Casper W. Bollen

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.

The Effect of Computerized Physician Order Entry on Medication Prescription Errors and Clinical Outcome in Pediatric and Intensive Care: A Systematic Review

CONTEXT. Pediatric and intensive care patients are particularly at risk for medication errors. Computerized physician order entry systems could be effective in reducing medication errors and improving outcome. Effectiveness of computerized physician order entry systems has been shown in adult medical care. However, in critically ill patients and/or children, medication prescribing is a more complex process, and usefulness of computerized physician order entry systems has yet to be established. OBJECTIVE. To evaluate the effects of computerized physician order entry systems on medication prescription errors, adverse drug events, and mortality in inpatient pediatric care and neonatal, pediatric or adult intensive care settings. METHODS. PubMed, the Cochrane library, and Embase up to November 2007 were used as our data sources. Inclusion criteria were studies of (1) children 0 to 18 years old and/or ICU patients (including adults), (2) computerized physician order entry versus no computerized physician order entry as intervention, and (3) randomized trial or observational study design. All studies were validated, and data were analyzed. RESULTS. Twelve studies, all observational, met our inclusion criteria. Eight studies took place at an ICU: 4 were adult ICUs, and 4 were PICUs and/or NICUs. Four studies were pediatric inpatient studies. Meta-analysis showed a significant decreased risk of medication prescription errors with use of computerized physician order entry. However, there was no significant reduction in adverse drug events or mortality rates. A qualitative assessment of studies revealed the implementation process of computerized physician order entry software as a critical factor for outcome. CONCLUSIONS. Introduction of computerized physician order entry systems clearly reduces medication prescription errors; however, clinical benefit of computerized physician order entry systems in pediatric or ICU settings has not yet been demonstrated. The quality of the implementation process could be a decisive factor determining overall success or failure.

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.

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.

Severity of Hypoxemia and Effect of High Frequency Oscillatory Ventilation in ARDS.

Rationale: High‐frequency oscillatory ventilation (HFOV) is theoretically beneficial for lung protection, but the results of clinical trials are inconsistent, with study‐level meta‐analyses suggesting no significant effect on mortality. Objectives: The aim of this individual patient data meta‐analysis was to identify acute respiratory distress syndrome (ARDS) patient subgroups with differential outcomes from HFOV. Methods: After a comprehensive search for trials, two reviewers independently identified randomized trials comparing HFOV with conventional ventilation for adults with ARDS. Prespecified effect modifiers were tested using multivariable hierarchical logistic regression models, adjusting for important prognostic factors and clustering effects. Measurements and Main Results: Data from 1,552 patients in four trials were analyzed, applying uniform definitions for study variables and outcomes. Patients had a mean baseline PaO2/FiO2 of 114 ± 39 mm Hg; 40% had severe ARDS (PaO2/FiO2 <100 mm Hg). Mortality at 30 days was 321 of 785 (40.9%) for HFOV patients versus 288 of 767 (37.6%) for control subjects (adjusted odds ratio, 1.17; 95% confidence interval, 0.94‐1.46; P = 0.16). This treatment effect varied, however, depending on baseline severity of hypoxemia (P = 0.0003), with harm increasing with PaO2/FiO2 among patients with mild‐moderate ARDS, and the possibility of decreased mortality in patients with very severe ARDS. Compliance and body mass index did not modify the treatment effect. HFOV increased barotrauma risk compared with conventional ventilation (adjusted odds ratio, 1.75; 95% confidence interval, 1.04‐2.96; P = 0.04). Conclusions: HFOV increases mortality for most patients with ARDS but may improve survival among patients with severe hypoxemia on conventional mechanical ventilation.

Outcome of invasive mechanical ventilation after pediatric allogeneic hematopoietic SCT: results from a prospective, multicenter registry.

Exact data on prognosis of children receiving invasive mechanical ventilation (IMV) after allogeneic hematopoietic SCT (HSCT) is lacking. We therefore started a prospective registry in four European university HSCT centers (Leiden, Paris, Prague and Utrecht) and their pediatric intensive care units (PICUs). The registry started in January 2009. In January 2013, the four centers together had treated a total of 83 admissions with IMV. The case fatality rate in these patients was 52%. Mortality 6 months after PICU discharge was 45%. There were significant differences between centers in the proportion of children who received IMV after HSCT (6–23%, P<0.01), in severity of disease on admission to PICU (predicted mortality 14–37%, P<0.01), in applying noninvasive ventilation before IMV (3–75% of admissions, P<0.01) and in the use of renal replacement therapy (RRT) (8–58% of admissions, P<0.01). Severe impairment in oxygenation, use of RRT and CMV viremia were independent predictors of mortality. Our study shows that mortality in children receiving IMV after HSCT remains high, but has clearly improved compared with older studies. Patient selection and treatment in PICU differed significantly between centers, which underscores the need to standardize and optimize the PICU admission criteria, ventilatory strategies and therapies applied in PICU.

Mycobacterial infection and atopy in childhood: A systematic review

The epidemiological relation between mycobacterial infection and the prevalence of atopic disease in humans is still unclear. This is in contrast to studies in murine models in which a clear suppression of atopic symptoms was observed after exposure to mycobacteria or mycobacterial products. We therefore wanted to provide a systematic overview of the published literature on the relationship between mycobacterial infection and atopic disease and to evaluate the causal relationship in a meta‐analysis. The EMBASE and MEDLINE databases were searched systematically for papers published in the English literature (1966–2005) on the relation between mycobacterial infection and atopic disease. Original observational or interventional studies involving the paediatric population were included. Two authors independently reviewed articles for data on mycobacterial exposure and atopic disease outcome. Any differences were resolved by discussion. Of a total of 1201 hits, 23 studies (19 cross‐sectionals, three case–controls and one prospective cohort) met the inclusion criteria. Only a minority of studies (40%) observed an association between mycobacterial infection and the prevalence of atopic disease outcome. In the meta‐analysis, only studies containing data on mycobacterial exposure and atopic disease outcome variables were included. Only cross‐sectional studies, in which the relation between a positive tuberculin skin test and allergic symptoms was studied, observed statistically significant negative correlation (odds ratio 0.63; 95% confidence interval: 0.51–0.79). The results of this review show that the evidence of the relationship of mycobacterial infection and atopic disease is based on observations of cross‐sectional studies. In a meta‐analysis, calculations showed a high level of heterogeneity (I2) within studies with similar design making it difficult to pool effects. This may partly be explained by differences in the type and definition of mycobacterial infection and lack of uniformity in the definition of atopy. The results show that only a minority of studies in the literature shows any evidence of inverse relationship between mycobacterial exposure and atopic disease outcome. The fact that the present epidemiological evidence on the relationship between mycobacterial infection and the development of atopic disease is based mainly on cross‐sectional observational studies indicates the need for population‐based prospective studies to address this issue. This issue needs to be addressed in view of recent suggestions to developing mycobacterial‐based vaccines against atopic disease in the future.

Sequential meta-analysis of past clinical trials to determine the use of a new trial

Background: Clinical trials can be stopped early based on interim analyses or sequential analyses. In principle, sequential analyses can also be used to decide whether enough evidence has been gathered in completed trials to make further trials unnecessary. We demonstrate such an application through a retrospective analysis of clinical trials comparing ventilation methods for the treatment of preterm newborns. Methods: We identified 5 recent trials that compared high-frequency ventilation with conventional mechanical ventilation in the treatment of preterm newborns. Death or chronic lung disease and chronic lung disease in survivors were the primary clinical outcomes of interest. We applied sequential meta-analyses to these 5 studies. Results: After including the first study of the last 5 trials in a sequential meta-analysis, the boundary of “no clinically relevant effect” was crossed for both outcomes (death or chronic lung disease). A sensitivity analysis using a reduction in the size of assumed clinically relevant effect showed the same findings after 2 trials. Conclusions: Sequential meta-analyses showed that a lack of clinically relevant effect had been established after the first of the 5 trials. If such an analysis had been conducted after the first or second of these clinical trials, it might have led to changes in the study design of subsequent trials or even to a reassessment of the need for further trials.