Chronic phase ventilation strategy in established severe bronchopulmonary dysplasia: A critical evaluation of the evidence

Abstract

We review the chronic phase ventilation (CPV) strategy recommended in infants with the most severe bronchopulmonary dysplasia (msBPD, mechanically ventilated at 36–40 weeks post-menstrual age). The safety and efficacy of CPV was important to scrutinize because msBPD is increasingly common, and infants with msBPD are often transferred to the Pediatric Intensive Care Unit (PICU) where the CPV strategy started in neonatal intensive care is expected to continue as the standard of care. First, we describe the CPV strategy, and the supporting evidence given by expert proponents. Second, we subject the supporting evidence to critical scrutiny and explain flaws that weaken support. Third, we give evidence that the strategy is based upon unsound pathophysiology and hence may be harmful. Fourth, we put this all together by making unstated (and unsupported) premises in explaining the benefit of CPV explicit. We made four conclusions. First, the literature suggested that CPV is based upon circular referencing among chapters and narrative reviews written by the same respected experts, and therefore, upon literature inadequately subjected to critical scrutiny. Second, these reviews explained physiologic theory with little supportive evidence that had likely been misinterpreted, and referred to outcome studies that did not examine the effect of the CPV strategy. Third, when implicit assumptions are made explicit, there is evidence to show a lack of consensus about and potential harms of the CPV strategy, and inaccurate interpretations of msBPD physiology. Fourth, there was no rationale that withstands critical scrutiny to suppose ventilated children with msBPD might be an exception to using a standard of care ventilation strategy used in acute lung disease. If the CPV strategy is beneficial, we urgently need better data to that effect; otherwise, it is too early to widely adopt what may be a harmful strategy as standard of care.

Introduction

Bronchopulmonary dysplasia (BPD) is chronic lung disease after premature birth, defined by respiratory support duration, and graded as mild, moderate, or severe.^1,2 Although there is debate about the best definition, this review refers to the most severe BPD (msBPD), those infants who are on invasive mechanical ventilation at 36–40 weeks postmenstrual age (PMA). The incidence of BPD is increasing as more extremely low gestational age newborns (<28 weeks gestation) and extremely-low birth weight newborns (<1000 g) survive the neonatal period.^1,2 The strongest risk factors for BPD are prematurity and low birth weight, with approximately 88% of infants 22–24 weeks gestational age and >43% of infants born at <29 weeks of age developing BPD, and 95% of infants with BPD having birth weight <1500 g.^2,3 In 2023 in Canada, 9% of those born at 23–24 weeks, and 4.5% of those born at <29 weeks, have msBPD, ³ and these infants required hospitalization for 150–300 days.^4–8 This has led to “new BPD,” in infants born during the canalicular-saccular stage of lung development, having developmental arrest of alveolar and lung vascular development.^1,2 In these vulnerable lungs, supplemental oxygen and ventilator-induced lung injury (VILI) contribute to inflammation and lung injury that culminate in BPD,^2,9–11 and ongoing respiratory morbidity. ¹²

A chronic phase ventilation (CPV) strategy in established msBPD has been endorsed by many experts (Table 1).^1,2,13–32 The safety and efficacy of CPV is important to examine because msBPD is becoming increasingly common, and the CPV strategy is affecting larger numbers of infants, and infants with msBPD are often transferred to the Pediatric Intensive Care Unit (PICU) where the CPV strategy started in neonatal intensive care by the referring neonatologists and parents is expected to continue as the standard of care. ⁵⁴

Table 1.

Book chapters and reviews that claim the chronic ventilation strategy in established severe BPD is suggested.

Chapter or review	Reference to other chapters or reviews to support the chronic phase ventilation strategy	Reference to an original empirical study to support the chronic phase ventilation strategy
		Direct: two-compartment model of lung	Indirect: expiratory flow limitation	Improved outcomes
Book chapter
Nelin et al. (2024) 1	22, 24, 31	Jarriel et al. (1993) 33	Shepherd et al. (2018) 39 ; Hofhuis et al. (2002) 40 ; Robin et al. (2004) 41 ; Filbrun et al. (2011) 42 ; Wauer et al. (1998) 43 ; Baraldi et al. (1997) 37 ; Thunqvist et al. (2015) 44	Shepherd et al. (2012) 49
Zhang and Bamat (2022) 13	18	Jarriel et al. (1993) 33	Baraldi et al. (1997) 37 ; Robin et al. (2004) 41 ; Filbrun et al. (2011) 42	—
Keszler and McKinney (2020) 14	1, 17, 18, 31	Jarriel et al. (1993) 33	—	—
Shepherd et al. (2020) 15	1, 17, 31	—	Shepherd et al. (2018) 39	Shepherd et al. (2012) 49 Murthy et al. (2017) 50
Bhandari et al. (2018) 16	31	—	—	—
Shepherd et al. (2016) 17	1, 18	Jarriel et al. (1993) 33 ; n = 1 example in Figure 2	Baraldi et al. (1997) 37 ; Thunqvist et al. (2015) 44 ; Fakhoury et al. (2010) 45	Shepherd et al. (2012) 49 Trittmann et al. (2013) 4
Castile and Nelin (2010) 18	Earlier reviews by Abman (Abman and Goothrius (1994); Abman and Davis (2006))	Jarriel et al. (1993) 33 ; n = 1 example in Figure 2	Baraldi et al. (1997) 37 ; Hofhuis et al. (2002) 40 ; Robin et al. (2004) 41 ; Wauer et al. (1998) 43 ; Filbrun et al. (2011) 42	—
Review publication
El-Ferzli et al. (2023) 19	22, 23, 24, 28, 29, 31	Wu et al. (2020)34a	Shepherd et al. (2018) 39 ; Baraldi et al. (1997) 37	Kielt et al. (2021) 5 ; Gien et al. (2017) 51
Hysinger and Ahlfeld (2023) 20	21, 26, 28, 29, 31	Higano et al. (2017) 35 ; Higano et al. (2018) 36	Shepherd et al. (2018) 39	—
Ozkan et al. (2022) 21	1, 14, 16, 18, 24, 25, 26, 28, 31	Baraldi et al. (1997)37a	—	—
Miller et al. (2022) 22	1, 15, 24, 25, 28, 31	—	Shepherd et al. (2018) 39	Bauer et al. (2020) 52
Logan et al. (2022) 23	24, 29, 31	—	Shepherd et al. (2018) 39 ; Islam et al. (2015) 46	Kielt et al. (2021) 5 ; McKinney et al. (2021) 6 ; Gien et al. (2017) 51 ; Shepherd et al. (2012) 49 ; Sanchez-Solis et al. (2012) 53 a
Sindelar et al. (2021) 24	1, 15, 18, 31	—	Shepherd et al. (2018) 39	Bauer et al. (2020) 52 ; Shepherd et al. (2012) 49
Baker (2021a) 25	1, 18, 28, 30, 31	Coalson (2003) (Pathology) 38	—	—
Baker (2021b) 26	1, 18, 28, 30, 31	—	—	Gien et al. (2017) 51
Gillfillan et al. (2021) 27	16, 30, 31	—	—	—
Gibbs et al. (2020) 28	13, 18, 31	Jarriel et al. (1993) 33	Shepherd et al. (2018) 39	—
Logan et al. (2019) 29	31, 32	—	Shepherd et al. (2018) 39 ; Yossef et al. (2018)47a; Choukroun et al. (2013)48a	Shepherd et al. (2012) 49
Baker (2019) 30	1, 18, 31	—	—	—
Thebaud et al. (2019) 2	1, 31	—	—	Gien et al. (2017) 51 ; Baker et al. (2016) 7
Abman et al. (2017) 31	1, 18	Jarriel et al. (1993) 33	—	Shepherd et al. (2012) 49
ATS Core Curriculum (2017) (Logan and Shepherd) 32	—	—	—	Shepherd et al. (2012) 49

BPD: Bronchopulmonary dysplasia. Most of the discussion of the chronic phase ventilation strategy is made without giving any references. References listed are to studies of “new BPD” (i.e. in the era of antenatal steroids, neonatal surfactant, and gentle ventilation), in the first year of life. Reviews and book chapters were limited to those from 2000 onwards.

a

These references did not support the point for which they were referenced: Wu et al. (2017) ³⁴ does not discuss or demonstrate different lung compartments in severe BPD. Baraldi et al. (1997) ³⁷ does not discuss or demonstrate different lung compartments in severe BPD. Choukroun et al. (2013) ⁴⁸ did not discuss or demonstrate any obstructive lung disease, nor that “infants with purely obstructive disease. . . tended to have a rather long transitional phase and very long ventilator courses.” ²⁹ Yossef et al. (2018) ⁴⁷ did not discuss or demonstrate obstructive airway disease in severe BPD infants. Sanchez-Solis et al. (2012) ⁵³ did not discuss ventilator settings or weaning of ventilation.

This review is organized as follows: First, we describe the CPV strategy, and the supporting evidence given by expert proponents. Second, we subject this supporting evidence to critical scrutiny and explain flaws that weaken this support. Third, we give evidence that the CPV strategy is based upon unsound pathophysiology and may be harmful. Fourth, we put this all together by making unstated (and unsupported) premises in explaining the benefit of CPV explicit. Finally, we draw conclusions and give suggestions for management of ventilation in infants with msBPD.

The new CPV strategy in established msBPD

Literature search

A search of PubMed was done in April 2025 and updated in September 2025. Search terms were “bronchopulmonary dysplasia” AND “ventilation” in title/abstract, limited to review articles in the past 5 years in humans, and written in English. Titles and abstracts were screened to determine eligibility, defined as publications in which ventilation strategies in infants with established severe BPD were discussed. Review of the full publication was done for potentially eligible reviews to verify eligibility. All references in the included papers that were used for discussion of ventilation in infants with established severe BPD were examined, and any other reviews (including book chapters) referenced were screened for inclusion, regardless of year of publication. If a book chapter was updated over the years, only the most recent update of the chapter was used.

What is the CPV strategy?

The CPV strategy for “improving the distribution of ventilation, minimizing physiologic dead space and gas trapping, and improving gas exchange” is based upon the idea that there is “marked regional variability in time constants.” ¹ The CPV is said to “reduce chronic retractions and respiratory distress and may decrease recurrent cyanotic spells in some patients,” which is important “in order to interact well with parents, caregivers, and environment or to be able to work on motor skills. . . These developmental treatments should focus on creating an age-appropriate sensory and social environment.” ¹ The CPV strategy involves (1) larger tidal volumes (VT, 10–12 ml/kg) and longer inspiratory time (Ti, ⩾0.6 s) to improve regional heterogeneity of ventilation, and (2) slower respiratory rate (RR) with long expiratory time (Te) to allow adequate time for exhalation and avoid gas trapping. ¹ This physiologically based CPV strategy was proposed by Castile and Nelin in a book chapter in 2010 based upon “heterogeneous airway obstruction with air trapping” compatible with a two-compartment model of the lung (i.e. a “fast compartment” with short time constants, and a “slow compartment” with long time constants due to high resistance) and expiratory flow limitation in severe BPD, and a “focus on exhalation” to prevent overinflation and resulting worsening ventilation to perfusion (V/Q) matching. ¹⁸ Importantly, Castile and Nelin suggested that “as the lung deflates areas of overinflation will decrease, which will bring the lung at end-expiration to a steeper portion of the compliance curve. Thereby, adequate tidal volumes can be generated at lower inspiratory pressure.” ¹⁸ There is a variable role for PEEP, to prevent end-expiratory alveolar and small and large airway collapse, and sometimes match auto-PEEP to improve ventilator synchrony and comfort.^{13–15,20,25,28,31} Spontaneous breaths are supported with moderate pressure support, to “ventilate the fast compartments with relatively faster respiratory rate and lower tidal volume” ¹⁴ (see also references 13, 21, 22, 28).

A number of book chapters and narrative reviews have championed this CPV strategy, which has evolved over time to include multiple lung compartments,^{14,19,21,24,30,31} and require very low RR of 10^-20 breaths/minute,^{13–15,19–26,28,30,31} higher VT of 12-15 ml/kg and even higher,^{14,27,20–24} resulting in PIP 30-40 cm H₂O and even higher.^13,19,22,28 The CPV is suggested to foster growth and neurodevelopment due to improved comfort, less sedation, and better tolerance of stimulating interactions.^{13,14,17,19–26,28,31,32}

What is the referenced evidence for the CPV Strategy?

Table 1 describes the evidence base provided in many book chapters and narrative reviews that recommend the CPV strategy.^{1,2,4–7,13–53} Several points can be made based on this evidence. First, there seems to be much circular referencing among many chapters and narrative reviews when evidence for the CPV strategy is provided (Figure 1). Most statements made in the chapters and narrative reviews do not have a reference provided other than to another chapter or narrative review. Second, the empirical evidence base for the CPV strategy is limited. The main pathophysiological basis of the CPV strategy, the two-compartment lung model, has only one empirical published study. ³³ Indirect evidence for high resistance in the lung, describing expiratory forced flow limitation, included reference to several studies.^37,39–46 Improved outcomes using the CPV strategy was suggested by reference to several studies.^{4–7,49–53}

Figure 1.

Relationship map of cross-referencing among the book chapters and narrative reviews recommending the chronic phase ventilation strategy in most severe bronchopulmonary dysplasia.

Critical scrutiny applied to the supporting evidence provided

We examine the details of the empirical evidence base referenced in the many book chapters and narrative reviews for the CPV strategy (Table 2).^{4–7,33–57}

Table 2.

Original empirical studies that support the chronic phase ventilation strategy in established severe BPD.

Published study	Study findings	Comments
Two compartment lung model
Jarriel et al. (1993) 33	In n = 6 VLBW infants that “displayed clinical evidence of pulmonary gas trapping including, diminished breath sounds or wheezing, and chest radiographs that showed hyperexpanded lung fields” at age 26 (SD 16) days. Passive exhalation to PEEP 2–5 cmH2O could be modeled as two-compartments (A, relatively normal Rrs, Crs, and TCrs; and B, very high Rrs).	Compartment A “approximately 40% of the exhaled tidal volume on average.”
Shepherd et al. (2016) 17	In n = 1 “typical patient with severe BPD” passive exhalation was fit using a two-compartment model. No other details of the patient were given.	Compartment A was 38% of exhaled tidal volume.
Castile and Nelin (2010) 18	In n = 1 patient passive exhalation was fit using a two-compartment model. No other details of the patient were given.	Compartment A was 33% of exhaled tidal volume.
Wu et al. (2020) 34	A retrospective single-center cohort of infants born <32 weeks who had CTA and echocardiogram at 40–50 weeks PMA from 2011 to 2015 (over 60% excluded that did not undergo testing). Of 73 sBPD infants, 57 (78%) had moderate-severe parenchymal disease (Ochiai score ⩾8 on CTA; using score ⩾10, 39 (57%)), 48 (66%) PHTN, 44 (60%) large-airway disease, and 23 (32%) all three. PHTN and large-airway disease were associated with the composite outcome (death before hospital discharge, tracheostomy, or home pulmonary vasodilator therapy). Moderate-severe parenchymal disease was not associated with the composite outcome.	No data on possible lung compartments in sBPD lungs.
Coalson (2003) 38	A narrative review of “new” BPD pathology, which showed “a lack of increased complexity (a decrease in alveolarization), an abnormal capillary morphology and an interstitium with variable cellularity/fibroproliferation. Bronchiolar and vascular lesions are not as prominently evident but can be present, especially in infants with severe disease who are autopsied.” There were “negligible airway epithelial lesions.” Thus, a “picture of developmental arrest” with “unevenly expanded airspaces.”	No mention of different lung compartments.
Higano et al. (2018) 36	In 42 referred neonates (20 severe, 6 moderate, 7 mild BPD, 9 non-BPD), UET-MRI scores during quiet-breathing (35% on positive pressure ventilation) predicted respiratory support at NICU discharge and at 40 weeks PMA, and were the strongest predictor of respiratory support duration in multivariable models. Scores in sBPD were 9.6 (3.0) (based on 0–2 for each of hyperexpansion; mosaic lung attenuation; emphysema (number of cysts/regions); emphysema (size); fibrous/interstitial, triangular, subpleural opacities; distribution of bronchovascular bundles; and subjective impression). The MRI structural information was not related to lung function tests, flow limitation, ventilator settings, or ventilation strategy.	No mention of lung compartments. Of note, another MRI study in spontaneously breathing (without oxygen or respiratory support) preterm infants at 36.1 (range 32.2–51.4) weeks found no significant difference in ventilation inhomogeneity (differences in signal intensities that assessed overall lung quadrants in caudocranial and anterior-posterior direction) between mild, moderate, and sBPD. 55
Higano et al. (2017) 35	A study showing UET MRI intensity of lung regions in neonates is comparable to CT density. n = 1 infant had sBPD.	Unclear how this supports the theory of two compartments.
Expiratory flow limitation indicating a high respiratory system resistance lung compartment
Shepherd et al. (2018) 39	At PMA 52 (Interquartile range 45, 63) weeks, of infants with sBPD “who were failing to make significant progress” (included only “~15% of all patients with sBPD” ), RVRTC spirometry and body plethysmography were done. 56 (51%) had obstructive (FEV0.5 <80% predicted, and TLC ⩾90% predicted), 44 (40%) mixed (TLC <90% predicted, and FEV0.5 and/or FVC <90% predicted), and 10 (9%) restrictive (TLC <90% predicted and FEV0.5 and/or FVC ⩾90% predicted) phenotypes. Only SGA had a small association with restrictive/mixed phenotype. Although 78% of mixed phenotype had “moderate or severe” degree of obstruction, this assessment was not defined (how many had “severe” obstruction was not stated).	“Strikingly” longer ventilation days in the obstructive phenotype compared to mixed and restrictive phenotypes, suggesting that the mixed phenotype was not similar to the obstructive phenotype. Relevance of these to non-forced tidal breathing, and to when adequate PEEP is applied (to counteract small and large airway obstruction at low lung volumes), are unclear.
Robin et al. (2004) 41	In 28 infants with moderate to sBPD ( “based on their oxygen requirement at hospital discharge” ) being followed “for ongoing symptoms of BPD,” at 68 (SD 36) weeks PMA, using RVRTC spirometry, FEFs showed “mild to moderate” airflow obstruction (FEF75 mean 59.5% (30.7) of predicted in “normal healthy full-term infants” ), most pronounced at end-expiration ( “suggesting preferential dysfunction of the peripheral airways” ), and high FRC and RV/TLC (indicative of air trapping). There was no statistically significant difference between those with recurrent wheezing vs without recurrent wheezing in flow limitation, FRC, or RV/TLC. 6/17 (35%) showed significant bronchodilator responsiveness with improved FEF75 (but not FEF25–75, indicating response “was localized to the smallest airways” ).	No correlation between “any measures of forced flow and birthweight, gestational age, days of mechanical ventilation, or days of oxygen therapy.” Relevance of these to non-forced tidal breathing, and to when adequate PEEP is applied (to counteract small and large airway obstruction at low lung volumes) are unclear.
Filbrun et al. (2011) 42	In 18 infants referred by pulmonology with moderate to sBPD testing with RVRTC was done at 59 (SD 18) and 91 (SD 31) weeks. Average FEF75, “a measure of flow at low lung volumes” was “severely reduced” to 55 (31)% and 55 (28)% of predicted (in the previous publication by this group 41 , average FEF75 of 59.5% was said to be “mild to moderate” airflow obstruction, and not “severe”). FEF25–75 was 68% and 71% of predicted in normal infants. RV/TLC was also increased (indicative of air-trapping). Bronchodilator responsiveness in FEF75 in 6/15 (40%) and 4/14 (29%) at the two time-points. Somatic growth was associated with improved RV/TLC, but not with parameters of airflow.	No correlation between any measure of pulmonary function and birthweight, gestational age, days of mechanical ventilation, or days of oxygen therapy. Relevance of these to non-forced tidal breathing, and to when adequate PEEP is applied (to counteract small and large airway obstruction indicated by the “severe reduction in flows at low-lung volumes” ) are unclear.
Baraldi et al. (1997) 37	In 17 neonates with BPD (not clearly sBPD), testing used TVRTC, VmaxFRC was <40% predicted (in normal infants) in 12/17 (70%) and <2SD in 10/17 (59%). Low compliance at ages 3, 6, and 9, months, “approaching low normalcy limits at 12 mo of life.” Specific conductance “showed a biphasic trend decreasing in the first 12 months of life”; however, this was likely due to FRC being underestimated from the nitrogen washout technique until air-trapping improved by age 9 months.	No correlation between VmaxFRC and birth weight, gestational age, FIO2, oxygen dependence, or duration of mechanical ventilation. No significant correlation between VmaxFRC and resistance of the respiratory system. Relevance of these to non-forced tidal breathing, and to when adequate PEEP is applied (to counteract small and large airway obstruction at low lung volumes) are unclear.
Fakhoury et al. (2010) 45	In 44 children with BPD (“mainly represents the moderate–to-severe spectrum”), testing used TVRTC, low VmaxFRC was found at 6, 12, and 24 months, with no change over time, and with 24/44 (55%), 14/35 (40%), and 14/31 (45%) having a z-score <2SD. Bronchodilator response was initially present in 11/37 (30%), 7/33 (21%), and 5/26 (20%). Responders had lower VmaxFRC but with P-value 0.046 uncorrected for multiple comparisons.	No correlation between VmaxFRC and gestational age, birth weight, length of mechanical ventilation, or length of CPAP. Relevance of these to non-forced tidal breathing, and to when adequate PEEP is applied (to counteract small and large airway obstruction at low lung volumes) are unclear.
Thunqvist et al. (2015) 44	In 55 infants with BPD having lung function testing at 6 and 18 months (with significant attrition bias). Compliance was low at 6 months in moderate/sBPD (z-score −2.6 (−4.4 to −1.1) ). VmaxFRC, FEV0.5, and MEF50 were not different between mild vs moderate/sBPD, they were “below, or close to below, normal limits compared to reference values” (<−1.96 z-scores in 18/46 (39%), 21/34 (62%), and 21/31 (68%)). The “absolute negative change in VmaxFRC over time was more pronounced in mild than moderate/sBPD.” Plethysmographic FRC was “within normal limits.”	No correlation flow limitation between mild vs moderate/sBPD; became worse over time more in the mild vs moderate/sBPD. Relevance of these to non-forced tidal breathing, and to when adequate PEEP is applied (to counteract small and large airway obstruction at low lung volumes) are unclear.
Islam et al. (2015) 46	A “comprehensive review” of studies on respiratory outcomes of survivors of preterm birth since 1990 (with heterogeneous study populations and shifting definition of BPD). Respiratory outcomes in 17 papers examining the first 5 years found, overall, “signs of substantial airway functional impairment as exhibited by abnormal measures of FEV, VC, and FRC. . . Using the RVRTC technique demonstrated significant airflow obstruction [3 studies]. . . Abnormalities in forced expiratory flow were shown to persist over time. . . even when clinical course improved. . . an increase in RV/TLC were consistent with a significant degree of ongoing gas trapping [5 studies]. . . only 1/3 of patients had improvement in airflow limitation after administration of bronchodilator [2 studies].” In addition, “survivors of BPD have impaired respiratory function compared with full-term control subjects. . . In general, these differences were less apparent when comparing children born prematurely with BPD to those born prematurely without BPD.”	“Children with a diagnosis of BPD appear to develop [lung function] similarly to children without BPD [after adjusting for differences in weight]. . . Other studies have shown no significant difference between the pulmonary outcomes (cough, wheezing, rehospitalization, and inhalation therapy) of VLBW infants (birth weight <1500 g) with and without BPD.” At school-age (6–18yr): “Overall, there were mixed results as to whether children with a history of VLBW and BPD exhibited any difference in lung function when compared with children with a history of VLBW but without BPD. . . physiologic and radiographic abnormalities were not always accompanied by clinical symptoms.”
Sanchez-Solis et al. (2012) 53	Lung function measured using RVRTC in preterm infants (excluding those with SGA), 43 with (n = 9 sBPD) and 32 without BPD, at age 2–28 months. BPD males (but not females) had significantly lower forced flows (z-score differences FEV0.5 −0.52, FEF50 −0.5, FEF75 −0.66, FEF25–75 −0.78). No difference in VmaxFRC between BPD and non-BPD. No significant differences between mild, moderate, and sBPD.	The difference in flow limitation z-scores between BPD and non-BPD would be considered mild.
Wauer et al. (1998) 43	FRC difference measured by plethysmography and nitrogen washout was determined in healthy newborns (n = 17), premature neonates without BPD (n = 13), and premature neonates with BPD studied at 36 weeks PMA (n = 14) and discharge (n = 16) (among lung function performed “in 165 infants with artificial ventilation during the neonatal period,” excluding infants with “clinical signs of [upper] airway obstruction or with respiratory frequencies >60/min” ). Compared to controls, FRC(pleth-N2) was significantly higher in no BPD, and both BPD groups, but not between these groups.	FRC(pleth-N2) is usually thought to result from trapped air that does not get ventilated preventing nitrogen washout. The authors however “speculate” it was “an indication of lung areas with distinctly different time constants” that resulted in “gas not in free communication with airways.”
Hofhuis et al. (2002) 40	In 36 infants born VLBW with BPD, 28 at 6.2 (SD 0.9) months, and 31 at 12.6 (SD 1.1) months had VmaxFRC lung function testing. VmaxFRC z-score was −1.7 (SD 0.1) and −2.2 (SD 0.1), worsening—0.5 (P < 0.001) between the two time periods. VmaxFRC was less reduced (by z-score 0.6, P = 0.008) at 12 months in infants initially treated with HFOV vs. conventional mechanical ventilation, suggesting some of the airway damage was ventilator induced. May be “due to airway damage and dysfunction of peripheral airways and central airway damage and collapse during dynamic compression.”	Relevance of these to non-forced tidal breathing, and to when adequate PEEP is applied (to counteract small and large airway (i.e. central airway malacia) obstruction at low lung volumes) are unclear
Improved outcomes with the chronic phase ventilation strategy
McKinney et al. (2021) 6	Retrospective comparison of outcomes of sBPD in those born 2008–2010 vs 2011–2016, excluding patients “lost to follow-up before their first outpatient appointment, or if they had less than 1.5 years of follow-up data available.” A sBPD multidisciplinary team was established in 2011. Found shorter NICU length of stay, higher weight z-score at discharge, less failure to thrive, and less likely to be discharged on oxygen. No difference in z-score for length at discharge, rate of readmissions in first 2 years, diagnosis with asthma in first 5 years, tracheostomy, or PHTN.	No data on ventilator settings. In the discussion section, the authors wrote that high PEEP, long Ti, high VT, and low RR “were recommended.” The first emergency department visit occurred sooner after discharge after 2011. The multidisciplinary team “did not appear to have long-lasting effects” (e.g., effect on readmissions, asthma, PHTN, or length).
Kielt et al. (2021) 5	Retrospective cohort of sBPD referred to single center with an interdisciplinary BPD program, after PMA 36 weeks (median admission PMA 47 (42, 53) weeks, between 2010 and 2018. The patients had grade III/IV IVH in 13%, surgical NEC in 0%, and culture positive sepsis in 2%. Overall, 65/71 (92%) survived to hospital discharge (47 (72%) to home, 15 (23%) to their home hospital). For those admitted on invasive mechanical ventilation, 46/52 (88%) survived to hospital discharge. The Respiratory Severity Score in survivors (but not nonsurvivors, and not stated overall) decreased by a relative 16% at 2 weeks and 27% at 4 weeks after admission (“relatively rapid improvement in pulmonary function over time”).	No data on ventilator settings. In the discussion section, the authors wrote that admission to their NICU was “usually accompanied by a change in respiratory support. . . based on the physiology of two-compartment lung disease.”
Bauer et al. (2020) 52	Retrospective cohort of 151 (of 496 patients, a 30% follow-up rate) patients with moderate to sBPD at a single center, neurodevelopmental impairment (NDI) (any diagnosis of cerebral palsy or any BSID composite score <80) did not occur in 84 (56%) (in sBPD, no NDI in 15/32 (47%)). Predictors of NDI were birth weight, and hospital days. This was less NDI than in some historical cohorts.	No data on ventilation strategies used. The center used a “multidisciplinary approach. . . (that) emphasizes neurodevelopmentally appropriate care.”
Gien et al. (2017) 51	Retrospective single-center study of sBPD who had tracheostomy comparing periods 2000 to 2005 vs. 2006 to 2013 (after the interdisciplinary ventilator care program). Survival to hospital discharge increased from 7/14 (50%) to 23/27 (85%) (P = 0.017). Improved survival “may have been secondary to increased tracheostomy placement and decreased withdrawal of support as the age of death was significantly different between the two time periods [282.2 vs. 422.2 days, P < 0.01] and cause of death was withdrawal of support (21% vs. 7%).” In addition, although not statistically significant, more in period 1 had necrotizing enterocolitis, retinopathy of prematurity, intra-ventricular hemorrhage, PHTN, and were receiving PHTN medication, and there was lower median gestational age and age at tracheostomy, suggesting a sicker cohort.	An interdisciplinary ventilator care program “to standardize approaches to the multisystem morbidities associated with severe ventilator-dependent BPD, to improve communication and continuity of care, and ultimately to improve survival.” No data on ventilator settings. In the discussion section, the authors wrote “in general, patients were transitioned. . . to a more chronic ventilator approach.” Of note, similar survival to hospital discharge was reported in 348 NICUs among infants having tracheostomy for BPD, 320/396 (81%), most likely not having an interdisciplinary ventilator care program. 56
Murthy et al. (2017) 50	Infants born <32 weeks referred to any of 29 Children’s Hospitals Neonatal Database NICUs between 2010 and 2013. Excluded if died or discharged prior to 36 weeks PMA (n = 7), had tracheostomy prior to referral (n = 14), or had airway or neurological abnormalities that may have served as indication for tracheostomy (n = 176). Of 2407 infants, 93 (6.7%) died prior to tracheostomy, 187 (13.5%) received a tracheostomy (of whom 27 (14.4%) died). Center was independently associated with death or tracheostomy (range 2%–46%) after adjusting for many pre- and postreferral characteristics. Center was not associated with death alone.	No data on ventilator settings, or ventilator strategies.
Baker et al. (2016) 7	An interdisciplinary ventilator care program developed a road map to standardize the discharge process for children with tracheostomy requiring chronic ventilation. This included creating discharge materials, instruction videos, a dedicated advanced practice nurse and rehabilitation respiratory therapist, simulation modules, and care conferences. In 2-year pre- and postintervention periods the length of stay and costs decreased, without a negative impact on patient safety. There were 8/18 and 16/30 patients in the pre- and postintervention periods with BPD, but data was not presented separately for BPD.	No data on ventilator settings or ventilator strategies. BPD practices were likely the same as in Gien et al. (2017) 51 , as this was from the same center.
Trittman et al. (2013) 4	Retrospective study of infants born at <27 weeks and transferred to referral center from 2004 to 2010. Neurodevelopmental impairment (available in 85%, BSID-III composite score cognitive, communication, or motor, <80, or cerebral palsy) was associated with mechanical ventilation ⩾28 days, grade III/IV intraventricular hemorrhage, and discharge at >43 weeks PMA, and not with discharge on oxygen.	No data on ventilator settings or ventilator strategies. A previous publication by this group wrote “The Small Baby Guideline did not include specific recommendations for ventilator strategies.” 57
Shepherd et al. (2012) 49	From 2007 to 2008 (excluding patients who had grade III/IV intraventricular hemorrhage or periventricular leukomalacia) 107/126 (85%) had Bayley-III determined at 18–24 months, and were compared to National Institute of Child Health and Human Development Neonatal Research Network BSID-II scores in 2005. For sBPD (n = 46), cognitive or language <70 15.2% vs. 49.8% (P < 0.005) and motor <70 10.9% vs. 41.7% (P < 0.005). One-month readmission rates before (2003) and after (2004–2008) dropped from 29% to <10%. Using a corrected Bayley-III cutoff score of 77 (to account for differences between BSID-II and Bayley-III scores), for sBPD cognitive or language was better (P < 0.002), but motor scores were not different (P = 0.23) - no numbers or proportions were given for this comparison.	An interdisciplinary team to “foster a physical and therapeutic environment that empowers the family to participate in the care,” with “developmental therapies three to five times per week.” No data on ventilator settings. In the introduction section, the authors wrote that they use “minimal-impact respiratory support. . . necessitating a slow respiratory rate to allow full exhalation.”

BSID: Bayley Scales of Infant Development; CTA: CT angiography of the lungs; FEF: forced expiratory flow; FEV: forced expiratory volume; FIO2: fraction of inspired oxygen concentration; FRC: functional residual capacity; FVC: forced vital capacity; MEF: maximal expiratory flow; PEEP: positive end expiratory pressure; PHTN: pulmonary hypertension; PMA: postmenstrual age; RR: respiratory rate; RV: residual volume; RVRTC: raised-volume rapid thoracic compression; sBPD: severe BPD; SD: standard deviation; SGA: small for gestational age; Ti: inspiratory time; TLC: total lung capacity; TVRTC: tidal volume rapid thoracic compression; UET-MRI: ultra-short echo time magnetic resonance imaging of the lungs; VC: vital capacity; VLBW: very low birth weight; VmaxFRC: maximal expiratory flow at functional residual capacity; VT: tidal volume.

What is the evidence for the two-compartment model of the lung?

The evidence is based on modeling the flow-volume loop of the lung. The only published study to do this included six VLBW infants “that displayed clinical evidence of pulmonary gas trapping including, diminished breath sounds or wheezing, and chest radiographs that showed hyperexpanded lung fields” at 26 (Standard Deviation, SD 16) days of life, using passive flow-volume loops during exhalation to PEEP 2–5 cmH2O. ³³ Despite the selection bias and small sample size, the long time-constant compartment was modeled as containing 60% of the exhaled VT. ³³ Two other infants are described, one in each of two chapters, with no details of their clinical state; the long time-constant compartment was modeled as containing 62% and 67% of the exhaled VT.^17,18 The other referenced studies did not provide data to suggest a two-compartment lung.^32–36,38 One MRI lung imaging study found that lungs with higher scores (e.g. hyperexpansion, emphysema, and lung opacities) were associated with respiratory support at 40 weeks PMA; ³⁶ yet, another MRI study found no significant difference in ventilation inhomogeneity (using differences in signal intensities) between mild, moderate, and severe BPD. ⁵⁵

The relevant empirical data are limited by small sample size, selection bias, and modeling (i.e. it is unclear how to extrapolate from modeling the flow-volume loop to actual ventilation as if the lung has two independent compartments). This is particularly the case given that 60% of the lung is theorized to be in the long time-constant compartment, not a large majority of the lungs.^{15,17,22,23,31} Despite these limitations, the two-compartment model has been used to produce Figure 2, reproduced in many of the chapters and reviews as the main justification for the CPV strategy.^1,2,14,21,31

Figure 2.

Theoretical effects of mechanical ventilator strategies for severe bronchopulmonary dysplasia.

Does evidence for forced expiratory flow limitation indicate a high respiratory system resistance lung compartment?

There are many references for flow limitation in severe BPD (sBPD), detailed in Table 2.^{37,39–46,53} Forced expiratory flow was measured using the tidal volume rapid thoracic compression technique (TVRTC, measuring Vmax at functional residual capacity (FRC), that is, at low lung volume)^37,40,44,45 or raised-volume rapid thoracic compression technique (RVRTC), measuring forced flows at various lung volumes.^39,41,42,53 There are several limitations of these studies including selection, referral, and/or attrition bias,^39,40–44 not being limited to msBPD (or even to sBPD),^{39–42,44,45} and small sample sizes.^37,41,42 Many studies found the flow limitation was mild to moderate,^37,41,42,44 most pronounced at low lung volumes,^{37,40,41,44,45,53} and unrelated to recurrent wheezing, ⁴¹ birthweight,^37,41,42,45 GA,^{37,39,41,42,45} days of mechanical ventilation,^37,41,42,45 days of oxygen therapy,^37,41,42 somatic growth, ⁴² or resistance of the respiratory system, ³⁷ that is, to the severity of BPD.^44,53 There was little change of forced expiratory flow limitation over time,^42,45,46 and often worsening over the first year of life,^40,44 even when the clinical course was improving. ⁴⁵ The flow limitation was less apparent when BPD infants were compared to preterm infants without BPD.^43,46,53 A more detailed critique of the largest and frequently referenced study, particularly concerning selection bias, unexpected physiologic findings, and difficulties in performing RVRTC in invasively ventilated patients, are given in the Supplemental discussion.^39,58–61

The relevance of forced expiratory flow to respiratory system resistance during tidal ventilation in infants with msBPD is unclear. This is particularly the case given the lack of association with many markers of the severity of BPD, the lack of improvement in forced expiratory flow as the respiratory clinical course improved, and minimal difference between BPD and non-BPD ex-preterm infants.^{37,39,42–46,53} Studies did not rule out intrathoracic tracheomalacia or bronchomalacia, which are common in msBPD, and will result in severe flow limitation on airway collapse during forced expiration. ⁶² Moreover, application of PEEP in invasively ventilated infants would be expected to prevent not just tracheal or bronchial collapse but also small airway collapse at low lung volumes responsible for the expiratory flow limitation.^{13–15,20,25,28,31} Finally, it is unclear how long Te is achieved with low set ventilator RR, when the spontaneous RR (usually well above 20 breaths/minute) will interrupt and shorten the predicted Te. Asserting that the pressure-supported spontaneous breaths only ventilate the fast time-constant compartment,^{13,14,21,22,28} not interrupting the long Te, does not make physiological sense. The relevance of these studies in relation to the theorized two-compartment lungs of msBPD infants is therefore, at best, unclear.

What is the evidence for improved outcomes using the CPV strategy?

There are many references suggesting improved outcomes (Table 2).^{4–7,49–52} These studies have limitations, including being retrospective,^4–6,51,52 historical controls,^6,7,49,51,52 single-center,^{4–7,49,51,52} with attrition^6,52 and referral^4,5 bias, and all with absent data on ventilator settings,^{4–7,49–52} and using multidisciplinary complex multipronged interventions.^{4–7,49,51,52} Some vaguely suggested they might be using the CPV strategy, highlighting the use of “minimal-impact respiratory support. . . necessitating a slow respiratory rate to allow full exhalation,” ⁴⁹ admission to the referral NICU was “usually accompanied by a change in respiratory support. . . based on the physiology of two-compartment lung disease,” ⁵ “in general, patients were transitioned. . . to a more chronic ventilator approach,” ⁵¹ high PEEP, long Ti, high VT, and low RR “were recommended.” ⁶ A few of the referenced studies did not attempt to determine whether there were improvements in outcomes by comparing interventions or time-periods.^4,5,50

Outcomes that improved with interdisciplinary teams included shorter NICU length of stay^6,7 (one study focused on an intervention to improve the discharge process in infants with tracheostomy, and data were not reported separately for BPD patients ⁷ ); higher weight z-score at discharge, less failure to thrive, and lower likelihood to be discharged on oxygen (without difference in z-score for length at discharge, or in longer-term outcomes of readmissions in first 2 years, diagnosis with asthma in first 5 years, tracheostomy, or PHTN, and with an earlier first ED visit); ⁶ less neurodevelopmental impairment ⁵² and improved Bayley-III cognitive and language scores, ⁴⁹ and improved survival. ⁵¹ These improvements must be considered in the context of study limitations, particularly that no study directly examined the effect of using the CPV strategy, and the use of historical controls. For example, the improved survival in one study ⁵¹ was similar to the contemporaneous survival reported across 348 NICUs among infants having tracheostomy for BPD, presumably with most not having an interdisciplinary ventilator care program. ⁵⁶ A more recent example in two BPD commentaries is discussed in the Supplemental Material.^54,63,64

Overall, studies did not examine or demonstrate an effect of the CPV strategy on any neurodevelopmental, lung, or survival outcome. The good outcomes among some of these centers are to be commended. Focusing on developmental care with an interdisciplinary BPD team,^31,65 to “foster a physical and therapeutic environment that empowers the family to participate in the care,” with “developmental therapies three to five times per week” ⁴⁹ is good practice. ⁶⁶ However, this does not demonstrate that the CPV strategy was responsible for improved outcomes.

Is the CPV strategy based on sound pathophysiology: Might the strategy be harmful?

We present evidence to argue that the CPV strategy is based on unsound physiology and may potentially be harmful (Table 3).^67–87

Table 3.

Publications suggesting the chronic phase ventilation strategy in established severe BPD is not supported by consensus, and can be harmful to lungs with heterogeneous time constants.

Published study	Study findings	Comments
Variable practice at expert centers indicating a lack of consensus
McKinney et al. (2022) 67	A multicenter BPD collaborative point prevalence study of 96 infants on IPPV for sBPD in 2019. At median PMA 52 (interquartile range 44, 64) weeks, there was significant variation in ventilator settings: median VT ⩾8 ml/kg in 6/10 centers, median PIP ⩾30 cmH2O in 5/11 centers, median RR ⩽20 in 6/14 centers, and median Ti ⩾0.6 sec in 6/13 centers.	Variation “reflects a lack of prospective, RCTs to specifically examine the relative merits of such strategies.” No outcome data.
Kielt et al. (2023) 68	The above study, by unsupervised clustering analysis of 78 infants on IPPV for sBPD in 2019 at PMA 54 (interquartile range 43, 66) weeks from 14 BPD Collaborative centers, identified “three discrete approaches to mechanical ventilation for infants with established type 2 sBPD,” that differed significantly in “median PIP, PEEP, set RR, and Ti,” and “varied significantly by center.” Cluster 3 (n = 18) had lower median PIP, PEEP, and MAP compared to clusters 1 and 2. Cluster 1 (n = 31) had lower PIP, higher set RR, and lower Ti compared to Cluster 2.	“Reflects a lack of agreement among providers regarding the best approaches of ventilatory care for infants with established type 2 sBPD. . . reflect the lack of compelling evidence to inform best ventilatory practice.” The differences “may be driven by center-specific strategies rather than physiologic or phenotypic differences between subjects.” No outcome data
Manimtim et al. (2023) 8	Multicenter BPD Collaborative Outpatient Registry study of infants with sBPD with tracheostomy and discharged home on ventilator support (excluded those who died after tracheostomy but before hospital discharge). Found variable median ages for all key events (tracheostomy placement, hospital discharge, ventilator liberation, tracheostomy decannulation) that differed significantly by center.	No information on ventilation strategies.
Amplification of lung injury in heterogeneous lungs
Lungs in sBPD have heterogeneous structure and pathology
Higano et al. (2022) 69	A review article found: CXR (showing “mixed areas of density and hyperlucency,” and “mixed lucent and opaque areas,” “a bubbly cystic appearance with coarse opacities intermixed with hyperlucent areas” characteristic of BPD), CT (showing hyperaeration (air-trapping, mosaic perfusion), emphysema (cysts), structural change (linear opacities, triangular subpleural opacities, and atelectasis/consolidative opacities) ), and MRI (high-intensity lung (fibrosis, edema, consolidation, atelectasis), abnormally hyperdense and hypodense tissue), all that suggest heterogeneous lung being inflated.	-
Van Mastrigt et al. (2016) 70	Review article (with references to many empirical BPD studies) 9 different semiquantitative high-resolution CT scoring methods to evaluate BPD found “decreased pulmonary attenuation (including mosaic perfusion, emphysema, and bullae), opacities (liner and/or subpleural triangular), consolidations (collapse and/or atelectasis), and bronchial wall thickening (found in children >8 years). . . and architectural distortion of the lung [abnormal displacement of bronchi, vessels, fissures, and/or septa].”	“Although ‘new’ BPD seems to have a different histopathological background, CT findings in infants with ‘new’ BPD show similar abnormalities and are still found to be associated with mechanical ventilation and oxygen exposure. . . structural changes remain fairly stable over time.”
Ochiai et al. (2008) 71	High-resolution CT at 41 weeks 6 days PMA (range 34 to 72 weeks 3 days) scoring system developed from n = 42 with BPD had acceptable reproducibility, and correlated with the clinical score at 36 weeks PMA (4 probable, 15 mild, 20 moderate, 3 sBPD) and the duration of oxygen therapy, but not with mechanical ventilation period. The score was based on hyperexpansion (including focal/global hyperexpansion, mosaic pattern of lung attenuation, intercostal bulging), emphysema (including number of bullae or blebs, size of bullae or blebs), and fibrous/interstitial changes (triangular subpleural opacities, distortion, or thickening of bronchovascular bundles, consolidation).	The scoring system often used to grade High Resolution CT severity of BPD.
In lungs with heterogeneous structure, ventilator-induced lung injury (VILI) is amplified
Von During et al. (2025) 72	Review article (with reference to many empirical non-BPD studies). VILI mechanisms are thought to be from volutrauma, atelectrauma, and biotrauma. These mechanisms are encompassed by mechanical power (MP), the total amount of energy transferred by the ventilator to the respiratory system over time. Limiting MP is a promising strategy to mitigate disruptive deformation of cells and the extracellular matrix caused by a high-energy load over time. MP was associated with increased risk for developing ARDS, mortality, and postoperative complications “across diverse patient populations.”	A main determinant of MP is dynamic ∆P = Ppeak – PEEP. This is 4× more important than RR in predicting mortality in patients with and without ARDS. “However, static measurements of CRS and ∆P using Pplateau may underestimate the maximum pressure experienced by vulnerable lung units during dynamic inflation in heterogeneous lungs.”
Ter Horst et al. (2024) 73	Review article (with references to many non-BPD empirical studies). VILI is from a combination of lung stress (retracting force experienced by the stretched lung) and strain (the deformation in size and shape of lung structure during a tidal breath). Mechanisms include volutruama, atelectrauma (increased pressure at the interface of open and closed alveoli), biotrauma, unified in the concept of MP (estimate of the mechanical energy per minute being applied to the respiratory system). Higher MP in adults was associated with mortality in ARDS. In children, higher MP was associated with longer ventilation time, and pro-inflammatory response, and in those with acute lung injury, higher mortality.	-
Marini et al. (2024) 74	A conceptual modeling study. Characterized “the amplification of stress (tension) and strain (area change) that occur under static conditions at interface boundaries between a sphere’s surface segments having different compliances.” Moreover, “although the airway pressure applied under no-flow conditions may be the same everywhere in healthy lungs, the pressures and stresses within a mechanically ventilated non-uniform ARDS lung are not.” Amplification multipliers occur when surfaces “undergo different amounts of stretch in response to the pressure increment, [that then] generate shear stresses at their interface. . .”	Amplification of stress is a ratio of tensions between surfaces. In the model, the difference between surfaces was due to different compliances. The same will occur, and actually be worse, due to different resistances. For example, with radius given by R, when one sphere has tension1 = (P)(R1/2), and the other T2=(¾P)(R2/2), since in compartment 2 only ¾ the pressure is experienced due to higher resistance. Then the tension or stress multiplier = T1/T2 = (R1/R2)(4/3).
Gattinoni et al. (2016) 75	Ventilator-related causes of lung injury may be unified in a single variable: the mechanical power, which increases exponentially with VT, driving pressure (∆P), inspiratory flow, and RR, and linearly with PEEP. Lung conditions favoring VILI depend on decreased lung dimensions (the smaller the “baby lung,” the lower the mechanical power needed to induce damage should be), increased inhomogeneity (an inhomogeneous distribution of forces), and cyclic collapse and decollapse.	No data on lung injury.
Marini et al. (2019) 76	To cause damage, a pressure (stress) must be paired with a volume change (strain). Mechanically, heterogeneous zones are most at risk of injury, with stress amplified “at the junction of mechanically dissimilar tissues. . .”. Power may “eventually overwhelm” relatively intact lung by “progressive overloading of still-intact filamentous interstitial elements by ‘sequential dropout’ [of stress-bearing elements].”	Theoretical discussion article.
Ventilation to long time constant regions is not improved by low RR, Long Ti, and Long Te
Gouwens et al. (2020) 77	UET-MRI in 17 nonsedated quiet-breathing infants with sBPD, at PMA 42 (SD 3) weeks, found Ti and RR did not correlate with VT of any analyzed lung region (total lung, total lung cysts, noncystic lung, or large cysts), and that PIP correlated with total lung and noncystic VT (but not with lung cyst VT).	Negative VT in “about a quarter of the large cysts” could be result of “pendelluft air movement from one region of the lung to the next.” “Contrasting with present theories that long Ti and slow RR are required to move air through the heterogeneous chronic BPD lung.”
Lungs in young infants with BPD have do not have inhomogeneous ventilation, not supporting a two-compartment model
Proietti et al. (2012) 78	Prospective study of 142 preterm infants at 44 weeks PMA having lung function during nonsedated sleep. LCI (the number of lung volume turnovers in terms of FRC required to reduce the sulfur hexafluoride to 1/40th the starting concentration; a measure of ventilation inhomogeneity) and tidal flows (tidal expiratory flows at 25%, and 50% of the remaining VT, and peak flow) were not associated with subsequent symptoms (during first year of life), with no differences between no or mild BPD versus moderate or sBPD.	—
Latzin et al. (2009) 79	At PMA 44 weeks, during nonsedated natural sleep in spontaneously breathing preterm (n = 58 no BPD; mild 44, moderate 53, sBPD 30) and healthy term born (n = 181) infants, with attrition due to quality control not being adequate (in 27 preterm and 44 term infants). There was “no clear trend in changes of FRC adjusted for body weight with increasing disease severity,” and LCI “did not differ systematically between groups.” There were “increased peak expiratory flows with disease severity.” The time to peak tidal expiratory flow (relative to expiratory time) was decreased with disease severity, “suggestive of a lower compliance with increasing disease severity.”	“Alternatively, lower LCI in these infants may also reflect the milder degree of ‘new’ BPD with more peripheral location of airway involvement and airway closure leading to more regional [e.g. dorsal lung collapse] than overall changes in ventilation distribution.”
Schulzke et al. (2010) 80	Prospective follow-up study of preterm and term healthy controls studied in quiet sedated sleep at 15–18 months corrected age. “Indices of ventilation inhomogeneity were unaltered by GA and the duration of endotracheal ventilation.” LCI and ventilation inhomogeneity during the early phase of, and at the end of, the washout were associated with body size, but not respiratory support days, endotracheal ventilation days, supplemental oxygen days, BPD, nor wheeze, or asthma during the first year of life. Change in LCI from newborn age to 15–18 months were not associated with “GA, neonatal lung disease, or any other explanatory variable considered.”	“Elevated ventilation inhomogeneity indices reflect poor gas mixing efficiency of the lungs,” and were not associated “with preterm birth and markers of neonatal lung disease.”
Hulskamp et al. (2009) 81	In 219 nonsedated preterm and term infants during quiet sleep, during the first few months of life, at 3 NICUs, lung function was determined in term controls (n = 64), preterm controls (n = 59), respiratory distress syndrome (n = 54), and BPD (n = 42) (at 41.3 (SD 3.8) weeks PMA). Increased LCI (ventilation inhomogeneity) had “very small but significant” association with duration of supplemental oxygen. Lower FRC was associated with reduced GA and birth weight z-score, and a “small but significant contribution” of supplemental oxygen days.	Some intercenter differences, which “could have confounded a smaller study or one relying on normative data collected elsewhere.”
Forced flow limitation may not be clinically relevant to severe BPD
Mahut et al. (2007) 82 a	Chest high-resolution CT and lung function testing in referred (“because of uncontrolled respiratory symptoms”) patients (n = 41) with BPD (19 with sBPD) at 16.0 (SD 3.2) months of age. VmaxFRC was below −1 (z-score) in 63%, suggesting an obstructive pattern. None of: FRC, frequent symptoms, or CT abnormalities (hyperlucent areas, bullae, linear opacities, and subpleural opacities) correlated with VmaxFRC. Lower compliance was associated with more CT abnormalities.	Hyperlucent areas “may therefore correspond mainly to abnormal alveolar development and reduced distal vascularization.” The results “do not argue for considering CT or lung function tests as helpful in routine practice in the care of infants with symptomatic BPD.”
O’Connor and Davies (2021) 83	In premature neonates (median GA 25.1, interquartile range (IQR) 24.2, 26.5 weeks, born at 23 to <30 weeks) with BPD, conventional mechanical ventilation at day 28 (n = 65), 42 (n = 27), and 56 (n = 13) was with VT median (IQR) 4.5 (4, 5), 4.7 (3.9, 5.3), and 4.7 (4.3, 5); RR 40 (40, 50), 50 (40, 55), and 35 (25, 45); and FIO2 29% (25, 35), 33% (30, 36), and 30% (28, 35). This provided blood gas pH median ⩾7.3 and pCO2 median ⩽56 at all-time points, “objectively showing that the VTs used (medians of 4.5–4.7 ml/kg) provided adequate ventilation.”	Concluded that patients “can be ventilated with much smaller tidal volumes and higher rates than those currently recommended. The use of smaller tidal volumes will indubitably reduce volutrauma. . .”
Friedrich et al. (2006) 84	In 62 preterm (33.4 (SD 2.11) weeks GA) infants having had <48 h supplemental oxygen, RVRTC found low (and below 5th percentile) FEF50 (31%), FEF75 (32%), FEF25–75 (32%), and FEV0.5 (10%) compared to 27 healthy full-term control infants.	“Prematurity is independently associated with reduced lung function,” with “some degree of airway obstruction.”

FRC: functional residual capacity of the lung; GA: gestational age; IPPV: invasive positive pressure ventilation; LCI: lung clearance index; PEEP: positive end expiratory pressure; PIP: peak inspiratory pressure; PMA: postmenstrual age; RCT: randomized controlled trial; RR: respiratory rate; RVRTC: raised-volume rapid thoracic compression; sBPD: severe bronchopulmonary dysplasia; SD: standard deviation; Te: expiratory time; Ti: inspiratory time; UET-MRI: ultra-short echo time magnetic resonance imaging of the lungs; VmaxFRC: maximal expiratory flow at functional residual capacity; VT: tidal volume.

a

In a systematic review, ⁷⁰ and the European Respiratory Society Guideline, ⁸⁵ this was found to be the only study examining the relation of high-resolution CT and lung function tests in patients with BPD under 2 years of age. One other study of 86 preterm children at 36 (SD 2) weeks PMA included 24 with BPD, but did not report results separately for BPD patients; in that study, lung resistance was not associated with the number of high-resolution CT abnormalities. ⁸⁶

Is there consensus on the CPV strategy?

Most of the chapters and narrative reviews^{1,2,13–15,17–19,22,24–26,28–32} and outcome studies discussed above^{4–7,49,51,52} were written by members of the BPD Collaborative. However, there does not appear to be a clinical consensus within that Collaborative. There was significant variation in ventilator settings among centers, including in VT, PIP, RR, and Ti. ⁶⁷ A clustering analysis suggested “three discrete approaches to mechanical ventilation for infants with established type 2 sBPD” differing in “median PIP, PEEP, set RR, and Ti” and that “varied significantly by center.” ⁶⁸ There were also variable ages for tracheostomy and discharge among centers. ⁸ The variability “reflects a lack of prospective RCTs to specifically examine the relative merits of such strategies” ⁶⁷ and “a lack of agreement among providers regarding the best approaches to ventilatory care for infants with established type 2 sBPD.” ⁶⁸

Many of the chapters and reviews also stated, regarding the CPV strategy, that there are “no objective studies,”^1,18 “absence of clinical trial evidence,” ¹⁴ “evidence from RCTs is lacking,” ¹³ “lack of high-level evidence,” ²² “no high-level evidence. . . no RCTs have been done,” ²⁴ “limited existence of robust clinical trials,” ²⁸ “no clinical trials to validate,” ³¹ “paucity of prospective human studies,” ³⁰ “absence of evidence from prospective RCTs,” ¹⁹ and “not subject to any prospective trials.” ²⁴ The implication seemed that the only option (other than CPV) is to await RCTs, which may not be feasible. However, when there are no RCTs, we should critically scrutinize other evidence available including observational studies, detailed pathophysiology, and indirect evidence, as we do below.

Might ventilator-induced lung injury be amplified in msBPD lungs with heterogeneous structure and pathology?

The lungs in msBPD have heterogeneous structure and pathology. The CXR, high-resolution CT scan (HRCT), and MRI of lungs in sBPD show “coarse opacities intermixed with hyperlucent areas”; hyperaeration, emphysema (cysts), and structural change (opacities); and abnormally hyperdense and hypodense tissue. ⁶⁹ In particular, HRCT scoring methods have found decreased pulmonary attenuation (emphysema and bullae), opacities, consolidations, and architectural distortion, that remain fairly stable over time.^60,61 This is compatible with sBPD pathology showing “unevenly expanded airspaces.” ³⁸

Ventilator-induced lung injury (VILI), from volutrauma (the force (stress) causing excessive stretching and distension of airspaces (strain)) and atelectrauma (repeated opening and closing of airspaces causing shear injury), may be unified by the concept of mechanical power (MP), the total amount of energy transferred by the ventilator to the respiratory system over time, deforming cells and extracellular matrix to “eventually overwhelm” lung tissue.^72,73,76 The MP has been associated with increased risk for developing ARDS, mortality, and postoperative complications in adults, ⁷² and with longer ventilation time, pro-inflammatory response, and, in those with acute lung injury, higher mortality in children. ⁷³ A main determinant of MP is ∆P_dyn = P_peak – PEEP, ⁷² and MP increases exponentially with VT, ∆P, inspiratory flow, and RR, and linearly with PEEP. ⁷⁵ Moreover, stress (tension) and strain (area change) are highly amplified at “a sphere’s surface segments having different compliances [and, we calculated, these are even more amplified when due to different resistances].” ⁷⁴ Surfaces that “undergo different amounts of stretch in response to the pressure increment, generate shear stresses at their interface.” ⁷⁴

Importantly, static measurements of ∆P “using P_plat may underestimate maximum pressure experienced by vulnerable lung units during dynamic inflation in heterogeneous lungs.” ⁷² This is because “although the airway pressure applied under no-flow conditions may be the same everywhere in healthy lungs, the pressures and stresses within a mechanically ventilated non-uniform ARDS [and, we hypothesize, msBPD] lung are not,” ⁷⁴ explaining the importance of using P_peak in calculation of ∆P_dyn. Pendelluft describes the phenomenon where inhomogeneous inflation or deflation of the lungs can cause dynamic pressure differences between regions and lead to interregional airflows, concentrated in poorly ventilated regions of the lung (i.e. may be more prominent in diseases with significant heterogeneity in both resistance and compliance (such as emphysema)). ⁸⁷ Pendelluft may lead to underestimation of the alveolar pressure using inspiratory hold to achieve zero flow ¹⁸ and may explain negative VT in some cysts in BPD lungs. ⁷⁷

These considerations suggest that in the structurally heterogeneous lungs of msBPD, VILI will be amplified, be related to VT and ∆P_dyn, and this is the case in both the theorized two-compartment lung (due to high resistance in one compartment) and in lungs with emphysema, cysts, bullae, and opacities (as in msBPD), each with different compliances. Indeed, we speculate whether the two-compartment modeling might be modified to reflect not different resistances, but rather different compliances due to some areas of lung being cystic and emphysematous, with expanded airspaces that fill more rapidly. Many of the chapters and narrative reviews seemed to imply that since lung injury had already occurred in established msBPD, VILI was not (or much less) of concern.^{1,15,17,19,20,23–26,30–32} However, as stated in the European Respiratory Society guideline on long-term management of BPD, “studies have shown that children with BPD have an impaired lung structure, lower lung function, including declining lung function over time, and increased risk of respiratory symptoms in later life. . . Previous studies observed elevated neutrophils and oxidative stress in airways, measured by induced sputum and exhaled breath condensate respectively, in children aged 11 years or adolescents born preterm compared with children born at term. This suggests that BPD reflects an ongoing respiratory disease after birth with long-term consequences and not just stabilized structural lung damage after the neonatal period.” ⁸⁵

Is ventilation in msBPD heterogeneously distributed as theorized by the CPV strategy and two-compartment model?

The lungs in msBPD have heterogeneous structure and pathology; however, this does not necessarily mean that ventilation is heterogeneously distributed. To our knowledge, the only study to empirically determine whether long Ti and slow RR improved the distribution of ventilation to the lungs of msBPD patients did not confirm this theory. ⁷⁷ Using UET-MRI in 17 nonsedated quiet-breathing infants with sBPD at PMA 42 (SD 3) weeks, Ti and RR did not correlate with VT of any analyzed lung region (total lung, total lung cysts, noncystic lung, or large cysts), “contrasting with present theories that long Ti and slow RR are required to move air through the heterogeneous chronic BPD lung.” ⁷⁷

Using lung clearance index (LCI) as a measure of ventilation inhomogeneity (the number of lung volume turnovers in terms of FRC required to reduce the inhaled sulfur hexafluoride to 1/40^th the starting concentration), studies in BPD patients found no differences between mild, moderate, and severe BPD,^78,79 no association with subsequent respiratory symptoms in the first year,^78,79 no association with respiratory support days, endotracheal ventilation days, supplemental oxygen days, or BPD, ⁸⁰ or only a ”very small but significant” association with duration of supplemental oxygen. ⁸¹

To our knowledge, the only study to examine the relationship between lung function testing and HRCT in BPD found VmaxFRC was below −1 z-score in 63%, suggesting an obstructive pattern; however, none of FRC, frequent symptoms, or HRCT abnormalities (hyperlucent areas, bullae, linear opacities, and subpleural opacities) correlated with VmaxFRC. ⁸² Studies also suggested that forced expiratory flow is similar in BPD when compared to non-BPD preterm infants,^43,46,53 with forced flow limitation in many preterm infants having had <48 h of supplemental oxygen. ⁸⁴ We conclude that forced flow limitation does not reflect inhomogeneous ventilation, and is compatible with structurally inhomogeneous lungs that are relatively homogeneously inflated.

Has critical care medicine found treatment based on physiology alone to be harmful?

The CPV strategy is based on physiology alone.^{1,13,14,17–22,24,25,28–32} This has often not served the field of critical care well, with practices based upon what, at one time, seemed to be sound physiology later proven to be ineffective, and even harmful (Supplemental Table S2).^{72,73,88–98} Sometimes this was based on inaccurate interpretation of physiology, and other times on attempting to achieve physiologic targets alone (Supplemental Table S2, and Supplemental discussion).^{72,73,88–98}

In our opinion, based upon evidence reviewed above, we are concerned that both these errors are being made using the CPV strategy in msBPD. First, inaccurate physiology, based upon likely inaccurate interpretations of the two-compartment model and forced expiratory flow limitation, is being used to predict inhomogeneous distribution of lung inflation and better distribution with low RR and long Ti. How long Te is achieved with low set ventilator RR, when the spontaneous RR will interrupt and shorten the predicted Te, is unclear. Second, attempting ventilation to achieve proposed physiologic targets alone, is a strategy which may have the undesired effect of worsening VILI in the heterogeneous lungs of msBPD.

Putting it all together: making unstated premises explicit

Applying critical scrutiny to the suggested CPV strategy revealed several explicit premises and many implicit premises that were not supported (and sometimes refuted) by evidence (Supplemental Table S1). Based on this, we suggest several empirical questions that should be investigated in msBPD before the CPV strategy can be supported (Table 4).

Table 4.

Empirical questions warranting investigation before the chronic phase ventilation strategy can be supported.

Topic	Questions
Modeling lung compartments	Does modeling support hypotheses other than the two-compartment lung (e.g. lung with different compliances)? With PEEP set to prevent end-expiratory collapse, does modeling support a two-compartment lung, or forced flow limitation? Are the two modeled lung compartments ventilated separately such that directing ventilator settings (high VT, low RR, and long Ti) to one hypothesized compartment will not adversely affect the other modeled compartment?
Ventilator settings in the CPV strategy	Do settings with high VT, low RR, and long Ti improve ventilation of the whole lung in msBPD? Will this improve homogeneity of lung ventilation in msBPD? Do settings with high VT and PIP cause volutrauma or tidal recruitment and amplified VILI? Do settings with high VT, low RR, and long Ti resolve air trapping and lead to lower PIP and improved V/Q matching reflected by reduced FIO2 needs? Does higher spontaneous RR than set RR result in shortened Te in the hypothesized lung compartment with high resistance?
Outcomes when using the CPV strategy	Are outcomes of survival, hospital stay, ventilation duration, and lung growth improved with the CPV strategy? Are outcomes of patient comfort, tolerance of activity, and developmental stimulation, or long-term (e.g. 2- or 5- year-old) neurodevelopmental and neurocognitive outcomes improved with the CPV strategy?

What strategy do we suggest?

In infants and children with severe acute lung disease in the PICU ventilation strategies are aimed at physiology that has withstood critical scrutiny (minimizing volutrauma, atelectrauma, oxygen toxicity, and mechanical power), and have been associated with improved clinical outcomes. ⁷³ This is also the experience in critically ill adults. ⁷² Our suggestions are based upon recent consensus publications considering systematic reviews of the literature (Supplemental Table S3).^9,99–104 Surrogates used to minimize volutrauma include avoiding high VT (VT 4–8 ml/kg), PIP (Pplat ⩽30 cmH20), and driving pressure (∆P ⩽15 cmH20). Surrogates to minimize atelectrauma include PEEP adequate to maintain ventilated lung on the descending limb of the pressure-volume curve (i.e. maintain end-expiratory volume), associated with minimizing the required FIO2 to <60%. Unlike in msBPD, in lungs with more homogeneous obstructive disease, such as asthma, higher PIP is allowed because this pressure is dissipated (before reaching alveoli) in overcoming the high respiratory system resistance, and lower respiratory rate is used because this avoids breath-stacking (i.e. when the next breath occurs before end-expiratory flow is complete) causing auto-PEEP.

In msBPD, applying these practices to avoid VILI should be individualized using clinicians’ best judgment. During acute episodes of deterioration (e.g. ventilator-associated pneumonia or viral bronchiolitis), similar targets are aimed for, while temporarily increasing respiratory support as indicated, just as gradual decreasing of respiratory support is aimed for over time in the chronic setting (which often lasts for many months). The only study we are aware of to describe lung protective ventilation in BPD was O’Connor and Davies that described adequate chronic ventilation in evolving BPD (at days 28, 42, and 56 of life after birth at gestational age 25.1 (interquartile range 24.4, 26.7) weeks) using a strategy to minimize volutrauma (VT at 56 days PMA median 4.7 (IQR 4.3, 5) ml/kg) and not focused on slow RR (at 56 days PMA median 35 (IQR 25, 45) breaths/minute). ⁸³ This does not prove lung-protective ventilation is necessary, but does show it was adequate for chronic ventilation at least in evolving BPD. We use this strategy in msBPD, and, as the infant’s lungs grow, the ventilator RR can be slowly weaned until settings appropriate for ward and then home ventilation are achieved, followed eventually by no need for ventilation.

Limitations

This review has limitations. First, this was not a systematic review of the literature, and important studies could have been missed. Examining all references in the eligible review articles may mitigate this concern. Second, we and authors that recommended CPV acknowledge that there is no evidence that conclusively describes the best practices for ventilation in msBPD. Our suggested strategy was not based on robust studies of ventilated infants with msBPD and was based on physiology and outcomes in children ventilated with acute lung disease. However, we found that the physiology in favor of CPV had, in our assessment, not been subjected to adequate critical scrutiny, and that was the main purpose of our review. Third, it may be that the CPV strategy was intended only for patients with msBPD who, still being ventilated 3–4 months after birth, have failed all other ventilation strategies. The reviews we included seemed to have meant to apply the CPV strategy in virtually all infants with established msBPD, and the few that gave descriptions of msBPD appropriate for the CPV strategy also seem to apply to the vast majority of infants ventilated for msBPD at term PMA (see Supplemental Discussion). Some intensivists may nevertheless consider the CPV strategy more selectively, only for msBPD patients that are not “thriving” or are clearly “failing” conventional lung-protective ventilation. This may be a better approach, but how to define the appropriate patients remains unclear, and evidence to support this more selective CPV strategy we still found lacking. We expand on some of these limitations below, by considering some objections.

Objection 1. There is no standard of care for managing ventilation in msBPD

There are no studies we are aware of that compare benefits and harms between the standard approach to ventilation and the CPV strategy in msBPD. We agree with a workshop that wrote “ventilation and respiratory management strategies for infants with established BPD have weak evidence to support current practices.” ⁹⁹ In that sense, it could be stated that there is no standard of care for managing ventilation in msBPD, and we cannot make definitive recommendations. However, our concern is that this would imply that what is known about VILI in other ventilated pediatric and adult patients with acute lung disease does not apply to msBPD. The literature on ventilation to avoid VILI is extensive, and we did not independently review the strength of this evidence. However, the reviews referenced for our suggested strategy, which is the standard of care for ventilated children and adults with acute lung disease, were based upon systematic reviews of empirical studies in the literature and structured transparent consensus interpretation of this evidence.^9,100–105 One can always choose a specific group of ventilated patients and claim that this evidence does not apply to that subgroup as there are few if any high-quality studies of ventilation in that subgroup. However, a rationale that withstands critical scrutiny for that subgroup to be an exception should be given (e.g. a reason why that group may not be susceptible to VILI). We remain unconvinced that msBPD, being a chronic lung disease, should be such an exception. First, why infants with a chronic lung disease would not be susceptible to VILI is unclear. Second, as discussed above, BPD likely has components of acute lung injury in that it “reflects an ongoing respiratory disease after birth with long-term consequences and not just stabilized structural lung damage after the neonatal period.” ⁸⁵ Third, also discussed above, the physiology explaining VILI is plausible. This is supported by the finding that mechanical power has been associated with several outcomes in adults and children with acute disease,^72,73 and that stress and strain are highly amplified at “a sphere’s surface segments having different compliances [and, we calculated, these are even more amplified when due to different resistances].” ⁷⁴ Until convincing evidence is available, we suggest that the current standard of care for ventilation in children and adults with acute lung disease can be applied in msBPD to prevent ongoing VILI, and we respectfully disagree with calls for local expert endorsed standardization, consensus guidelines, and protocols for using the CPV strategy in the management of msBPD.^106,107

Objection 2. Bias is evident in the critical evaluation of evidence without emphasizing the strengths of the CPV strategy

We relied on the published rationale and evidence provided by many experts for the CPV approach in order to discuss its strengths and weaknesses. We first transparently gave this rationale and evidence (i.e., what could be considered the strengths) for the CPV strategy, and then critically evaluated these. Bias perceived may be because we found this evidence unconvincing, based upon transparently stated evidence throughout the review. Whether our suggested strategy is best can and should be debated; however, the evidence to support CPV we found to be inadequate to recommend what may be harmful ventilator settings.

Objection 3. Ventilation in msBPD may be similar to that for asthma or chronic obstructive lung disease, closer to the CPV strategy

The ventilation strategy for asthma and chronic obstructive lung disease (COPD) is not similar to the CPV strategy. Evidence reviews of ventilation in obstructive lung disease in adults emphasized allowing sufficient time for exhalation to avoid dynamic hyperinflation, with short Ti allowing an inspiratory-to-expiratory ratio of 1:2 to 1:4..^100,108,109 These reviews also emphasized that VT should be 6–8 ml/kg and P_plat <28–30 cmH₂O to minimize VILI, with minute ventilation minimized further if P_plat is higher (i.e. to lower VT and/or lower respiratory rate).^90,108,109 PEEP is set to counterbalance auto-PEEP and therefore reduce the effort needed to trigger the ventilator, and to prevent airway collapse at end-expiration.^90,108,109 The same recommendations are made for asthma and bronchiolitis in children.^110–113

In addition, msBPD has important differences from asthma and COPD. As discussed in detail above, differences include the degree of heterogeneity of lung structure, and the questionable relevance of evidence for forced expiratory flow limitation in suggesting a high respiratory system resistance lung compartment. We did not find description of P_plat in msBPD, likely because measurement with an inspiratory hold would be accurate only if there is no spontaneous respiratory effort (i.e. during pharmacologic paralysis). However, if there is zero flow on the ventilator flow-time trace at end-inspiration (i.e. just prior to expiration), this would mean that PIP=P_plat, which in our experience has been the case.

Objection 4. That lungs in msBPD have heterogeneous structure and pathology is evidence for a two- or multicompartment model of the lung

This is a misunderstanding of the two-compartment model of the lung. The two-compartment model suggested that there are two independently ventilated compartments of the lung, such that CPV will ventilate the slow compartment and not harm the fast compartment (Figure 2). However, despite the known structural heterogeneity, the lungs in msBPD appear to have relatively homogeneous distribution of ventilation.^77–82 The high VT, high PIP (and P_plat), and long Ti (that, despite the low set RR, is associated with a faster spontaneous RR and hence short Te) affect all regions of the heterogeneous lungs, and, we have argued, will cause VILI.

Conclusions

We made four conclusions

1. We suggest (Table 1, Figure 1, and Figure 2) that CPV is based upon repeated circular referencing among chapters and narrative reviews often written by the same experts. Evidence reviewed above suggested that, in our opinion, the CPV strategy in msBPD is based upon literature that had not been adequately subjected to critical scrutiny, and therefore, CPV has prematurely become considered a suggested strategy.

2. We suggest that these reviews, in our assessment, explained physiologic theory that has little supportive evidence and that has likely been misinterpreted, and referred to outcome studies that did not examine the effect of the CPV strategy (Table 2).

3. When implicit assumptions are made explicit (Supplemental Table S1), there is evidence to show a lack of consensus about the CPV strategy, potential harms of the strategy, and what we argued were inaccurate interpretations of msBPD physiology (Table 3).

4. The standard approach to ventilation in children is based upon best evidence available for acute lung disease, and we have argued that no rationale that withstands our critical scrutiny has been given to suppose the subgroup of ventilated children with msBPD might be an exception to using this strategy (e.g. in our assessment, no rationale for why the msBPD group with chronic lung disease may not be susceptible to VILI).

We do not know the optimal strategy for ventilation in established msBPD. We acknowledge that these patients are difficult to manage using any strategy and that, in this context, teams that are working to make care better should be encouraged. We also acknowledge that CPV proponents may disagree with our critical interpretation of the available literature. We believe that this is how science moves forward, with reasoned debate that leads to work to obtain better evidence. In that spirit, we conclude that, if the CPV strategy is beneficial, we urgently need better evidence to that effect; otherwise, we have argued, it is too early to adopt this potentially harmful strategy as a standard of care. Moving forward, future well-designed observational studies of clinically relevant outcomes using different ventilation strategies in msBPD are a priority need. Then, if supported by this background work, a multicenter RCT enriched for certain subgroups of msBPD may be indicated to settle the issue.

Supplemental Material

sj-docx-1-smo-10.1177_20503121261431454 – Supplemental material for Chronic phase ventilation strategy in established severe bronchopulmonary dysplasia: A critical evaluation of the evidence

Supplemental material, sj-docx-1-smo-10.1177_20503121261431454 for Chronic phase ventilation strategy in established severe bronchopulmonary dysplasia: A critical evaluation of the evidence by Ari R. Joffe and Robert P. Lemke in SAGE Open Medicine