Introduction: Ventilator-induced Lung Injury: Not Only Air Leaks Ventilation-induced Pulmonary Edema and Related Findings: A Historical Perspective Ventilation-induced Pulmonary Edema: Hydrostatic or Permeability Edema? Experimental Evidence for Increased Vascular Transmural Pressure Evidence for Alterations in Alveolar–Capillary Permeability Contributions of the Static and Dynamic Lung Volume Components to Ventilator-induced Edema High-volume Lung Edema Low Lung Volume Injury Effects of High-volume Ventilation on Abnormal Lungs Effects of High-volume Ventilation on Injured Lungs Interaction between Severe Alveolar Flooding and Mechanical Ventilation Effects of Resting the Lung on Ventilator-induced Lung Injury Possible Mechanisms of Ventilation-induced Lung Injury Mechanisms of Increased Vascular Transmural Pressure Mechanisms of Altered Permeability Clinical Relevance

Ventilator-induced lung injury: lessons from experimental studies.

Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn

A borderline viability model of bronchopulmonary dysplasia (BPD)/chronic lung disease of infancy (CLD) with pathophysiologic parameters consistent with those in extremely immature humans with BPD/CLD is described. After prenatal steroid treatment of pregnant dams, 12 premature baboons were delivered by cesarean-section at 125 d (term gestation, 185 d), treated with exogenous surfactant, and maintained on appropriate oxygen and positive pressure ventilation for at least 1 to 2 mo. In spite of appropriate oxygenation (median Fi O2 at 28 d = 0.32; range, 0.21 to 0.50) and ventilatory strategies to prevent volutrauma, the baboons exhibited pulmonary pathologic lesions known to occur in extremely immature humans of less than 1,000 g: alveolar hypoplasia, variable saccular wall fibrosis, and minimal, if any, airway disease. The CLD baboon lungs showed significantly decreased alveolization and internal surface area measurements when compared with term and term + 2-mo air-breathing controls. A decrease in capilla...

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.160.4.9810071

Neonatal Chronic Lung Disease in Extremely Immature Baboons

Background
Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although the use of intermittent positive pressure ventilation (IPPV) in neonates with respiratory failure saves lives, its use is associated with lung injury and chronic lung disease. A newer form of ventilation called high frequency oscillatory ventilation has been shown in experimental studies to result in less lung injury.

Objectives
The objective of this review was to determine the effect of the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation (CV) on the incidence of chronic lung disease (CLD), mortality and other complications associated with prematurity and assisted ventilation in preterm infants who were mechanically ventilated for respiratory distress syndrome (RDS).

Search methods
Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conference and symposia proceedings; and from expert informants and handsearching of journals by The Cochrane Collaboration, mainly in the English language. The search was updated in January 2009 and again in November 2014.

Selection criteria
Randomised controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who required assisted ventilation. Randomisation and commencement of treatment needed to be as soon as possible after the start of CV and usually in the first 12 hours of life.

Data collection and analysis
The methodological quality of each trial was independently reviewed by the review authors. The standard effect measures were relative risk (RR) and risk difference (RD). From 1/RD the number needed to benefit (NNTB) to produce one outcome was calculated. For all measures of effect, 95% confidence intervals (CIs) were used. For interpretation of subgroup analyses, a P value for subgroup differences as well as the I2 statistic for between-subgroup heterogeneity were calculated. Meta-analysis was performed using both a fixed-effect and a random-effects model. Where heterogeneity was over 50%, the random-effects model RR was also reported.

Main results
Nineteen eligible studies involving 4096 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on mortality at 28 to 30 days of age or at approximately term equivalent age. These results were consistent across studies and in subgroup analyses. The risk of CLD in survivors at term equivalent gestational age was significantly reduced with the use of HFOV but this effect was inconsistent across studies, even after the meta-analysis was restricted to studies that applied a high lung volume strategy with HFOV. Subgroup analysis by HFOV strategy showed a similar effect in trials with a more strict lung volume recruitment strategy, targeting a very low fraction of inspired oxygen (FiO2), and trials with a less strict lung volume recruitment strategy and with a somewhat higher or unspecified target FiO2. Subgroup analyses by age at randomisation, routine surfactant use or not, type of high frequency ventilator (oscillator versus flow interrupter), inspiratory to expiratory (I:E) ratio of high frequency ventilator (1:1 versus 1:2) and CV strategy (lung protective or not) could not sufficiently explain the heterogeneity. Pulmonary air leaks, defined as gross air leaks or pulmonary interstitial emphysema, occurred more frequently in the HFOV group, whereas the risk of severe retinopathy of prematurity was significantly reduced.

Although in some studies an increased risk of severe grade intracranial haemorrhage and periventricular leukomalacia was found, the overall meta-analysis revealed no significant differences in effect between HFOV and CV. The short-term neurological morbidity with HFOV was only found in the subgroup of two trials not using a high volume strategy with HFOV. Most trials did not find a significant difference in long-term neurodevelopmental outcome, although one recent trial showed a significant reduction in the risk of cerebral palsy and poor mental development.

Authors' conclusions
There is evidence that the use of elective HFOV compared with CV results in a small reduction in the risk of CLD, but the evidence is weakened by the inconsistency of this effect across trials. Probably many factors, both related to the intervention itself as well as to the individual patient, interact in complex ways. In addition, the benefit could be counteracted by an increased risk of acute air leak. Adverse effects on short-term neurological outcomes have been observed in some studies but these effects are not significant overall. Most trials reporting long-term outcome have not identified any difference.

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants

Background The efficacy and safety of early high-frequency oscillatory ventilation as compared with conventional synchronized intermittent mandatory ventilation for the treatment of infants with very low birth weight have not been established. Methods We conducted a randomized, multicenter clinical trial to determine whether infants treated with early high-frequency oscillatory ventilation were more likely than infants treated with synchronized intermittent mandatory ventilation to be alive without requiring supplemental oxygen at 36 weeks of postmenstrual age. Eligible infants weighed 601 to 1200 g at birth, were less than four hours of age, had received one dose of surfactant, and required ventilation with a mean airway pressure of at least 6 cm of water and a fraction of inspired oxygen of at least 0.25. Infants were stratified according to birth weight and exposure to prenatal corticosteroids and then randomly assigned to high-frequency oscillatory ventilation or synchronized intermittent mandatory ve...

High-Frequency Oscillatory Ventilation versus Conventional Mechanical Ventilation for Very-Low-Birth-Weight Infants

To test the hypothesis that hyaline membrane disease (HMD) has a multifactorial etiology in which barotrauma plays a major role, we compared the immediate institution of high-frequency oscillatory ventilation (HFOV; 15 Hz, n = 5) with positive-pressure ventilation with positive end-expiratory pressure (PPV; n = 7) in premature baboons (140-days gestation) with HMD. Measurements of ventilation settings and physiological parameters were obtained and arterial-to-alveolar O2 (PaO2-to-PAO2) ratio and oxygenation index [(PaO2/PAO2)-to-mean airway pressure ratio (IO2)] were calculated. At death (24 h), static pressure-volume (PV) curves were performed, and phospholipids (PL) and platelet-activating factor (PAF) were measured in lung lavage fluid. Morphological inflation patterns were analyzed using a panel of standards. By design, mean airway pressure was initially higher (19 vs. 13 cmH2O) in the HFOV animals. PaO2-to-PAO2 ratio and IO2 progressively deteriorated in the PPV animals and then stabilized at significantly lower levels than with HFOV. PV curves from HFOV animals had significant increases in lung volume at maximum distending pressure, deflation volume at 10 cmH2O, and hysteresis area compared with PPV, which showed no hysteresis. Seven of seven PPV and only one of five HFOV animals had morphological findings of HMD. PL amount and composition in both groups were consistent with immaturity, even though the quantity was significantly greater in the PPV group. PAF was present (greater than or equal to 0.10 pmol) in six of seven PPV and in the only HFOV animal with HMD. We conclude that HFOV protected PL-deficient premature baboons from changes in gas exchange, lung mechanics, and morphology typical of HMD in this model.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of lung injury in the pathogenesis of hyaline membrane disease in premature baboons

To assess the efficacy of high frequency oscillatory ventilation (HFOV) in the management of infants with hyaline membrane disease (HMD), we compared two HFOV strategies with conventional positive pressure ventilation with positive end expiratory pressure (PPV) for 24 h in premature baboons (140 d gestation). Three out of 14 PPV, five out of five HFOV-E (begun at birth; 15 Hz; I:E 1:2), and none of 10 HFOV-L (begun after 3 h PPV; 10 Hz; I:E 1:2) were killed at 24 h for morphologic examination. Physiologic (Paw, Pa/AO2, IO2, B.P., pulse, blood gases) data on all animals in each group were assessed at each 3 h interval and over time. Intergroup differences in radiographs at 0 and 24 h and in morphology were quantitatively assessed by comparison with a panel of standards. All animals had radiographic HMD. Initial Paw was set higher with HFOV-E (16.8) than PPV or HFOV-L (14.1, 14.1). PPV baboons required increasing Paw to maintain constant Pa/AO2. Six out of 14 PPV animals developed airleak and three out of three had morphologic HMD. In contrast Pa/AO2 was higher in both HFOV groups at lower Paw by 24 h. None of 15 HFOV animals developed airleak. HFOV-E lungs had dramatic differences in morphology with uniform saccular opening and decreased edema and hyaline membranes compared to PPV. HFOV-L had less dramatic effects because of lower Paw and delayed application. Early use of HFOV at a high Paw favorably alters the course of HMD. Unless closely monitored, this strategy results in lung overinflation which may adversely affect venous return and cardiac output.

A comparison of ventilation strategies for the use of high‐frequency oscillatory ventilation in the treatment of hyaline membrane disease

We hypothesized that total parenteral nutrition accelerates growth and development of diaphragm muscle (DPH) in prematurely delivered baboons (140 days gestation). For 10 days after delivery by cesarean section, we administered parenteral nutrition containing glucose, electrolytes, and water or total parenteral nutrition containing lipids, amino acids, glucose, vitamins, and electrolytes. After 10 days of care, dorsolateral and ventrolateral (VL) costal DPH were sampled for histochemically determined mean fiber area (MFA) and fiber type percentages. We determined isolated bundle isometric tension (normalized for cross-sectional area), time to peak tension, half-relaxation time, force-frequency relationship, and fatigability. Neither sex nor nutritional treatment affected contractile properties. Differences among sexes and muscle sites, but not among nutritional treatments, were observed for histochemical characteristics. In females, the VL DPH had a lower percentage of type IIo fibers and a greater MFA of type IIc fibers than the dorsolateral DPH and a lower percentage of type IIo fibers and greater MFA of type IIc and IIo fibers than the VL DPH in males. Mean fiber cross-sectional area of VL DPH was significantly greater in females than males. The larger fibers in females than males suggest a stronger DPH in females. Earlier growth of type II fibers in females could contribute to a better outcome for female than male premature infants with hyaline membrane disease.

K. S. Meredith

Papers

Role of lung injury in the pathogenesis of hyaline membrane disease in premature baboons

A comparison of ventilation strategies for the use of high‐frequency oscillatory ventilation in the treatment of hyaline membrane disease

Total parenteral nutrition does not improve diaphragm development in premature baboons.