Prognostic factors for multi-organ dysfunction in pediatric oncology patients admitted to the pediatric intensive care unit.

Background: Pediatric oncology patients who require admission to the pediatric intensive care unit (PICU) have worse outcomes compared to their non-cancer peers. Although multi-organ dysfunction (MOD) plays a pivotal role in PICU mortality and morbidity, risk factors for MOD have not yet been identified. We aimed to identify risk factors at PICU admission for new or progressive MOD (NPMOD) during the first week of PICU stay. Methods: This retrospective cohort study included all pediatric oncology patients aged 0 to 18 years admitted to the PICU between June 2018 and June 2021. We used the recently published PODIUM criteria for defining multi-organ dysfunction and estimated the association between covariates at PICU baseline and the outcome NPMOD using a multivariable logistic regression model, with PICU admission as unit of study. To study the predictive performance, the model was internally validated by using bootstrap. Results: A total of 761 PICU admissions of 571 patients were included. NPMOD was present in 154 PICU admissions (20%). Patients with NPMOD had a high mortality compared to patients without NPMOD, 14% and 1.0% respectively. Hemato-oncological diagnosis, number of failing organs and unplanned admission were independent risk factors for NPMOD. The prognostic model had an overall good discrimination and calibration. Conclusion: The risk factors at PICU admission for NPMOD may help to identify patients who may benefit from closer monitoring and early interventions. When applying the PODIUM criteria, we found some opportunities for fine-tuning these criteria for pediatric oncology patients, that need to be validated in future studies.

Continuous Data-Driven Monitoring in Critical Congenital Heart Disease: Clinical Deterioration Model Development.

BACKGROUND: Critical congenital heart disease (cCHD)-requiring cardiac intervention in the first year of life for survival-occurs globally in 2-3 of every 1000 live births. In the critical perioperative period, intensive multimodal monitoring at a pediatric intensive care unit (PICU) is warranted, as their organs-especially the brain-may be severely injured due to hemodynamic and respiratory events. These 24/7 clinical data streams yield large quantities of high-frequency data, which are challenging in terms of interpretation due to the varying and dynamic physiology innate to cCHD. Through advanced data science algorithms, these dynamic data can be condensed into comprehensible information, reducing the cognitive load on the medical team and providing data-driven monitoring support through automated detection of clinical deterioration, which may facilitate timely intervention. OBJECTIVE: This study aimed to develop a clinical deterioration detection algorithm for PICU patients with cCHD. METHODS: Retrospectively, synchronous per-second data of cerebral regional oxygen saturation (rSO2) and 4 vital parameters (respiratory rate, heart rate, oxygen saturation, and invasive mean blood pressure) in neonates with cCHD admitted to the University Medical Center Utrecht, the Netherlands, between 2002 and 2018 were extracted. Patients were stratified based on mean oxygen saturation during admission to account for physiological differences between acyanotic and cyanotic cCHD. Each subset was used to train our algorithm in classifying data as either stable, unstable, or sensor dysfunction. The algorithm was designed to detect combinations of parameters abnormal to the stratified subpopulation and significant deviations from the patient's unique baseline, which were further analyzed to distinguish clinical improvement from deterioration. Novel data were used for testing, visualized in detail, and internally validated by pediatric intensivists. RESULTS: A retrospective query yielded 4600 hours and 209 hours of per-second data in 78 and 10 neonates for, respectively, training and testing purposes. During testing, stable episodes occurred 153 times, of which 134 (88%) were correctly detected. Unstable episodes were correctly noted in 46 of 57 (81%) observed episodes. Twelve expert-confirmed unstable episodes were missed in testing. Time-percentual accuracy was 93% and 77% for, respectively, stable and unstable episodes. A total of 138 sensorial dysfunctions were detected, of which 130 (94%) were correct. CONCLUSIONS: In this proof-of-concept study, a clinical deterioration detection algorithm was developed and retrospectively evaluated to classify clinical stability and instability, achieving reasonable performance considering the heterogeneous population of neonates with cCHD. Combined analysis of baseline (ie, patient-specific) deviations and simultaneous parameter-shifting (ie, population-specific) proofs would be promising with respect to enhancing applicability to heterogeneous critically ill pediatric populations. After prospective validation, the current-and comparable-models may, in the future, be used in the automated detection of clinical deterioration and eventually provide data-driven monitoring support to the medical team, allowing for timely intervention.

The effect of a decision support system on the incidence of prescription errors in a PICU.

WHAT IS KNOWN AND OBJECTIVE: Paediatric intensive care patients are at high risk for prescription errors due to the more complex process of medication prescribing. Clinical decision support systems (CDSS) have shown good results in effectively reducing prescription errors. A specific dosing CDSS was developed that can check and suggest normal dose, dose limits and administration frequencies. This study aimed to assess the effect of this CDSS on protocol deviation (as measure of prescription error) types and frequency in a paediatric intensive care unit (PICU). METHODS: A retrospective observational study was conducted evaluating 9342 prescriptions in a 4-month period before and after the implementation of a CDSS in the PICU of the University Medical Center Utrecht. Medication forms were reviewed to identify protocol deviations (and therefore possible prescription errors). The incidence and nature of deviations from evidence-based protocols that were unintended and needed to be adjusted, were determined. RESULTS AND DISCUSSION: In the period before the dosing CDSS, we identified 45 protocol deviations in 5034 prescriptions (0.89%), 28 of which could not be justified (0.56%) and 11 needed to be adjusted (0.22%). In the period after the implementation of the CDSS, there were 21 protocol deviations in 4308 prescriptions (0.49%) of which ten without a valid reason (0.23%) of which two were adjusted (0.05%). WHAT IS NEW AND CONCLUSION: The specific dosing CDSS was able to significantly reduce unintentional prescription dose deviations and the number of prescriptions that needed to be adjusted, in an existing low incidence situation.

Severity of Hypoxemia and Effect of High-Frequency Oscillatory Ventilation in Acute Respiratory Distress Syndrome.

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.

High-Frequency Oscillatory Ventilation in Pediatric Acute Lung Injury: A Multicenter International Experience.

OBJECTIVE: We aim to describe current clinical practice, the past decade of experience and factors related to improved outcomes for pediatric patients receiving high-frequency oscillatory ventilation. We have also modeled predictive factors that could help stratify mortality risk and guide future high-frequency oscillatory ventilation practice. DESIGN: Multicenter retrospective, observational questionnaire study. SETTING: Seven PICUs. PATIENTS: Demographic, disease factor, and ventilatory and outcome data were collected, and 328 patients from 2009 to 2010 were included in this analysis. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Patients were classified into six cohorts based on underlying diagnosis. We used univariate analysis to identify factors associated with mortality risk and multivariate logistic regression to identify independent predictors of mortality risk. An oxygenation index greater than 35 and immunocompromise exhibited the greatest predictive power (p < 0.0001) for increased mortality risk, and respiratory syncytial virus was associated with lowest mortality risk (p = 0.003). Differences in mortality risk as a function of oxygenation index were highly dependent on primary underlying condition. A trend toward an increase in oscillator amplitude and frequency was observed when compared with historical data. CONCLUSIONS: Given the number of centers and subjects included in the database, these findings provide a robust description of current practice regarding the use of high-frequency oscillatory ventilation for pediatric hypoxic respiratory failure. Patients with severe hypoxic respiratory failure and immunocompromise had the highest mortality risk, and those with respiratory syncytial virus had the lowest. A means of identifying the risk of 30-day mortality for subjects can be obtained by identifying the underlying disease and oxygenation index on conventional ventilation preceding the initiation of high-frequency oscillatory ventilation.

The effect of a computerized prescribing and calculating system on hypo- and hyperglycemias and on prescribing time efficiency in neonatal intensive care patients.

BACKGROUND: Prescribing glucose requires complex calculations because glucose is present in parenteral and enteral nutrition and drug vehicles, making it error prone and contributing to the burden of prescribing errors. OBJECTIVE: Evaluation of the impact of a computerized physician order entry (CPOE) system with clinical decision support (CDS) for glucose control in neonatal intensive care patients (NICU) focusing on hypo- and hyperglycemic episodes and prescribing time efficiency. METHODS: An interrupted time-series design to examine the effect of CPOE on hypo- and hyperglycemias and a crossover simulation study to examine the influence of CPOE on prescribing time efficiency. NICU patients at risk for glucose imbalance hospitalized at the University Medical Center Utrecht during 2001-2007 were selected. The risks of hypo- and hyperglycemias were expressed as incidences per 100 patient days in consecutive 3-month intervals during 3 years before and after CPOE implementation. To assess prescribing time efficiency, time needed to calculate glucose intake with and without CPOE was measured. RESULTS: No significant difference was found between pre- and post-CPOE mean incidences of hypo- and hyperglycemias per 100 hospital days of neonates at risk in every 3-month period (hypoglycemias, 4.0 [95% confidence interval, 3.2-4.8] pre-CPOE and 3.1 [2.7-3.5] post-CPOE, P = .88; hyperglycemias, 6.0 [4.3-7.7] pre-CPOE and 5.0 [3.7-6.3] post-CPOE, P = .75). CPOE led to a significant time reduction of 16% (1.3 [0.3-2.3] minutes) for simple and 60% (8.6 [5.1-12.1] minutes) for complex calculations. CONCLUSIONS: CPOE including a special CDS tool preserved accuracy for calculation and control of glucose intake and increased prescribing time efficiency.

Clinical pharmacy interventions in paediatric electronic prescriptions.

OBJECTIVE: To examine the frequency, nature and determinants of clinical pharmacy interventions in paediatric electronic prescriptions. DESIGN: Prospective cohort with nested case-control study. SETTING: Tertiary children's hospital, The Netherlands. PATIENTS: Patients 0-18 years with at least one drug prescription admitted to hospital between 1 March 2004 and 1 January 2008, excluding patients receiving intensive care. INTERVENTIONS: Electronic medication prescriptions for paediatric inpatients were verified and if necessary interventions were made by the paediatric clinical pharmacy. Prescriptions requiring intervention (cases) were compared with prescriptions not requiring interventions (controls). MAIN OUTCOME MEASURES: Frequency of clinical pharmacy interventions, per 10 000 paediatric electronic prescriptions, and the determinants thereof. RESULTS: Interventions were made for 1577 (1.1%) of 138 449 prescriptions. 81% of the interventions concerned correction of a prescription that might have had adverse clinical consequences. Interventions in prescriptions for antibacterial agents for systemic use were made most often. Most corrections concerned wrong doses (45%). 1577 cases were compared with 1983 controls. The risk of interventions was higher for children aged 1 month to 2 years than for 12-18-year-olds (OR=1.97 (95% CI 1.63 to 2.38)). The risk for 'free-text' prescriptions was five times higher than for 'standardised structured template' prescriptions. No differences were found between day, evening and night shift prescriptions. Significantly more interventions were made in the oral dosage form (OR=1.63 (95% CI 1.41 to 1.88)) and administration route (OR=1.80 (95% CI 1.55 to 2.09)) than for other reasons. CONCLUSIONS: Paediatric prescribing errors occur frequently and are not completely prevented by electronic prescribing systems. This study provides information for improvements in electronic prescribing for paediatric patients. Incorporating tailored solutions, such as minimised free-text entry, certain obligatory fields and integrated dose checking and indications, can improve the quality and efficiency of electronic prescribing in paediatrics.

Bedside prediction rule for infections after pediatric cardiac surgery.

PURPOSE: Infections after pediatric cardiac surgery are a common complication, occurring in up to 30% of cases. The purpose of this study was to develop a bedside prediction rule to estimate the risk of a postoperative infection. METHODS: All consecutive pediatric cardiac surgery procedures between April 2006 and May 2009 were retrospectively analyzed. The primary outcome variable was any postoperative infection, as defined by the Center of Disease Control (2008). All variables known to the clinician at the bedside at 48 h post cardiac surgery were included in the primary analysis, and multivariable logistic regression was used to construct a prediction rule. RESULTS: A total of 412 procedures were included, of which 102 (25%) were followed by an infection. Most infections were surgical site infections (26% of all infections) and bloodstream infections (25%). Three variables proved to be most predictive of an infection: age less than 6 months, postoperative pediatric intensive care unit (PICU) stay longer than 48 h, and open sternum for longer than 48 h. Translation into prediction rule points yielded 1, 4, and 1 point for each variable, respectively. Patients with a score of 0 had 6.6% risk of an infection, whereas those with a maximal score of 6 had a risk of 57%. The area under the receiver operating characteristic curve was 0.78 (95% confidence interval 0.72-0.83). CONCLUSIONS: A simple bedside prediction rule designed for use at 48 h post cardiac surgery can discriminate between children at high and low risk for a subsequent infection.

Off-hours admission and mortality in two pediatric intensive care units without 24-h in-house senior staff attendance.

PURPOSE: To compare risk-adjusted mortality of children non-electively admitted during off-hours with risk-adjusted mortality of children admitted during office hours to two pediatric intensive care units (PICUs) without 24-h in-house attendance of senior staff. DESIGN: Prospective observational study, performed between January 2003 and December 2007, in two PICUs without 24-h in-house attendance of senior staff, located in tertiary referral children's hospitals in the Netherlands. METHODS: Standardized mortality rates (SMRs) of patients admitted during off-hours were compared to SMRs of patients admitted during office hours using Pediatric Index of Mortality (PIM1) and Pediatric Risk of Mortality (PRISM2) scores. Office hours were defined as week days between 8:00 a.m. and 6:00 p.m., with in-house attendance of senior staff, and off-hours as week days between 6:00 p.m. and 8:00 a.m., Saturdays, Sundays and public holidays, with one resident covering the PICU and senior staff directly available on-call. RESULTS: Of 3,212 non-elective patients admitted to the PICUs, 2,122 (66%) were admitted during off-hours. SMRs calculated according to PIM1 and PRISM2 did not show a significant difference with those of patients admitted during office hours. There was no significant effect of admission time on mortality in multivariate logistic regression with odds ratios of death in off-hours of 0.95 (PIM1, 95% CI 0.71-1.27, p = 0.73) and 1.03 (PRISM2, 95% CI 0.76-1.39, p = 0.82). CONCLUSION: Off-hours admission to our PICUs without 24-h in-house attendance of senior staff was not associated with higher SMRs than admission during office hours when senior staff were available in-house.

Sequential meta-analysis: an efficient decision-making tool.

BACKGROUND: A cumulative meta-analysis of successive randomized controlled trials (RCTs) can be used to decide whether enough evidence has been obtained comparing a control and an intervention treatment or whether a new RCT should be initiated. In general, no adjustment is made for repeatedly testing the null hypothesis of treatment equivalence on cumulative data. Neither can the power of the statistical test be quantified. Recently, trial sequential analysis (TSA) was suggested to '. . . establish when firm evidence is reached in cumulative meta-analysis'. TSA is based on alpha-spending functions and necessitates a prior estimate of the total information size. Various information sizes were suggested. PURPOSE: The aim of this study is to compare TSA with sequential meta-analysis (SMA) following Whitehead's boundaries approach. METHODS: We compare TSA and SMA by re-analysis of a number of published examples. RESULTS: Re-analysis of the examples shows that for an SMA: (1) no prior estimate for total information size is necessary and thus one set of boundaries suffices; (2) stopping a cumulative meta-analysis for futility is an option; (3) the power can be quantified; (4) point and interval estimates are adjusted for the multiple testing; and (5) gains in efficiency can be achieved, both for efficacy and for futility and thus ethical and economical benefits can be obtained. LIMITATIONS: Estimates for between-trial variability are unstable for a small number of trials. The behavior of a newly proposed estimate should be subject of further investigation. CONCLUSION: SMA is a useful tool to investigate the cumulative evidence from successive RCTs.

Mechanical ventilation for respiratory failure in children with severe neurological impairment: is it futile medical treatment?

AIM: To assess outcome for children with severe neurological impairment receiving invasive mechanical ventilation for respiratory failure. METHOD: Medical charts for all such children treated in our intensive care unit (ICU) between January 2003 and July 2008 were reviewed. Outcomes were compared with those for children with moderate neurological impairment. RESULTS: Twenty-two children with severe neurological impairment were included (nine females, 13 males; median age 7y 10mo; range 4mo-17y). The median duration of mechanical ventilation was 16 days. Six children had an uneventful 1-year survival, the others required reintubation or readmission to the ICU, or died. Eleven children were still alive 1 year after discharge from the ICU. Nine patients died of respiratory failure. None of the children in the severe group died of a heart defect. Eleven children with moderate neurological impairment were included (eight females, three males; median age 1y 1mo, range 4mo-13y). Four children had an uneventful 1-year survival. Eight children were still alive 1 year after discharge from the ICU. Two of the three non-survivors died of their heart defects. INTERPRETATION: Mechanical ventilation for respiratory failure in children with severe neurological impairment is complex and associated with limited survival. However, it cannot be regarded as futile medical treatment. Further studies are urgently needed for the rational guidance of clinical decision-making.

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.

The effect of aprotinin, tranexamic acid, and aminocaproic acid on blood loss and use of blood products in major pediatric surgery: a meta-analysis.

OBJECTIVE: Aprotinin reduces the blood loss and transfusion of blood products in children undergoing major surgery. Aprotinin has been associated with severe side effects in adults, and tranexamic acid and aminocaproic acid have been found to be safer alternatives in adults. This systematic review addresses the question of whether tranexamic acid and aminocaproic acid are equally effective as aprotinin for reducing blood loss and transfusion in children undergoing major surgery. DATA SOURCES: A systematic review of the literature was conducted to identify all randomized controlled trials of aprotinin, tranexamic acid, and aminocaproic acid involving children undergoing cardiac or scoliosis surgery. STUDY SELECTION AND DATA EXTRACTION: Twenty-three cardiac studies, totaling 1893 patients, met the inclusion criteria. None of the studies directly compared aprotinin to an alternative antifibrinolytic. Five scoliosis studies, totaling 207 patients, met the inclusion criteria. Data on blood loss and use of blood products in the first 24 postoperative hours were extracted. Only homogenously distributed outcomes were pooled. DATA SYNTHESIS: Tranexamic acid showed a homogeneously distributed reduction of blood loss by 11 mL/kg (95% confidence interval [CI] 9-13 mL/kg). Outcomes of blood loss reduction by aprotinin and aminocaproic acid were too heterogeneously distributed to be pooled, so the effect on blood loss could not be evaluated. Both aprotinin and tranexamic acid significantly reduced packed red cell transfusion (4 mL/kg, 95% CI 2-7 mL/kg and 7 mL/kg, 95% CI 5-10 mL/kg, respectively). Type of antifibrinolytic was not a determining factor that explained differences in outcome among trials in a meta-regression analysis. In the scoliosis studies, aprotinin and tranexamic acid significantly reduced blood loss compared with placebo (385 mL, 95% CI 727-42 mL and 682 mL, 95% CI 1149-214 mL, respectively). CONCLUSIONS: There is no evidence that suggests that, compared with aprotinin, alternative antifibrinolytics such as tranexamic acid were less effective in reducing blood loss in major pediatric surgery.

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.

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.

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 (I(2)) 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.

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

OBJECTIVE: There 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. DESIGN: Meta-regression analysis of 15 randomized trials. MEASUREMENTS AND RESULTS: Variables 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. CONCLUSIONS: Variation 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.