Adrianus J. van Vught

High frequency oscillatory ventilation compared with conventional mechanical ventilation in adult respiratory distress syndrome: a randomized controlled trial [ISRCTN24242669].

IntroductionTo compare the safety and efficacy of high frequency oscillatory ventilation (HFOV) with conventional mechanical ventilation (CV) for early intervention in adult respiratory distress syndrome (ARDS), a multi-centre randomized trial in four intensive care units was conducted.MethodsPatients with ARDS were randomized to receive either HFOV or CV. In both treatment arms a priority was given to maintain lung volume while minimizing peak pressures. CV ventilation strategy was aimed at reducing tidal volumes. In the HFOV group, an open lung strategy was used. Respiratory and circulatory parameters were recorded and clinical outcome was determined at 30 days of follow up.ResultsThe study was prematurely stopped. Thirty-seven patients received HFOV and 24 patients CV (average APACHE II score 21 and 20, oxygenation index 25 and 18 and duration of mechanical ventilation prior to randomization 2.1 and 1.5 days, respectively). There were no statistically significant differences in survival without supplemental oxygen or on ventilator, mortality, therapy failure, or crossover. Adjustment by a priori defined baseline characteristics showed an odds ratio of 0.80 (95% CI 0.22–2.97) for survival without oxygen or on ventilator, and an odds ratio for mortality of 1.15 (95% CI 0.43–3.10) for HFOV compared with CV. The response of the oxygenation index (OI) to treatment did not differentiate between survival and death. In the HFOV group the OI response was significantly higher than in the CV group between the first and the second day. A post hoc analysis suggested that there was a relatively better treatment effect of HFOV compared with CV in patients with a higher baseline OI.ConclusionNo significant differences were observed, but this trial only had power to detect major differences in survival without oxygen or on ventilator. In patients with ARDS and higher baseline OI, however, there might be a treatment benefit of HFOV over CV. More research is needed to establish the efficacy of HFOV in the treatment of ARDS. We suggest that future studies are designed to allow for informative analysis in patients with higher OI.

Ventilator-induced lung injury and multiple system organ failure: a critical review of facts and hypotheses

ObjectiveTo review how biotrauma leads to the development of multiple system organ failure (MSOF).Design and settingPublished articles on experimental and clinical studies and review articles in the English language were collected and analyzed.ResultsThe concept that ventilation strategies using “large” tidal volumes and zero PEEP of injured lungs can enhance injury by the release of inflammatory mediators into the lungs and circulation, a mechanism that has been called biotrauma, is supported by evidence from experimental models ranging from mechanically stressed cell systems, to isolated lungs, intact animals, and humans. Biotrauma may lead to MSOF via spillover of lung-borne inflammatory mediators into the systemic circulation. However, spillover of other agents such as bacteria and soluble proapoptotic factors may also contribute to the onset of MSOF. Other less well studied mechanisms such as peripheral immunosuppression and translocation of bacteria and/or products from the gut may play an important role. Finally, genetic variability is a crucial factor.ConclusionsThe development of MSOF is a multifactorial process. Our proposed mechanisms linking mechanical ventilation and MSOF suggest several novel therapeutic approaches. However, it will first be necessary to study the mechanisms described above to delineate more precisely the contribution of each proposed factor, their interrelationships, and their time course. We suggest that scientific advances in immunology may offer novel approaches for prevention of MSOF secondary to ventilator-induced lung injury.

CD8+ T Cell Responses in Bronchoalveolar Lavage Fluid and Peripheral Blood Mononuclear Cells of Infants with Severe Primary Respiratory Syncytial Virus Infections

A protective role for CD8+ T cells during viral infections is generally accepted, but little is known about how CD8+ T cell responses develop during primary infections in infants, their efficacy, and how memory is established after viral clearance. We studied CD8+ T cell responses in bronchoalveolar lavage (BAL) samples and blood of infants with a severe primary respiratory syncytial virus (RSV) infection. RSV-specific CD8+ T cells with an activated effector cell phenotype: CD27+CD28+CD45RO+CCR7−CD38+HLA-DR+Granzyme B+CD127− could be identified in BAL and blood. A high proportion of these CD8+ T cells proliferated and functionally responded upon in vitro stimulation with RSV Ag. Thus, despite the very young age of the patients, a robust systemic virus-specific CD8+ T cell response was elicited against a localized respiratory infection. RSV-specific T cell numbers as well as the total number of activated effector type CD8+ T cells peaked in blood around day 9–12 after the onset of primary symptoms, i.e., at the time of recovery. The lack of a correlation between RSV-specific T cell numbers and parameters of disease severity make a prominent role in immune pathology unlikely, in contrast the T cells might be involved in the recovery process.

Ventilator-induced endothelial activation and inflammation in the lung and distal organs

IntroductionResults from clinical studies have provided evidence for the importance of leukocyte-endothelial interactions in the pathogenesis of pulmonary diseases such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), as well as in systemic events like sepsis and multiple organ failure (MOF). The present study was designed to investigate whether alveolar stretch due to mechanical ventilation (MV) may evoke endothelial activation and inflammation in healthy mice, not only in the lung but also in organs distal to the lung.MethodsHealthy male C3H/HeN mice were anesthetized, tracheotomized and mechanically ventilated for either 1, 2 or 4 hours. To study the effects of alveolar stretch in vivo, we applied a MV strategy that causes overstretch of pulmonary tissue i.e. 20 cmH2O peak inspiratory pressure (PIP) and 0 cmH20 positive end expiratory pressure (PEEP). Non-ventilated, sham-operated animals served as a reference group (non-ventilated controls, NVC).ResultsAlveolar stretch imposed by MV did not only induce de novo synthesis of adhesion molecules in the lung but also in organs distal to the lung, like liver and kidney. No activation was observed in the brain. In addition, we demonstrated elevated cytokine and chemokine expression in pulmonary, hepatic and renal tissue after MV which was accompanied by enhanced recruitment of granulocytes to these organs.ConclusionsOur data implicate that MV causes endothelial activation and inflammation in mice without pre-existing pulmonary injury, both in the lung and distal organs.

Intensive care unit mortality trends in children after hematopoietic stem cell transplantation: a meta-regression analysis.

Background:There is ongoing discussion whether intensive care unit mortality has decreased over time for children after hematopoietic stem cell transplantation. Objective:To analyze intensive care unit mortality trends in children after hematopoietic stem cell transplantation. Data Sources:Search of MEDLINE, EMBASE, and Cochrane databases, and a manual review of reference lists. Study Selection:Prospective and retrospective cohort studies containing intensive care unit mortality data of children after hematopoietic stem cell transplantation. Data Extraction:Mortality statistics and features associated with mortality were abstracted from studies of interest. To assess mortality over time, the median years of inclusion in original studies were included as risk factor. A multiple random-effects meta-regression analysis was conducted to assess the independent contribution of prognostic factors on mortality. Data Synthesis:Twenty-three studies were included, reporting on 1101 intensive care unit admissions. Overall intensive care unit mortality was 60% (range, 25%–91%). Once mechanical ventilation was necessary (n = 822), mean intensive care unit mortality was 71% (range, 25%–91%). Over the years, significantly fewer intensive care unit admitted patients received mechanical ventilation (p < 0.001). Univariable analysis in all intensive care unit admitted patients showed a significant decrease in mortality associated with year of inclusion. Mechanical ventilation and pulmonary disease were associated with increased mortality. In the multiple meta-regression analysis, only pulmonary disease remained significantly associated with mortality (odds ratio = 1.21, 95% confidence interval 1.01–1.46 per 10% increase in the number of patients with pulmonary disease in studies). The association between year of inclusion and intensive care unit mortality was less pronounced (odds ratio = 0.92, 95% confidence interval 0.84–1.01). Conclusion:There is a widely held impression that intensive care unit mortality clearly decreased in children after hematopoietic stem cell transplantation. However, characteristics of intensive care unit admitted patients significantly changed over time. After correcting for this, an improvement in intensive care unit survival was less evident. More studies are needed before a true improvement in intensive care unit survival can be confirmed.

Survival in a recent cohort of mechanically ventilated pediatric allogeneic hematopoietic stem cell transplantation recipients.

There is ongoing discussion whether survival improved for children requiring mechanical ventilation after hematopoietic stem cell transplantation (HSCT). We reviewed the outcomes of 150 children who received an allogeneic HSCT between January 1999 and April 2007, in a pediatric university hospital in The Netherlands. Thirty-five of the 150 patients received mechanical ventilation on 38 occasions. None of the recorded risk factors was significantly associated with the requirement of mechanical ventilation. Sixteen admissions resulted in death in the intensive care unit (ICU), giving a case fatality rate of 42% (95% confidence interval 26%-58%). ICU mortality was associated with multiorgan failure on the second day of admission and with the use of high frequency oscillatory ventilation. Patients had higher pediatric risk of mortality scores than in previous studies, reflecting higher acuity of illness on admission to the ICU. Six-month survival in patients discharged from the ICU was 82%. Compared to previous studies, we found an improvement in ICU survival and survival 6 months after ICU discharge in a recent cohort of ventilated children after allogeneic HSCT, even though our patients were more severely ill. Our results are promising, but they need to be confirmed in larger, preferably multicenter, studies.

Systematic review of determinants of mortality in high frequency oscillatory ventilation in acute respiratory distress syndrome

IntroductionMechanical ventilation has been shown to cause lung injury and to have a significant impact on mortality in acute respiratory distress syndrome. Theoretically, high frequency oscillatory ventilation seems an ideal lung protective ventilation mode. This review evaluates determinants of mortality during use of high frequency oscillatory ventilation.MethodsPubMed was searched for literature reporting randomized trials and cohort studies of high frequency ventilation in adult patients with acute respiratory distress syndrome. Data on mortality and determinants were extracted for patients treated with high frequency oscillatory ventilation. Linear regression analyses were conducted to produce graphical representations of adjusted effects of determinants of mortality.ResultsCohorts of patients treated with high frequency oscillatory ventilation from two randomized trials and seven observational studies were included. Data from cohorts comparing survivors with non-survivors showed differences in age (42.3 versus 51.2 years), prior time on conventional mechanical ventilation (4.0 versus 6.2 days), APACHE II score (22.4 versus 26.1), pH (7.33 versus 7.26) and oxygenation index (26 versus 34). Each extra day on conventional ventilation was associated with a 20% higher mortality adjusted for age and APACHE II score (relative risk (RR) 1.20, 95% confidence interval (CI) 1.15–1.25). However, this association was confounded by differences in pH (pH adjusted RR 1.03, 95% CI 0.73–1.46). Oxygenation index seemed to have an independent effect on mortality (RR 1.10, 95% CI 0.95–1.28).ConclusionProlonged ventilation on conventional mechanical ventilation prior to high frequency oscillatory ventilation was not related to mortality. Oxygenation index was a determinant of mortality independent of other disease severity markers.

Static pressure-volume curve characteristics are moderate estimators of optimal airway pressures in a mathematical model of (primary/pulmonary) acute respiratory distress syndrome

ObjectiveTo study the value of objective pressure-volume characteristics for predicting optimal airway pressures and the development of atelectasis and overstretching during a structured lung volume recruitment procedure with subsequent reduction in airway pressures.MethodsWe used a mathematical model of a lung with adjustable characteristics of acute respiratory distress syndrome (ARDS) characteristics. Simulations were performed in five grades of ARDS in the presence of pure alveolar or combined alveolar-small airway closure as well complete or incomplete lung volume recruitability. For each simulation optimal end-expiratory pressure was determined. A static pressure-volume curve was constructed and objective characteristics of this curve calculated. The predictive value of these characteristics for end-expiratory atelectasis, overstretching, and optimal end-expiratory pressure was assessed.ResultsSimultaneous alveolar recruitment and overstretching during inflation were more pronounced than alveolar derecruitment and overstretching during deflation. End-expiratory pressure needed to prevent significant alveolar collapse in severe ARDS resulted in maximal safe tidal volumes that may be insufficient for adequate ventilation using conventional mechanical ventilatory modes. Plateau pressures well below the “upper corner point” (airway pressure where compliance decreases) resulted in significant alveolar overstretching.ConclusionsA recruitment maneuver followed by subsequent reduction in airway pressure limits end-expiratory atelectasis, overstretching, and pressure. None of the objective characteristics of the pressure-volume curve was predictive for end-expiratory atelectasis, overstretching, or optimal airway pressure.

Angiopoietin-1 Treatment Reduces Inflammation but Does Not Prevent Ventilator-Induced Lung Injury

Background Loss of integrity of the epithelial and endothelial barriers is thought to be a prominent feature of ventilator-induced lung injury (VILI). Based on its function in vascular integrity, we hypothesize that the angiopoietin (Ang)-Tie2 system plays a role in the development of VILI. The present study was designed to examine the effects of mechanical ventilation on the Ang-Tie2 system in lung tissue. Moreover, we evaluated whether treatment with Ang-1, a Tie2 receptor agonist, protects against inflammation, vascular leakage and impaired gas exchange induced by mechanical ventilation. Methods Mice were anesthetized, tracheotomized and mechanically ventilated for 5 hours with either an inspiratory pressure of 10 cmH2O (‘low’ tidal volume ∼7.5 ml/kg; LVT) or 18 cmH2O (‘high’ tidal volume ∼15 ml/kg; HVT). At initiation of HVT-ventilation, recombinant human Ang-1 was intravenously administered (1 or 4 µg per animal). Non-ventilated mice served as controls. Results HVT-ventilation influenced the Ang-Tie2 system in lungs of healthy mice since Ang-1, Ang-2 and Tie2 mRNA were decreased. Treatment with Ang-1 increased Akt-phosphorylation indicating Tie2 signaling. Ang-1 treatment reduced infiltration of granulocytes and expression of keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, monocyte chemotactic protein (MCP)-1 and interleukin (IL)-1β caused by HVT-ventilation. Importantly, Ang-1 treatment did not prevent vascular leakage and impaired gas exchange in HVT-ventilated mice despite inhibition of inflammation, vascular endothelial growth factor (VEGF) and Ang-2 expression. Conclusions Ang-1 treatment downregulates pulmonary inflammation, VEGF and Ang-2 expression but does not protect against vascular leakage and impaired gas exchange induced by HVT-ventilation.

Meta-regression analysis of high-frequency ventilation vs conventional ventilation in infant respiratory distress syndrome

ObjectiveThere is considerable heterogeneity among randomized trials comparing high-frequency ventilation (HFV) with conventional mechanical ventilation (CMV) in premature neonates with respiratory distress syndrome. We investigated what factors explained differences in outcome among these trials.DesignMeta-regression analysis of 15 randomized trials.Measurements and resultsVariables were extracted to explain heterogeneity: year of publication; use of Sensormedics 3100A ventilator for HFV; time on CMV prior to start of study; gestational age; use of surfactant; high lung volume strategy in HFV; and lung protective ventilation strategy in CMV and baseline risk. Chronic lung disease (CLD) and death or CLD were outcome measures. Relative risk ratios were calculated to estimate effect sizes of explanatory variables on reported relative risks. Adjusted estimates of relative risk ratios of high lung volume strategy and lung protective ventilation strategy were 0.42 (95% CI 0.06–2.48) and 2.02 (95% CI 0.18–23.12) for CLD, respectively. The effect of gestational age was less pronounced (RRR = 1.17 (95% CI 0.16–8.32) for CLD, respectively). Use of Sensormedics and prior time on CMV had the smallest effects [RRR = 0.96 (95% CI 0.47–1.94) and RRR = 0.85 (95% CI 0.58–1.24) for CLD, respectively)]. The same results applied to CLD or death as outcome.ConclusionsVariation in ventilation strategies that were used in trials comparing HFV with CMV in premature neonates offered the most likely explanation for the observed differences in the outcome of these trials compared with other explanatory factors.