Anton H. van Kaam

Positive Pressure Ventilation with the Open Lung Concept Optimizes Gas Exchange and Reduces Ventilator-Induced Lung Injury in Newborn Piglets

Previous studies demonstrated that high-frequency oscillatory ventilation using the open lung concept (OLC) resulted in superior gas exchange and a reduction in ventilator-induced lung injury (VILI). We hypothesized that these beneficial effects could also be achieved by applying the OLC during positive pressure ventilation. After repeated whole-lung-lavage, newborn piglets were assigned to either OLC positive pressure ventilation (PPVOLC), OLC high-frequency oscillatory ventilation (HFOVOLC), or conventional positive pressure ventilation (PPVCON) and ventilated for 5 h. In both OLC groups, collapsed alveoli were actively recruited and thereafter stabilized using the lowest possible airway pressures. In the PPVCON group, ventilator settings were adjusted to prevent critical hypoxia. Airway pressure, blood gas analysis, pressure-volume curve, and alveolar protein infiltration was recorded. A lung injury score was used for histologic comparison. Mean airway pressures were comparable in the three ventilation groups over time (1.2-1.5 kPa). Arterial oxygenation increased to mean values above 60 kPa in both OLC groups compared with 10 kPa in the PPVCON group (p < 0.001). Maximal lung compliance was superior in both OLC groups (PPVOLC: 91 ± 23; HFOVOLC: 90 ± 31 mL/kPa/kg, p < 0.01) compared with the PPVCON group (39 ± 14 mL/kPa/kg). Alveolar protein infiltration was significantly reduced in the PPVOLC group (0.33 ± 0.10 mg/mL, p < 0.01) and the HFOVOLC group (0.40 ± 0.13 mg/mL, p < 0.01) compared with the PPVCON group (0.70 ± 0.15 mg/mL). Lung injury scores were significantly higher in the PPVCON group (33.5 ± 9.5, p < 0.01) compared with both OLC groups (PPVOLC: 10.5 ± 2.6; HFOVOLC: 11 ± 2.2). There were no differences between the two OLC groups. We conclude that, in surfactant-depleted newborn piglets, application of the OLC during PPV is feasible and results in superior gas exchange and a reduction in VILI compared with conventional PPV. These beneficial effects are comparable to HFOV.

Chest electrical impedance tomography examination, data analysis, terminology, clinical use and recommendations: consensus statement of the TRanslational EIT developmeNt stuDy group

Electrical impedance tomography (EIT) has undergone 30 years of development. Functional chest examinations with this technology are considered clinically relevant, especially for monitoring regional lung ventilation in mechanically ventilated patients and for regional pulmonary function testing in patients with chronic lung diseases. As EIT becomes an established medical technology, it requires consensus examination, nomenclature, data analysis and interpretation schemes. Such consensus is needed to compare, understand and reproduce study findings from and among different research groups, to enable large clinical trials and, ultimately, routine clinical use. Recommendations of how EIT findings can be applied to generate diagnoses and impact clinical decision-making and therapy planning are required. This consensus paper was prepared by an international working group, collaborating on the clinical promotion of EIT called TRanslational EIT developmeNt stuDy group. It addresses the stated needs by providing (1) a new classification of core processes involved in chest EIT examinations and data analysis, (2) focus on clinical applications with structured reviews and outlooks (separately for adult and neonatal/paediatric patients), (3) a structured framework to categorise and understand the relationships among analysis approaches and their clinical roles, (4) consensus, unified terminology with clinical user-friendly definitions and explanations, (5) a review of all major work in thoracic EIT and (6) recommendations for future development (193 pages of online supplements systematically linked with the chief sections of the main document). We expect this information to be useful for clinicians and researchers working with EIT, as well as for industry producers of this technology.

Ventilation practices in the neonatal intensive care unit: a cross-sectional study

OBJECTIVE To assess current ventilation practices in newborn infants. STUDY DESIGN We conducted a 2-point cross-sectional study in 173 European neonatal intensive care units, including 535 infants (mean gestational age 28 weeks and birth weight 1024 g). Patient characteristics, ventilator settings, and measurements were collected bedside from endotracheally ventilated infants. RESULTS A total of 457 (85%) patients were conventionally ventilated. Time cycled pressure-limited ventilation was used in 59% of these patients, most often combined with synchronized intermittent mandatory ventilation (51%). Newer conventional ventilation modes like volume targeted and pressure support ventilation were used in, respectively, 9% and 7% of the patients. The mean tidal volume, measured in 84% of the conventionally ventilated patients, was 5.7 ± 2.3 ml/kg. The mean positive end-expiratory pressure was 4.5 ± 1.1 cmH(2)O and rarely exceeded 7 cmH(2)O. CONCLUSIONS Time cycled pressure-limited ventilation is the most commonly used mode in neonatal ventilation. Tidal volumes are usually targeted between 4 to 7 mL/kg and positive end-expiratory pressure between 4 to 6 cmH(2)O. Newer ventilation modes are only used in a minority of patients.

Lung-protective ventilation strategies in neonatology: what do we know--what do we need to know?

Objective:Randomized controlled trials (RCTs) investigating various lung-protective ventilation modes or strategies in newborn infants have failed to show clear differences in mortality or bronchopulmonary dysplasia. This review tries to identify possible reasons for this observation, applying modern concepts on ventilator-induced lung injury and lung-protective ventilation. Data Source:Published RCTs and systematic reviews on mechanical ventilation in newborn infants were identified by searching PubMed and the Cochrane Library. Data Synthesis:A total of 16 RCTs and four systematic reviews comparing high-frequency ventilation with conventional mechanical ventilation (CMV) failed to show consistent differences in mortality and bronchopulmonary dysplasia. Unfortunately, clear information or data on ventilation and oxygenation targets in the search for optimal lung volumes during high-frequency ventilation or CMV is lacking in many RCTs, questioning the validity of the results and the meta-analytic subgroup analysis. Based on improvement in oxygenation, only three RCTs successfully applied the optimal lung volume strategy during high-frequency ventilation. A total of 24 RCTs and three systematic reviews comparing various CMV modes and settings and two RCTs investigating permissive hypercapnia reported no differences in mortality or bronchopulmonary dysplasia. However, the intervention arms in these RCTs did not differ in tidal volume or positive end-expiratory pressures, variables that are considered important determinants in ventilator-induced lung injury. In fact, no RCT in newborn infants has substantiated so far the experimental finding that avoiding large tidal volumes and low positive end-expiratory pressure during CMV is lung protective in newborn infants. Conclusion:RCTs investigating lung-protective ventilation in neonates have mainly focused on comparing high-frequency ventilation with CMV. Most of these RCTs show weaknesses in the design, which may explain the inconsistent effect of high-frequency ventilation on bronchopulmonary dysplasia. RCTs on CMV only focused on comparing various modes and settings, leaving the important question whether reducing tidal volume or increasing positive end-expiratory pressure is also lung protective in newborn infants unanswered.

Finding the Optimal Postnatal Dexamethasone Regimen for Preterm Infants at Risk of Bronchopulmonary Dysplasia: A Systematic Review of Placebo-Controlled Trials

CONTEXT. Postnatal dexamethasone therapy reduces the incidence of bronchopulmonary dysplasia in preterm infants but may be associated with an increased risk for adverse neurodevelopmental outcome. OBJECTIVE. Our goal was to determine if the effects of dexamethasone on mortality and pulmonary and neurodevelopmental sequelae in preterm infants are modified by the cumulative dose given. METHODS. Randomized, controlled trials comparing dexamethasone with placebo in ventilated preterm infants >7 days old were identified by searching the electronic databases and the abstracts from the Pediatric Academic societies and by performing manual reference searches. Two reviewers independently assessed eligibility and quality of trials and extracted data on study design, patient characteristics, and relevant outcomes. Original trialists were asked to provide additional data. RESULTS. Sixteen trials including 1136 patients were analyzed by using meta-analysis and metaregression. Additional data were provided by 12 original trialists. Trials with a moderately early (7- to 14-day) or delayed (>3-week) postnatal treatment onset were analyzed separately. Higher dexamethasone doses reduced the relative risk for the combined outcome, mortality or bronchopulmonary dysplasia, with the largest effect in trials that used a cumulative dose of >4 mg/kg. No effect was found of doses on the risk of neurodevelopmental sequelae in the delayed treatment studies, but in the moderately-early-treatment studies the risk of mortality or cerebral palsy decreased by 6.2%, and the risk of a Mental Developmental Index below −2 SDs decreased by 6.6% for each incremental mg/kg cumulative dexamethasone dose. CONCLUSIONS. Higher cumulative dexamethasone doses administered after the first week of life may decrease the risk for bronchopulmonary dysplasia without increasing the risk for neurodevelopmental sequelae in ventilated preterm infants. A large randomized trial is needed to confirm or refute these findings.

Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-II): an open-label, randomised controlled trial

BACKGROUND There is little evidence to guide the management of women with hypertensive disorders in late preterm pregnancy. We investigated the effect of immediate delivery versus expectant monitoring on maternal and neonatal outcomes in such women. METHODS We did an open-label, randomised controlled trial, in seven academic hospitals and 44 non-academic hospitals in the Netherlands. Women with non-severe hypertensive disorders of pregnancy between 34 and 37 weeks of gestation were randomly allocated to either induction of labour or caesarean section within 24 h (immediate delivery) or a strategy aimed at prolonging pregnancy until 37 weeks of gestation (expectant monitoring). The primary outcomes were a composite of adverse maternal outcomes (thromboembolic disease, pulmonary oedema, eclampsia, HELLP syndrome, placental abruption, or maternal death), and neonatal respiratory distress syndrome, both analysed by intention-to-treat. This study is registered with the Netherlands Trial Register (NTR1792). FINDINGS Between March 1, 2009, and Feb 21, 2013, 897 women were invited to participate, of whom 703 were enrolled and randomly assigned to immediate delivery (n=352) or expectant monitoring (n=351). The composite adverse maternal outcome occurred in four (1·1%) of 352 women allocated to immediate delivery versus 11 (3·1%) of 351 women allocated to expectant monitoring (relative risk [RR] 0·36, 95% CI 0·12-1·11; p=0·069). Respiratory distress syndrome was diagnosed in 20 (5·7%) of 352 neonates in the immediate delivery group versus six (1·7%) of 351 neonates in the expectant monitoring group (RR 3·3, 95% CI 1·4-8·2; p=0·005). No maternal or perinatal deaths occurred. INTERPRETATION For women with non-severe hypertensive disorders at 34-37 weeks of gestation, immediate delivery might reduce the already small risk of adverse maternal outcomes. However, it significantly increases the risk of neonatal respiratory distress syndrome, therefore, routine immediate delivery does not seem justified and a strategy of expectant monitoring until the clinical situation deteriorates can be considered. FUNDING ZonMw.

Changes in Lung Volume and Ventilation during Surfactant Treatment in Ventilated Preterm Infants

RATIONALE The immediate and regional effects of exogenous surfactant in open lung high-frequency oscillatory ventilated (HFOV) preterm infants are unknown. OBJECTIVES To assess regional changes in lung volume, mechanics, and ventilation during and after surfactant administration in HFOV preterm infants with respiratory distress syndrome (RDS). METHODS Using electrical impedance tomography, changes in lung volume were continuously recorded during a stepwise recruitment procedure before, during, and after surfactant administration in 15 preterm infants (gestational age: 28.3 wk; birth weight: 1,000 g). Deflation limbs of the pressure-impedance curve before and after surfactant were mapped and the effect of surfactant on oscillation volumes and ventilation was determined. Data were analyzed for the whole cross-section and the left, right, ventral, and dorsal lung regions. MEASUREMENTS AND MAIN RESULTS Surfactant increased lung volume by 61 ± 39% within a median time of 241 seconds. The ventral to dorsal ratio in lung volume changed significantly from 1.16 before to 0.81 after surfactant administration. The upper inflection point of the deflation limb after surfactant (10.4 ± 2.4 cm H(2)O) was significantly lower compared with before surfactant (16.4 ± 3.1 cm H(2)O). Surfactant increased maximal compliance of the respiratory system, and this effect was reached at lower airway pressures. Surfactant caused a transient decrease in oscillatory volume but did not alter its regional distribution. CONCLUSIONS Surfactant treatment in HFOV preterm infants with RDS causes a rapid increase and subsequent stabilization of lung volume, which is most prominent in dependent lung regions. It increased maximal compliance, but this effect is only reached at lower airway pressures.

Changes in Lung Volume and Ventilation during Lung Recruitment in High-Frequency Ventilated Preterm Infants with Respiratory Distress Syndrome

OBJECTIVES To assess global and regional changes in lung volume and ventilation during lung recruitment in preterm infants with respiratory distress syndrome. STUDY DESIGN Using electrical impedance tomography, changes in lung volume and ventilation were measured in 15 high-frequency oscillatory ventilated preterm infants during oxygenation-guided recruitment maneuvers. The inflation and deflation limbs were mapped, and the lower and upper inflection points were calculated using both oxygenation and impedance data. The impedance data were also used to determine recruitment-related changes in oscillation volume and distribution. RESULTS During inflation, lower and upper inflection points were identified in the majority of infants. The deflation limb showed clear lung hysteresis in all infants. The upper inflection point was significantly lower when comparing the pressure/oxygenation and pressure/impedance curves. Lung volume changes differed between the ventral and dorsal regions, but did not show a consistent pattern. Optimal recruitment increased the oscillation volume, but the distribution of ventilation was relatively homogeneous along the ventral-dorsal axis. CONCLUSIONS Lung hysteresis is present in preterm infants with respiratory distress syndrome. Regional differences in lung volume changes and ventilation during high-frequency oscillatory ventilation with lung recruitment are relatively modest and do not follow a gravity-dependent distribution.

Neonatal outcome of pregnancies complicated by hypertensive disorders between 34 and 37 weeks of gestation : a 7 year retrospective analysis of a national registry

OBJECTIVE The objective of the study was to determine the neonatal morbidity in late preterm infants born from mothers with a hypertensive disorder. STUDY DESIGN Data were obtained from the national Perinatal Registry in The Netherlands on women who delivered between 34(+0) and 36(+6) weeks with gestational hypertension (n = 4316), preeclampsia (n = 1864), and normotensive controls (n = 20,749). RESULTS Children from mothers with preeclampsia had an increased risk for admission to the neonatal intensive care unit compared with children from normotensive mothers (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.8-2.2). A cesarean delivery and decreasing gestational age were independent risk factors for neonatal respiratory morbidity. Gestational hypertension or preeclampsia reduced the risk of respiratory distress syndrome compared with the control group (OR, 0.81; 95% CI, 0.64-1.0 and OR, 0.69; 95% CI, 0.49-0.96, respectively). CONCLUSION Neonatal morbidity in the late preterm period is considerable. Hypertensive disorders appear to protect for neonatal respiratory morbidity, but higher rates of cesarean section diminish this protective effect.

Application of the Open-Lung Concept during Positive-Pressure Ventilation Reduces Pulmonary Inflammation in Newborn Piglets

It has been shown that application of the open-lung concept (OLC) during high-frequency oscillatory ventilation (HFOV) attenuates pulmonary inflammation. We hypothesized that this attenuation could also be achieved by applying the OLC during positive-pressure ventilation (PPV). After repeated whole-lung lavage, newborn piglets were assigned to one of three ventilation groups: (1) PPVOLC; (2) HFOVOLC, or (3) conventional PPV (PPVCON). After a ventilation period of 5 h, analysis of bronchoalveolar lavage fluid showed a reduced influx of polymorphonuclear neutrophils, interleukin 8, and thrombin activity in both OLC groups as compared with the PPVCON group. There were no differences in tumor necrosis factor alpha levels. We conclude that application of the OLC during PPV reduces pulmonary inflammation as compared with conventional PPV and that the magnitude of this reduction is comparable to that of HFOV.