective, randomised 6. Björklund L.J., Ingimarsson J., Curstedt T. et al. 18. Singh J., Sinha S.K., Alsop E. et al. Long-term follow- study. Int Care Med 1997;23:975-81. Let readers know what’s going on

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