Paediatric Respiratory Reviews 23 (2017) 89–96

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Paediatric Respiratory Reviews

Review

Lung-protective ventilatory strategies in intubated preterm neonates with RDS F. Reiterer 1,*, B. Schwaberger 1, T. Freidl 1, G. Schmo¨lzer 2,3, G. Pichler 1, B. Urlesberger 1 1

Division of Neonatology, Department of Pediatrics and Adolescence Medicine, Medical University Graz, Austria Centre for the Studies of Asphyxia and Resuscitation, Neonatal Research Unit, Royal Alexandra Hospital, Edmonton, Canada 3 Department of Pediatrics, University of Alberta, Edmonton, Canada 2

EDUCATIONAL AIMS  To get [48_TD$IF]a closer insight into the mechanism of lung injury during mechanical ventilation and the available lung protective ventilatory strategies (LPVS) in intubated preterm neonates with RDS.  To describe the different LPVS used in the management of RDS.  To emphasize the importance of monitoring during LPVS.  To evaluate short-and longterm-outcomes in studies with LPVS.

A R T I C L E I N F O

S U M M A R Y

Keywords: Lung protective strategies mechanical ventilation RDS preterm infants short- and long-term outcome

This article provides a narrative review of lung-protective ventilatory strategies (LPVS) in intubated preterm infants with RDS. A description of strategies is followed by results on short-and long-term respiratory and neurodevelopmental outcomes. Strategies will include patient-triggered or synchronized ventilation, volume targeted ventilation, the technique of intubation, surfactant administration and rapid extubation to NCPAP (INSURE), the open lung concept, strategies of high-frequency ventilation, and permissive hypercapnia. Based on this review single recommendations on optimal LPVS cannot be made. Combinations of several strategies, individually applied, most probably minimize or avoid potential serious respiratory and cerebral complications like bronchopulmonary dysplasia and cerebral palsy. ß 2016 Published by Elsevier Ltd.

* Corresponding author. Division of Neonatology, Department of Pediatrics and Adolescence Medicine, Medical University of Graz, Auenbruggerplatz 30, 8036 Graz, Austria. E-mail address: [email protected] (F. Reiterer). Abbreviations: BPD (36 wks), Bronchopulmonary Dysplasia (diagnosed at 36 weeks postmenstrual age); CMV, Conventional Mechanical Ventilation; CPAP, Continuous Positive Airway Pressure; FRC, Functional Residual Capacity; HFV, High Frequency Ventilation; HFJV, High Frequency Jet Ventilation; HFOV, High Frequency Oscillatory Ventilation; HLVS, High Lung Volume Strategy; HFPPV, High Frequency Positive Pressure Ventilation; HFNC, High Flow Nasal Cannula; INSURE, INtube, SURfactant - Extubate to NCPAP; IMV, Intermittent Mandatory Ventilation; LISA, Less Invasive Surfactant Administration; LPVS, Lung Protective Ventilatory Strategy; MIST, Minimal Invasive Surfactant Therapy; MV, Mechanical Ventilation; NAVA, Neurally Adjusted Ventilatory Drive; NCPAP, Nasal Continuous Positive Airway Pressure; NIPPV, Nasal Intermittent Positive Pressure Ventilation; NIV, Noninvasive Ventilation; PEEP, Positive End-expiratory Pressure; PH, Permissive Hypercapnia; PLV, Pressure Limited Ventilation; PPV, Positive Pressure Ventilation; PRVCV, Pressure Regulated Volume Control Ventilation; PSV, Pressure Support Ventilation; PTV, Patient Triggered Ventilation; SIMV, Synchronized Intermittent Mandatory Ventilation; SIPPV, Synchronized Intermittent Positive Pressure Ventilation; TCPL, Time Cycled Pressure Limited; TV, Tidal Volume; VCV, Volume Controlled Ventilation; VG, Volume Guarantee; VILI, Ventilator Induced Lung Injury; VTV, Volume Targeted Ventilation. http://dx.doi.org/10.1016/j.prrv.2016.10.007 1526-0542/ß 2016 Published by Elsevier Ltd.

INTRODUCTION There is an increasing interest for avoiding endotracheal intubation by increased use of non-invasive ventilation (NIV) [1–4], including nasal continuous positive airway pressure (NCPAP), nasal intermittent positive airway pressure (NIPPV), nasal high frequency ventilation (nHFO), and high flow nasal cannula (HFNC) for respiratory support in preterm infants. Nevertheless, endotracheal intubation and mechanical ventilation (MV) is a lifesaving therapy and is commonly required, either in the delivery room (DR) or neonatal intensive care unit (NICU). Failure of NIV may be as high as 60%, depending on gestational age, birth weight, disease severity, mode of NIV and other perinatal variables [5,6]. However, early and even short MV with high intrathoracic airway pressures and tidal volumes (TV) may cause injury [32_TD$IF]to the lungs and other organs like the brain due to hemodynamic disturbances and/or inflammatory mediator-induced systemic responses [7,8]. Acute and chronic pulmonary ventilator- induced/or associated lung injury (VILI) are pulmonary air leaks such

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as pneumothorax or pulmonary interstitial emphysema (PIE) and bronchopulmonary dysplasia (BPD), a form of chronic lung disease (CLD). BPD, regardless of diagnostic criteria [either continued oxygen requirement at 28 days of life or at 36 weeks postmenstrual age (BPD 36wks)], is the most common short-term adverse outcome in very preterm infants and may be associated with impairments in respiratory and neurological long-term outcomes [[3_TD$IF]9–12]. Although the ‘‘classical, old’’ picture of BPD changed in the last decade [9], with the increased survival of infants with extremely low gestational age (< 28 weeks) and birth weight (< 1000 g, ELBWI) the overall BPD incidence has not changed and continues to be a challenging problem in neonatology [1]. Therefore, various lung-protective ventilatory strategies (LPVS) were introduced to minimize lung injury associated with MV. These are the different modes of patient triggered or synchronized ventilation (PTV, High Frequency Positive Pressure Ventilation with short inspiratory times and ventilator rates > 60/min (HFPPV)), volume targeted ventilation (VTV), INSURE strategy (INtube, SURfactantExtubate to NCPAP), High Frequency Ventilation (HFV) (including High Frequency Oscillatory Ventilation (HFOV) and High Frequency Jet Ventilation (HFJV) and permissive hypercapnia (PH). Furthermore, one may add lung recruitment with the ‘‘open lung’’ concept, and the manual or automatic control of oxygen to facilitate appropriate targeting of peripheral oxygen saturation (SpO2). The main goals of LPVS are avoidance of volutrauma, atelectotrauma, and oxygen toxicity. The aim of this narrative review article is to provide an update of LPVS during MV including the evaluation of long-term effects on pulmonary and neurodevelopmental outcomes in preterm infants with respiratory distress syndrome (RDS). For SpO2 monitoring and the option of automated oxygen control we refer to other recently published articles in the literature [13–17]. PATIENT-TRIGGERED, SYNCHRONIZED VENTILATION Synchronization of spontaneous breathing efforts with inflations provided by the ventilator, either by adjusting ventilator rate and inspiratory time or by using triggered ventilation, has shown to have several benefits compared to non synchronized ventilation including consistent TV, improved oxygenation, less use of sedatives/analgesic drugs, and shorter duration of MV [18]. There are different PTV-techniques available in modern ventilators like ‘‘Synchronized Intermittent Mandatory Ventilation’’ (SIMV), ‘‘Assist/Control’’ or ‘‘Synchronized Intermittent Positive Pressure Ventilation’’ (SIPPV), ‘‘Pressure Support Ventilation’’ (PSV), SIMV + Pressure Support (PS), ‘‘Pressure-Regulated Volume Control Ventilation’’ (PRVCV) and ‘‘Proportional Assist Ventilation’’. While all these techniques work with a pneumatic or flow/volume trigger for synchronization, a recently introduced technique called NAVA (Neurally Adjusted Ventilatory Drive) uses a neural trigger mechanism. A specialized electrode equipped nasogastric catheter signals the onset and magnitude of diaphragmatic activation reflecting the patient’s neural respiratory drive to the respirator, which then delivers a synchronized breath [19–23]. NAVA is a promising and safe synchronization technique for invasive as well as non-invasive MV but so far there are no studies demonstrating a major benefit in short-term outcome compared to conventional mechanical ventilation (CMV). Long-term outcomes have not been reported[2_TD$IF]. There is extensive literature on the efficacy of various PTV modes [24–28]. Very recently an updated Cochrane Review of 22 randomised or quasi-randomized trials on synchronized mechanical ventilation in neonates requiring respiratory support (mainly preterm infants) was published [29]. A benefit was demonstrated for both HFPPV and PTV compared to CMV with regard to[3_TD$IF] a reduction in air leak and a shorter duration of ventilation, respectively. SIMV or SIMV + PS compared to HFO was

associated with a greater risk of moderate/severe BPD and a longer duration of mechanical ventilation. AC compared to SIMV was associated with a shorter duration of weaning. Triggered ventilation in the form of SIMV  PS resulted in a greater risk of BPD and duration of ventilation compared to HFO. Neither HFPPV nor PTV was associated with a significant reduction in the incidence of BPD. Longterm pulmonary or neurological outcomes were not reported. The authors argue that in none of the trials complex respiratory monitoring was undertaken and thus it was not possible to conclude that the mechanism of producing those benefits is by provocation of synchronised ventilation. Triggered ventilation in the form of SIMV  PS resulted in a greater risk of BPD and duration of ventilation compared to HFO. Nowadays PTV modes can be used with VTV in order to combine the advantages of patient synchronization and volume targeting. In a recently published network-meta-analysis of various mechanical ventilation modes attempting to provide suggestions for the treatment of preterm infants with RDS [30], the SIMV-VG mode was associated with the greatest potential to reduce mortality. Data on long-term neurological outcome were not reported. VOLUME TARGETED VENTILATION From experimental and clinical studies in the late 1980s and 1990s in adults, it became increasingly evident that not pressure but volume significantly contributes to lung injury during MV [31–33]. The historical and classical term barotrauma was then shifted to other types of VILI like volutrauma, rheotrauma, atelectotrauma, biotrauma [34], volutrauma being considered to be the key determinant of VILI [34]. For a long period ‘‘Time Cycled Pressure Limited’’ ventilation with TV varying from inflation to inflation was standard for CMV in neonates. With the better understanding of the pathogenesis of VILI and driven by advances in ventilator microprocessor technology VTV was introduced in the neonatal field. The aim of VTV was to establish a stable TV, and thus aims to reduce lung overdistension, hypocapnia, and lung injury. One mode of VTV is Volume Guarantee (VG) in which the microprocessor compares exhaled TV of the previous breath to the desired target TV, set by the operator, and adjusts the inspiratory pressure up or down to achieve that TV [35]. The most appropriate TV level for preterm with RDS has not been determined. It seems that volume targeted levels of 5 to 6 ml/kg bodyweight to be most appropriate for preterm with RDS [35,36]. Lower levels my lead to repeated [34_TD$IF]collapse of the [35_TD$IF]airways resulting in increased work of breathing, alveolar instability, atelectasis and increased inflammatory response [37,38]. In two recently published systematic reviews and meta-analyses of all randomised and quasi-randomised trials comparing the use of VTV versus pressure limited ventilation (PLV) in preterm infants of various gestational age, VTV had several favourable outcomes [39,40]. These included a reduction in the combined outcome of death or BPD, BPD alone, pneumothorax, days of ventilation, hypocarbia, failure of primary mode of ventilation, and single or combined outcome of periventricular leukomalacia (PVL) and grade 3-4 intraventricular hemorrhage (IVH). We found only a few studies of VTV compared to other ventilatory modes reporting long-term respiratory and or neurodevelopmental outcomes [41–44] ([36_TD$IF]Table 1). Recent surveys on the clinical practice of VTV in Europe, Australia and the Nordic Countries [45–47] showed a large variation in the use of VTV and the target VT and the perceptions as to whether the use of VTV modes led to improved outcomes. Since some new HFOV ventilators now provide a VGmode, there has been some interest to evaluate this strategy during HFOV in small experimental and clinical studies [48–51]. It has been demonstrated that HFOV+VG is feasible in

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Table 1 Evaluation of long-term outcomes in VTV-studies during CMV. Ventilation Mode

GA, wks mean (SD) median (range)

No. of infants

Study design

Study population

Study age

Outcome parameter

Main results

Authors ref., year of publication

PRCV vs SIMV

 24

104 vs 108

randomized, not masked

6-9 months corrected age

neurodevelopmental

no difference in NDI

D’Angio et al [44], 2005

VG-PSV vs PCV

26 (25-28) vs 26 (24-27)

135 vs 135

retrospective, observational

VLBWI 500-1249g, RDS VLBWI  1250g

18 months

neurodevelopmental

Stefanescu et al [43], 2009

VCV vs PLV

27.3 (1.7) vs 27.7 (1.9)

35 vs 40

RCT

around 2 yrs

respiratory, gross neurological status

benefits for the combined outcome death or NDI significant less inhaler use, no difference in severe disability

RDS, surfactant treatment

Singh et al[1_TD$IF] [41][15_TD$IF], 2009*

* Follow up of the study population of Singh et al 2006. NDI: neurodevelopmental impairment[17_TD$IF].

preterm infants and compared to HFOV without VG attenuates fluctuations of SpO2 and CO2 clearance. Due to the limited numbers of studies and small sample sizes it has yet to be proven whether HFOV + VG offers short-and long-term advantages over HFOV alone or CMV+ VG. In particular, further studies are needed to identify which VTV strategy may be advantageous in terms of short and long-term outcomes for preterm infants with RDS.

INSURE-STRATEGY The clinical implementation of surfactant as a safe and efficient therapy for preterm infants with RDS during MV in the early 1990s can be considered as a milestone in neonatal intensive care resulting in a significant reduction in neonatal mortality and shortterm respiratory morbidity [1,52,53]. Nevertheless, the incidence of BPD has not changed. This might be explained by its multifactorial etiology and the invasive nature of intubation, positive pressure ventilation (PPV) and continuous oxygen exposure to an immature lung [54]. A Danish-Swedish group introduced the combination of surfactant and less-invasive ventilation using NCPAP in spontaneously breathing preterm infants as a new strategy in the early 1990s [55,56]. In a randomized controlled trial [55] it could be demonstrated that in preterm infants (gestational age 25-35 weeks) with moderateto-severe RDS a single surfactant dose administered during a short endotracheal intubation could significantly reduce the subsequent need for MV compared to a non-blinded control group (43% vs. 85%, p=0.003). This approach with early endotracheal intubation for surfactant administration followed by brief mechanical ventilation with planned extubation within one hour is now known as ‘‘INSURE’’ procedure. A Cochrane review indicates that preterm infants with or at risk for RDS treated with INSURE less likely need MV, less likely develop BPD and less likely suffer from air leak syndrome compared to infants with surfactant plus continued MV [57]. But INSURE has not yet been proven to reduce BPD rates and failure rates may be high, especially in ELBWI. In addition there are currently no randomized controlled INSURE trials reporting on long-term respiratory and neurodevelopmental outcomes. Recently, several studies have been published applying a modified INSURE strategy using a thin catheter or feeding tube briefly placed into the trachea to administer surfactant avoiding sedation, intubation and PPV. These less invasive (LISA) or minimal invasive (MIST) surfactant administration strategies are promising and may be superior to the classical INSURE approach. However, despite several benefits for neonatal short-term adverse outcome parameters these strategies have rarely shown to increase the survival without BPD [4,58,59]. Long-term-outcomes have still to be evaluated.

LUNG RECRUITMENT AND THE ‘‘OPEN LUNG’’ CONCEPT RDS is the most frequent respiratory disease in preterm neonates and it’s severity correlates inversely with gestational age. Surfactant deficient lungs of preterm infants with severe RDS are characterized by marked lung opacification, poor lung function with low compliance and functional residual capacity (FRC), high oxygen requirements and poor gas exchange. Despite surfactant replacement therapy being a landmark in the treatment of RDS the basic ventilation concept in atelectatic lungs is still to apply a continuous positive airway pressure (CPAP) and/or positive endexpiratory pressure (PEEP). In addition to other physiological effects of CPAP/PEEP on respiratory activity, PEEP has been demonstrated to have a synergistic role on FRC in surfactant treated preterm infants [60]. After successful lung recruitment the further lung protective concept is to keep the lung open, thus avoiding the potential lung damaging effect of repeated collapse and reopening of alveoli [1]. This concept can be visualized by the pressure-volume curve in which a ‘‘save window’’ between a zones of decruitment or atelectasis and overdistension has been described. By applying stepwise PEEP and peak inspiratory pressure guided by continuous SpO2 measurements, used as an indirect parameter for lung volume, lung protective TV-ventilation may be achieved in this window. A recently described approach during this concept is monitoring functional residual capacity and tidal ventilation by using electrical impedance tomography (EIT) [61–70]. Alveolar recruitment during HFO is also referred as ‘‘High Lung Volume Strategy’’ (HLVS) compared to a strategy to maintain low volume. This open lung concept has been mainly investigated in animal models of neonatal RDS and ARDS and in ventilated adults with ARDS, but has not been evaluated systematically in preterm infants. In a study by Salvo et al [63] in preterm infants with moderate to severe RDS the technique of recruitment and lung volume optimization during HFOV was associated with several benefits compared to CMV. Benefits include a reduction in the need for surfactant re-dosing, and shortened duration of ventilation and hospitalization, although the incidence of BPD (36 wks) was not different. Long-term outcome has not been reported till now. In a retrospective study by Rimensberger et al [64] initiating HFO immediately after intubation and attempting early lung volume optimization before surfactant administration in VLBWI, this strategy showed a reduction of respiratory support and significant differences in the incidence of BPD in comparison to a historical CMV group (0 vs. 34%). PERMISSIVE HYPERCAPNIA The tolerance of arterial partial pressure of carbon dioxide (pCO2) >45 mmHg by using a minimal ventilatory support strategy

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is referred to as permissive hypercapnia (PH). PH is common in many NICUs and neonatologists have PH accepted as a way of facilitating weaning from MV with the potential of reducing VILI. Mariani et al [71] first described in 1999 a ventilator strategy of PH in preterm neonates who received assisted ventilation to be feasible, safe and reducing the duration of ventilation. Nevertheless they found no difference in mortality, air leaks, IVH, PVL, retinopathy of prematurity and PDA. Carlo et al[37_TD$IF]. [72][38_TD$IF] found in a randomized controlled trial no difference in their primary outcome BPD at 36 weeks postmenstrual age between a minimal ventilation group with a pCO2 target >52 mmHg compared to a control group with a pCO2 target <48 mmHg. Neurodevelopmental outcome at 18 to 22 month’s corrected age was also similar in the two groups. Further studies did also not [73–75] demonstrate a significant overall benefit of PH. Most recently, Thome et al [76] published data from a randomized, national-multicenter trial in preterm infants 23-28 weeks of gestation that needed endotracheal intubation and MV within 24 h after birth. It showed no significant differences in the primary endpoint rate of moderate to severe BPD or death between a high target group (pCO2 55-75 mm Hg) and a slightly hypercapnic control group (pCO2 40-60 mm Hg). However, in the high pCO2 group a significant increased incidence of necrotising enterocolitis was noticed. The authors’ hypothesized hypercapnic acidosis might have led to impaired function of intestinal cells. Furthermore, in neonates with more severe lung disease the incidence of BPD or death was increased, which finally led to the premature cessation of the study. Therefore, it seems that PH has no significant lung protective effects and might even be harmful when higher pCO2 targets are used from the first day of life in ELBWI. Nevertheless, in weaning patients from MV mild to moderate PH will remain a standard. CONVENTIONAL VERSUS UNCONVENTIONAL MECHANICAL VENTILATION CMV is generally referred to as PPV with frequencies and VT in the physiological range of a spontaneously breathing preterm infant and is considered a standard treatment for RDS. Unconventional MV is usually defined as a strategy using supra-physiological ventilator frequencies and VT close to the airway dead space with lower inflation pressures at the alveolar level compared to CMV. There are generally two types of HFV used in the NICU, HFOV and HFJV [77], HFOV being more commonly used. HFOV was introduced in the late

1970s as a promising strategy to minimize VILI. Despite benefits shown in experimental studies clinical outcome studies comparing CMV versus HFOV are controversial and do not show a consistent lung or neuroprotective effect. In a recent Cochrane review [78] elective HFOV was compared to CMV in preterm infants with pulmonary dysfunction, mainly RDS, including nineteen studies carried out over 25 years. HFOV, using a lung protective HLVS, resulted in a significant reduction in the risk of CLD at term equivalent gestational age. But the evidence was weakened and biased by the inconsistency of this effect across trials, the various interventions and characteristics such as the use and mode of LPVS during CMV (increasing over time), type of ventilator and study population (Table 2). It has also to be pointed out that there was a higher incidence of acute PIE in the HFOV-group. In the review above there were 8 studies reporting on long-term neurodevelopmental outcomes (infants being assessed between one and two years of age). In most of the studies no significant difference was seen, except in one trial in preterm infants of less than 30 weeks with RDS [79] in which the incidence of severe IVH with 24% in the HFO- group compared to 14% in the CMV group. Contrary to the initial concern of an increased rate of severe IVH in the HFO-group, the results of the follow- up study suggested, that early use of HFO may be associated with a better neuromotor outcome, with a significant reduction in the risk of cerebral palsy (CP) (4% vs. 17% [80]. Recently data were published from the United Kingdom Oscillatory Study Group reporting[4_TD$IF] better lung function at 11 to 14 years of age in an HFOV-group, although the incidence of BPD had not been significantly different [81]. A summary of long-term outcomes in comparative RCT between HFOV and CMV is presented in Table 3 [78–83]. Comparative studies between HFJV and CMV are rare. In a recently published systematic review in preterm infants less than 35 weeks with severe pulmonary dysfunction only one trial was included [84]. No significant differences in short-term pulmonary and neurological outcomes were found. In another multicenter controlled trial in preterm infants < 36 weeks gestation [85] with uncomplicated RDS, HFJV reduced the incidence of BPD (36 wks) (20% vs. 40%) and the need for home oxygen compared to CMV. However, no study meets inclusion criteria for a Cochrane metaanalysis comparing HFOV and HFJV for pulmonary dysfunction in preterm infants [86]. Long-term pulmonary and neurodevelopmental outcomes after HFJV have not been reported[2_TD$IF]. Therefore, at the moment there is no evidence that supports the use of HFJV as rescue therapy in preterm neonates with RDS.

Table 2 Ventilatory [2_TD$IF]strategy [3_TD$IF]in [4_TD$IF]comparative [5_TD$IF]studies [6_TD$IF]between [7_TD$IF]HFO [8_TD$IF]and [9_TD$IF]CMV. Author*[18_TD$IF]6;year of ref.

GA,wk

HFO- HLVS yes/no

Bw,g HIFI-study group, 1989 Clark, 1992 Ogawa, 1993 Gerstman, 1996 Thome, 1998 Rettwitz, 1998 Plavka, 1999 Moriette, 2001 Durand, 2001 Courtney, 2002 Johnson, 2002 Van Reempts, 2003 Schreiber, 2003 Craft, 2003 Vento, 2005 Danii, 2006 Lista, 2008 Salvo, 2012 *

[19_TD$IF]All the listed authors included in ref[20_TD$IF]. [78].

750-2000 g < 35 wk 750-2000 g <36 wk 24-29 wk 750-1500 g 500-1500 g 24-29 wk 501-1200 g 601-1200 g 25-28 wk < 32 wk < 34 wk 23-34 wk 24-29 wk < 30 wk 25-42 wk < 30 wk

CMV- LPVS yes/no Type of LPVS strategy

no yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes yes

no no not stated no yes, HFPPV no probably no, sync not in all probably yes, SIMV yes, SIMV yes, SIMV, VT 4-7 ml/kg probably yes, sync not in all yes, IMV/HFPPV (80/min) probably no probably yes, SIMV yes, SIMV, VT 4-6 ml/kg yes, PSV+VG (VT 5 ml/kg) yes, SIPV+VG (VT 5 ml/kg) yes, SIMV

Table 3 [10_TD$IF]Comparison [1_TD$IF]of [12_TD$IF]HFO [13_TD$IF]vs [14_TD$IF]CMV [15_TD$IF]with [16_TD$IF]regard [17_TD$IF]to [18_TD$IF]long-term outcomes. Ventilation Mode

GA, wks mean (SD) median (range)

No. of infants

Study design

Study population

Study age

Outcome parameter

Main results

Authors ref., year of publication

HFOV vs CMV

28.4 (2.3) vs 28.3 (2.2)

105 vs 118

RCT

birth weight 750 to 2000 g, severe RDS, MV

9 months corrected age 16 to 24 months corrected age

respiratory, growth

No differences

neurodevelopmental

1 year

Increased rate of moderate to severe abnormality in HFOV group no difference

The HIFI Study Group [78][21_TD$IF], 1990a* The HIFI Study Group [78], 1990b*[21_TD$IF]

185 vs 201

HFOV vs CMV

RCT

36 vs 33

RCT

42 vs 34

RCT

176 vs 196

26.7 (1.5) vs 27.0 (1.2) HFOV vs CMV

HFOV vs CMV

HFOV vs CMV

HFOV vs CMV

birth weight 750 to 2000 g, MV <36 wks gestation, RDS, MV

mean age of 6.4 years

motor or mental development respiratory, neurodevelopmental

23-28 wks gestation

11-14 months

Lung function

RCT

22-28 months corrected age

160 vs 159

RCT

12.5 (0.6) vs 12.6 (0.6) yrs

Respiratory, anthropometric measurements Lung function, school ratings

27.2 (2.7)

66 vs 72

RCT

<34 wks gestation or <2000g, RDS, receiving iNO

2 yrs

Anthropometric measurements, neurodevelopmental

27.6 27.8 28.6 28.7

97 vs 95

RCT

24-29 wks gestation, RDS

2 yrs

neurodevelopmental

70 vs 68 (7-12 month follow-up, 26 vs 25 (18-24 month) 13 vs 12

RCT

<30 wks gestation or 1250g or cranial lesions

7-12 months and 18-24 months corrected age

neurodevelopmental

single center, observational RCT

severe RDS with or without BPD preterm infants <32 wks, severe RDS, <1,500 g

7 yrs

Lung function, whole body plethysmography neurodevelopmental

26.2 26.4 26.7 26.8

(1.6) vs (1.6) (1.4) vs (1.3)

(1.4) vs (1.5) (1.5) vs (1.6)

HFOV vs AC+VG

27 (2)

HFOV vs SIMV-PSV

29.5 (2.3) vs 29.3 (2.5)

145 vs 143

18 months corrected age

Ogawa et al. [78][21_TD$IF], 1993 Gerstmann et al. [78][21_TD$IF], 2001**

Improved respiratory function, but no differences in symptoms, no difference in neurodevelopmental status No differences

Thomas et al. [78], 2004***[21_TD$IF]

No differences

Marlow et al. [82][2_TD$IF], 2006***

Superior results on lung function and better school ratings No difference in mean height, weight or head circumference. No differences in Bayley’s Scales and Pediatric neurological assessment significantly lower cerebral palsy No significant difference in Bayley motor and mental developmental indices similar obstructive deficits Significantly lower cerebral palsy, lower rate of mental developmental index < 70

Zivanovic et al. [81], 2014***[23_TD$IF]

Schreiber et al. [78], 2003

Truffert et al. [80][24_TD$IF], 2007**** Van Reempts et al. [78], 2003

F. Reiterer et al. / Paediatric Respiratory Reviews 23 (2017) 89–96

46 vs 46

HFOV vs CMV

29 (2.3) vs 29 (2.1) 30.8 (2.4) vs 30.6 (2.4)

Lista et al. [42], 2014*****[25_TD$IF] Sun et [26_TD$IF]al. [83], 2014

*

Follow up of the study population of The HIFI Study Group [27_TD$IF]1989. Follow up of the study population of Gerstmann et al [28_TD$IF]1995. Follow up of the study population of Johnson et al [29_TD$IF]2002. **** Follow up of the study population of Moriette et al [30_TD$IF]2001. ***** Follow up of the study population of Lista et al [31_TD$IF]2008. **

***

93

[(Figure_1)TD$IG]

94

F. Reiterer et al. / Paediatric Respiratory Reviews 23 (2017) 89–96

 HFO with an high-lung volume strategy or using a lungprotective concept during CMV seems equally effective.  There are inconsistencies in short- and long-term benefits for respiratory and neurological outcomes[6_TD$IF]. References

Figure 1. Monitoring and lung protective ventilation in patients with RDS. NIV starting in the DR being a potential important first step (1) in the prevention of lung injury. In case of NIV failure the INSURE approach (2) or continued MV (3) either as CMV or HFV may be applied.

CONCLUSION Various approaches have been developed and implemented in the respiratory care of preterm infants over recent decades. Techniques and strategies of LPVS aim to accelerate weaning from MV and to protect against VILI. There are different modes of LPVS, with inconsistencies in short- and long-term benefits for respiratory and neurological outcomes. Currently several LPVS may be combined or individually and sequentially applied (Fig. 1), NIV starting in the DR being a potentially important first step in the prevention of VILI and BPD. HFO or using a lung-protective concept during CMV seems equally effective. DIRECTIONS FOR FUTURE RESEARCH [5_TD$IF]Future studies should examine further improvements of efficiency of NIV and MV applied in the DR and NICU and to evaluate their impact on various gestational ages, and disease severity, focusing on long-term respiratory and neurological outcomes. It will be important to combine LPVS with new modalities and techniques to prevent lung and/or brain injury. Among these are optimization of exogenous surfactant treatment [[39_TD$IF]87,88], early low-dose hydrocortisone [[40_TD$IF]89] and high-dose oral vitamin A in ELBWI [[41_TD$IF]90], NAVA [19], automated control of inspired oxygen [16,17], neuroprotective drugs [[42_TD$IF]91], near-infrared spectroscopy [[43_TD$IF]92,93] and complex non-invasive respiratory monitoring including non-invasive measurements of lung volume [[4_TD$IF]70,94,95]. An important aspect in the selection of any respiratory support modality in the NICU is to understand the physiology and pathophysiology of the underlying lung condition and to be familiar with it’s principles, benefits and limitations [[45_TD$IF]77,96]. For the general management of RDS in preterm infants there exist regularly updated guidelines with new evidence from recent Cochrane reviews and the medical literature including a grading system for evaluation the evidence [[46_TD$IF]97]. MV- protocols may be helpful for a respiratory management approach in the NICU, despite the lack of a compelling evidence to support their use in neonates [[47_TD$IF]98–100]. [49_TD$IF]PRACTICE POINTS  A single recommendations on optimal LPVS cannot be made.  Different modes of LPVS may be may be combined or individually and sequentially applied, early use of non-invasive ventilation being a potential important first step in the prevention of lung injury.

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