Association between Intermittent Hypoxemia and Severe Bronchopulmonary Dysplasia in Preterm Infants.

Rationale: Bronchopulmonary dysplasia increases the risk of disability in extremely preterm infants. Although the pathophysiology remains uncertain, prior exposure to intermittent hypoxemia may play a role in this relationship. Objectives: To determine the association between prolonged episodes of intermittent hypoxemia and severe bronchopulmonary dysplasia. Methods: A post hoc analysis of extremely preterm infants in the Canadian Oxygen Trial who survived to 36 weeks' postmenstrual age was performed. Oxygen saturations <80% for ⩾1 minute and the proportion of time per day with hypoxemia were quantified using continuous pulse oximetry data that had been sampled every 10 seconds from within 24 hours of birth until 36 weeks' postmenstrual age. The study outcome was severe bronchopulmonary dysplasia as defined in the 2001 NIH Workshop Summary. Measurements and Main Results: Of 1,018 infants, 332 (32.6%) developed severe bronchopulmonary dysplasia. The median number of hypoxemic episodes ranged from 0.8/day (interquartile range, 0.2-1.1) to 60.2/day (interquartile range, 51.4-70.3) among the least and most affected 10% of infants. Compared with the lowest decile of exposure to hypoxemic episodes, the adjusted relative risk of severe bronchopulmonary dysplasia increased progressively from 1.72 (95% confidence interval, 1.55-1.90) at the 2nd decile to 20.40 (95% confidence interval, 12.88-32.32) at the 10th decile. Similar risk gradients were observed for time in hypoxemia. Significant differences in the rates of hypoxemia between infants with and without severe bronchopulmonary dysplasia emerged within the first week after birth. Conclusions: Prolonged intermittent hypoxemia beginning in the first week after birth was associated with an increased risk of developing severe bronchopulmonary dysplasia among extremely preterm infants. Clinical trial registered with www.isrctn.com (ISRCTN62491227) and www.clinicaltrials.gov (NCT00637169).

Drugs to Prevent Bronchopulmonary Dysplasia: Effect of Baseline Risk on the Number Needed to Treat.

Infants born very preterm have a variable baseline risk of bronchopulmonary dysplasia (BPD). Using the example of evidence-based drug therapies to prevent BPD, we designed a visual aid that displays the "number needed to treat" with CIs for caffeine, vitamin A, and hydrocortisone over a range of baseline risks.

Nasal Intermittent Positive Pressure Ventilation Versus Nasal Continuous Positive Airway Pressure to Prevent Primary Noninvasive Ventilation Failure in Extremely Low Birthweight Infants.

Reducing the risk of primary noninvasive ventilation failure in extremely low birthweight infants is linked to reducing bronchopulmonary dysplasia. In a secondary analysis of randomized data, we identified that failure rates and time to failure were similar for nasal intermittent positive pressure ventilation vs nasal continuous positive airway pressure.

Variation in Positive End-Expiratory Pressure Levels for Mechanically Ventilated Extremely Low Birth Weight Infants.

OBJECTIVE: To test the hypothesis that significant positive end-expiratory pressure (PEEP) level variation exists between neonatal centers. STUDY DESIGN: We performed a secondary analysis cohort study of the Nasal Intermittent Positive-Pressure Ventilation trial. Our study population was extremely low birth weight infants requiring mechanical ventilation within 28 days of life. The exposure was neonatal center; 34 international centers participated in the trial. Subjects from centers with fewer than 5 eligible cases were excluded. The main outcome was the maximal PEEP level used during the first course of mechanical ventilation. Infant characteristics judged a priori to directly influence clinical PEEP level selection and all characteristics associated with PEEP at P <.05 in bivariable analyses were included with and without center in multivariable linear regression models. Variation in PEEP level use between centers following adjustment for infant characteristics was assessed. RESULTS: A total of 278 extremely low birth weight infants from 17 centers were included. Maximal PEEP ranged from 3 to 9 cm H2O, mean = 5.7 (SD = 0.9). Significant variation between centers remained despite adjustment for infant characteristics (P < .0001). Further, center alone explained a greater proportion of the PEEP level variation than all infant characteristics combined. CONCLUSIONS: Marked variation in PEEP levels for extremely low birth weight infants exists between neonatal centers. Research providing evidence-based guidance for this important aspect of respiratory care in preterm infants at high risk of lung injury is needed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00433212.

Academic Performance, Motor Function, and Behavior 11 Years After Neonatal Caffeine Citrate Therapy for Apnea of Prematurity: An 11-Year Follow-up of the CAP Randomized Clinical Trial.

Importance: Caffeine citrate therapy for apnea of prematurity reduces the rates of bronchopulmonary dysplasia, severe retinopathy, and neurodevelopmental disability at 18 months and may improve motor function at 5 years. Objective: To evaluate whether neonatal caffeine therapy is associated with improved functional outcomes 11 years later. Design, Setting, and Participants: A follow-up study was conducted at 14 academic hospitals in Canada, Australia, and the United Kingdom from May 7, 2011, to May 27, 2016, of English- or French-speaking children who had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between October 11, 1999, and October 22, 2004. A total of 1202 children with birth weights of 500 to 1250 g were eligible for this study; 920 (76.5%) had adequate data for the main outcome. Interventions: Caffeine citrate or placebo until drug therapy for apnea of prematurity was no longer needed. Main Outcomes and Measures: Functional impairment was a composite of poor academic performance (defined as at least 1 standard score greater than 2 SD below the mean on the Wide Range Achievement Test-4), motor impairment (defined as a percentile rank of ≤5 on the Movement Assessment Battery for Children-Second Edition), and behavior problems (defined as a Total Problem T score ≥2 SD above the mean on the Child Behavior Checklist). Results: Among the 920 children (444 females and 476 males; median age, 11.4 years [interquartile range, 11.1-11.8 years]), the combined rates of functional impairment were not significantly different between the 457 children assigned to receive caffeine compared with the 463 children assigned to receive placebo (145 [31.7%] vs 174 [37.6%]; adjusted odds ratio, 0.78; 95% CI, 0.59-1.02; P = .07). With all available data, including those from up to 24 Swedish trial participants, the rates of poor academic performance on 1 or more of 4 subtests (66 of 458 [14.4%] vs 61 of 462 [13.2%]; adjusted odds ratio, 1.11; 95% CI, 0.77-1.61; P = .58) and behavior problems (52 of 476 [10.9%] vs 40 of 481 [8.3%]; adjusted odds ratio, 1.32; 95% CI, 0.85-2.07; P = .22) were broadly similar between the group that received caffeine and the group that received placebo. However, caffeine therapy was associated with a reduced risk of motor impairment compared with placebo (90 of 457 [19.7%] vs 130 of 473 [27.5%]; adjusted odds ratio, 0.66; 95% CI, 0.48-0.90; P = .009). Conclusions and Relevance: Caffeine therapy for apnea of prematurity did not significantly reduce the combined rate of academic, motor, and behavioral impairments but was associated with a reduced risk of motor impairment in 11-year-old children with very low birth weight. At the doses used in this trial, neonatal caffeine therapy is effective and safe into middle school age. Trial Registration: clinicaltrials.gov Identifier: NCT00182312; isrctn.org Identifier: ISRCTN44364365.

A comparison of bilevel and ventilator-delivered non-invasive respiratory support.

OBJECTIVE: To compare the rates of death or bronchopulmonary dysplasia (BPD) in infants who received nasal intermittent positive pressure ventilation (NIPPV) delivered by a conventional mechanical ventilator (CMV) or a bilevel device. DESIGN: A preplanned non-randomised comparison of infants randomised to the NIPPV arm of the NIPPV trial. SETTING: Thirty-six tertiary neonatal units in three continents. PATIENTS: Infants <1000 g and <30 weeks gestational age at birth. INTERVENTIONS: Infants received treatment with CMV NIPPV or bilevel NIPPV, as a primary mode of respiratory support or following first extubation. RESULTS: 241 received mainly bilevel NIPPV and 215 mainly CMV NIPPV. No difference was found in death or BPD at 36 weeks corrected age (adjusted OR 0.88 (95% CI 0.57 to 1.35)). More deaths occurred in infants receiving bilevel NIPPV (9.4%) than in CMV NIPPV (2.3%) (adjusted OR 5.01: 95% CI 1.74 to 14.4). There was a corresponding but not statistically significant decrease in BPD in the bilevel NIPPV group (30% vs 37%) (adjusted OR 0.64 (95% CI 0.41 to 1.02)). No difference was observed in extubation failure or age at last extubation. A post hoc test of interaction between device type and synchronisation was not statistically significant. CONCLUSIONS: We did not observe a statistically significant difference in the composite outcome of death or BPD between infants who received mostly bilevel NIPPV compared with mostly CMV NIPPV. Differences in component outcomes of morbidity and BPD may be due to the competing nature of these outcomes or differences in baseline characteristics of infants. TRIAL REGISTRATION NUMBER: NCT00433212.

Prediction of Late Death or Disability at Age 5 Years Using a Count of 3 Neonatal Morbidities in Very Low Birth Weight Infants.

OBJECTIVE: To evaluate bronchopulmonary dysplasia (BPD), serious brain injury, and severe retinopathy of prematurity (ROP) as predictors of poor long-term outcome in very low birth weight infants. STUDY DESIGN: We examined the associations between counts of the 3 morbidities and long-term outcomes in 1514 of 1791 (85%) infants with birth weights of 500-1250 g who were enrolled in the Caffeine for Apnea of Prematurity trial from October 1999, to October 2004, had complete morbidity data, and were alive at 36 weeks postmenstrual age (PMA). BPD was defined as use of supplemental oxygen at 36 weeks PMA. Serious brain injury on cranial ultrasound included grade 3 and 4 hemorrhage, cystic periventricular leucomalacia, porencephalic cysts, or ventriculomegaly of any cause. Poor long-term outcome was death after 36 weeks PMA or survival to 5 years with 1 or more of the following disabilities: motor impairment, cognitive impairment, behavior problems, poor general health, deafness, and blindness. RESULTS: BPD, serious brain injury, and severe ROP occurred in 43%, 13%, and 6% of the infants, respectively. Each of the 3 morbidities was similarly and independently correlated with poor 5-year outcome. Rates of death or disability (95% CI) in children with none, any 1, any 2, and all 3 morbidities were 11.2% (9.0%-13.7%), 22.9% (19.6%-26.5%), 43.9% (35.5%-52.6%), and 61.5% (40.6%-79.8%), respectively. CONCLUSIONS: In very low birth weight infants who survive to 36 weeks PMA, a count of BPD, serious brain injury, and severe ROP predicts the risk of a late death or survival with disability at 5 years.

Long-term effects of caffeine therapy for apnea of prematurity on sleep at school age.

RATIONALE: Apnea of prematurity is a common condition that is usually treated with caffeine, an adenosine receptor blocker that has powerful influences on the central nervous system. However, little is known about the long-term effects of caffeine on sleep in the developing brain. OBJECTIVES: We hypothesized that neonatal caffeine use resulted in long-term abnormalities in sleep architecture and breathing during sleep. METHODS: A total of 201 ex-preterm children aged 5-12 years who participated as neonates in a double-blind, randomized, controlled clinical trial of caffeine versus placebo underwent actigraphy, polysomnography, and parental sleep questionnaires. Coprimary outcomes were total sleep time on actigraphy and apnea-hypopnea index on polysomnography. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in primary outcomes between the caffeine group and the placebo (adjusted mean difference of -6.7 [95% confidence interval (CI) = -15.3 to 2.0 min]; P = 0.13 for actigraphic total sleep time; and adjusted rate ratio [caffeine/placebo] for apnea-hypopnea index of 0.89 [95% CI = 0.55-1.43]; P = 0.63). Polysomnographic total recording time and total sleep time were longer in the caffeine group, but there was no difference in sleep efficiency between groups. The percentage of children with obstructive sleep apnea (8.2% of caffeine group versus 11.0% of placebo; P = 0.22) or elevated periodic limb movements of sleep (17.5% in caffeine group versus 11% in placebo group) was high, but did not differ significantly between groups. CONCLUSIONS: Therapeutic neonatal caffeine administration has no long-term effects on sleep duration or sleep apnea during childhood. Ex-preterm infants, regardless of caffeine status, are at risk for obstructive sleep apnea and periodic limb movements in later childhood.

A trial comparing noninvasive ventilation strategies in preterm infants.

BACKGROUND: To reduce the risk of bronchopulmonary dysplasia in extremely-low-birth-weight infants, clinicians attempt to minimize the use of endotracheal intubation by the early introduction of less invasive forms of positive airway pressure. METHODS: We randomly assigned 1009 infants with a birth weight of less than 1000 g and a gestational age of less than 30 weeks to one of two forms of noninvasive respiratory support--nasal intermittent positive-pressure ventilation (IPPV) or nasal continuous positive airway pressure (CPAP)--at the time of the first use of noninvasive respiratory support during the first 28 days of life. The primary outcome was death before 36 weeks of postmenstrual age or survival with bronchopulmonary dysplasia. RESULTS: Of the 497 infants assigned to nasal IPPV for whom adequate data were available, 191 died or survived with bronchopulmonary dysplasia (38.4%), as compared with 180 of 490 infants assigned to nasal CPAP (36.7%) (adjusted odds ratio, 1.09; 95% confidence interval, 0.83 to 1.43; P=0.56). The frequencies of air leaks and necrotizing enterocolitis, the duration of respiratory support, and the time to full feedings did not differ significantly between treatment groups. CONCLUSIONS: Among extremely-low-birth-weight infants, the rate of survival to 36 weeks of postmenstrual age without bronchopulmonary dysplasia did not differ significantly after noninvasive respiratory support with nasal IPPV as compared with nasal CPAP. (Funded by the Canadian Institutes of Health Research; NIPPV ClinicalTrials.gov number, NCT00433212; Controlled-Trials.com number, ISRCTN15233270.).

Impact of delivery room resuscitation on outcomes up to 18 months in very low birth weight infants.

OBJECTIVE: To examine the relationships between intensity of delivery room resuscitation and short- and long-term outcomes of very low birth weight infants enrolled in the Caffeine for Apnea of Prematurity (CAP) Trial. STUDY DESIGN: The CAP Trial enrolled 2006 infants with birthweights between 500 and 1250 g who were eligible for caffeine therapy. All levels of delivery room resuscitation were recorded in study participants. We divided infants in 4 groups of increasing intensity of resuscitation: minimal, n = 343; bag-mask ventilation, n = 372; endotracheal intubation, n = 1205; and cardiopulmonary resuscitation (chest compressions/epinephrine), n = 86. We used multivariable logistic regression models to compare outcomes across the 4 groups. RESULTS: The observed rates of death or disability, death, cerebral palsy, cognitive deficit, and hearing loss at 18 months increased with higher levels of resuscitation. Risk of bronchopulmonary dysplasia, severe retinopathy of prematurity, and brain injury also increased with higher levels of resuscitation. Adjustment for prognostic variables reduced the differences between the groups for most outcomes. Only the adjusted rates of bronchopulmonary dysplasia and severe retinopathy remained significantly higher after more intense resuscitation. CONCLUSIONS: In CAP Trial participants, the risk of death or neurodevelopmental disability at 18 months did not increase substantially with increasing intensity of delivery room resuscitation.

A clinical prediction model to stratify retinopathy of prematurity risk using postnatal weight gain.

OBJECTIVE: To develop an efficient clinical prediction model that includes postnatal weight gain to identify infants at risk of developing severe retinopathy of prematurity (ROP). Under current birth weight (BW) and gestational age (GA) screening criteria, <5% of infants examined in countries with advanced neonatal care require treatment. PATIENTS AND METHODS: This study was a secondary analysis of prospective data from the Premature Infants in Need of Transfusion Study, which enrolled 451 infants with a BW < 1000 g at 10 centers. There were 367 infants who remained after excluding deaths (82) and missing weights (2). Multivariate logistic regression was used to predict severe ROP (stage 3 or treatment). RESULTS: Median BW was 800 g (445-995). There were 67 (18.3%) infants who had severe ROP. The model included GA, BW, and daily weight gain rate. Run weekly, an alarm that indicated need for eye examinations occurred when the predicted probability of severe ROP was >0.085. This identified 66 of 67 severe ROP infants (sensitivity of 99% [95% confidence interval: 94%-100%]), and all 33 infants requiring treatment. Median alarm-to-outcome time was 10.8 weeks (range: 1.9-17.6). There were 110 (30%) infants who had no alarm. Nomograms were developed to determine risk of severe ROP by BW, GA, and postnatal weight gain. CONCLUSION: In a high-risk cohort, a BW-GA-weight-gain model could have reduced the need for examinations by 30%, while still identifying all infants requiring laser surgery. Additional studies are required to determine whether including larger-BW, lower-risk infants would reduce examinations further and to validate the prediction model and nomograms before clinical use.

Using a count of neonatal morbidities to predict poor outcome in extremely low birth weight infants: added role of neonatal infection.

OBJECTIVE: A count of 3 neonatal morbidities (bronchopulmonary dysplasia, brain injury, and severe retinopathy of prematurity) strongly predict the risk of death or neurosensory impairment in extremely low birth weight infants who survive to 36 weeks' postmenstrual age. Neonatal infection has also been linked with later impairment. We examined whether the addition of infection to the count of 3 neonatal morbidities further improves the prediction of poor outcome. METHODS: We studied 944 infants who participated in the Trial of Indomethacin Prophylaxis in Preterms and survived to 36 weeks' postmenstrual age. Culture-proven sepsis, meningitis, and stage II or III necrotizing enterocolitis were recorded prospectively. We investigated the incremental prognostic importance of neonatal infection by adding terms for the different types of infection to a logistic model that already contained terms for the count of bronchopulmonary dysplasia, brain injury, and severe retinopathy. Poor outcome at 18 months of age was death or survival with 1 or more of the following: cerebral palsy, cognitive delay, severe hearing loss, and bilateral blindness. RESULTS: There were 414 (44%) infants with at least 1 episode of infection or necrotizing enterocolitis. Meningitis and the presence of any type of infection added independent prognostic information to the morbidity-count model. The odds ratio associated with infection or necrotizing enterocolitis in this model was 50% smaller than the odds ratio associated with each count of the other 3 neonatal morbidities. Meningitis was rare and occurred in 22 (2.3%) of 944 infants. CONCLUSIONS: In this cohort of extremely low birth weight infants who survived to 36 weeks' postmenstrual age, neonatal infection increased the risk of a late death or survival with neurosensory impairment. However, infection was a weaker predictor of poor outcome than bronchopulmonary dysplasia, brain injury, and severe retinopathy.

Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the Trial of Indomethacin Prophylaxis in Preterms.

OBJECTIVES: To determine whether surgical closure of a patent ductus arteriosus (PDA) is a risk factor for bronchopulmonary dysplasia (BPD), severe retinopathy of prematurity (ROP), and neurosensory impairment in extremely low birth weight (ELBW) infants. STUDY DESIGN: We studied 426 infants with a symptomatic PDA, 110 of whom underwent PDA ligation and 316 of whom received medical therapy only. All infants participated in the multicenter Trial of Indomethacin Prophylaxis in Preterms (TIPP) and were observed to a corrected age of 18 months. RESULTS: Of the 95 infants who survived after PDA ligation, 50 (53%) had neurosensory impairment, compared with 84 of the 245 infants (34%) who survived after receiving only medical therapy (adjusted odds ratio, 1.98; 95% CI, 1.18-3.30; P = .0093). BPD (adjusted odds ratio, 1.81; 95% CI, 1.09-3.03; P = .023) and severe ROP (adjusted odds ratio, 2.20; 95% CI, 1.19-4.07; P = .012) were also more common after surgical PDA closure. CONCLUSIONS: PDA ligation may be associated with increased risks of BPD, severe ROP, and neurosensory impairment in ELBW infants.

The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants.

OBJECTIVE: To determine whether extremely low birth weight infants (ELBW) transfused at lower hemoglobin thresholds versus higher thresholds have different rates of survival or morbidity at discharge. STUDY DESIGN: Infants weighing <1000 g birth weight were randomly assigned within 48 hours of birth to a transfusion algorithm of either low or high hemoglobin transfusion thresholds. The composite primary outcome was death before home discharge or survival with any of either severe retinopathy, bronchopulmonary dysplasia, or brain injury on cranial ultrasound. Morbidity outcomes were assessed, blinded to allocation. RESULTS: Four hundred fifty-one infants were randomly assigned to low (n = 223) or high (n = 228) hemoglobin thresholds. Groups were similar, with mean birth weight of 770 g and gestational age of 26 weeks. Fewer infants received one or more transfusions in the low threshold group (89% low versus 95% high, P = .037). Rates of the primary outcome were 74.0% in the low threshold group and 69.7% in the high (P = .25; risk difference, 2.7%; 95% CI -3.7% to 9.2%). There were no statistically significant differences between groups in any secondary outcome. CONCLUSIONS: In extremely low birth weight infants, maintaining a higher hemoglobin level results in more infants receiving transfusions but confers little evidence of benefit.

Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP).

OBJECTIVES: To determine the risk of bronchopulmonary dysplasia (BPD) in subgroups of infants with and without patent ductus arteriosus (PDA) who were randomized to indomethacin prophylaxis or placebo, and to examine whether adverse drug effects on edema formation and oxygenation may explain why indomethacin prophylaxis does not reduce BPD. STUDY DESIGN: We studied 999 extremely low birth weight infants who participated in the Trial of Indomethacin Prophylaxis in Preterms (TIPP) and who survived to a postmenstrual age of 36 weeks. RESULTS: The incidence of BPD in the 2 subgroups of infants with PDA was 52% (55/105) after indomethacin prophylaxis and 56% (137/246) after placebo. In contrast, rates of BPD in the 2 subgroups without a PDA were 43% (170/391) after indomethacin prophylaxis and 30% (78/257) after placebo (P [interaction] = .015). Logistic regression analysis with adjustment for prognostic baseline factors showed that adverse and independent effects of indomethacin prophylaxis on the need for supplemental oxygen and on weight loss by the end of the first week of life may increase the risk of BPD in infants without PDA. CONCLUSIONS: Harmful side effects on oxygenation and edema formation may explain why indomethacin prophylaxis does not prevent BPD even though it reduces PDA.

Caffeine therapy for apnea of prematurity.

BACKGROUND: Methylxanthines reduce the frequency of apnea of prematurity and the need for mechanical ventilation during the first seven days of therapy. It is uncertain whether methylxanthines have other short- and long-term benefits or risks in infants with very low birth weight. METHODS: We randomly assigned 2006 infants with birth weights of 500 to 1250 g during the first 10 days of life to receive either caffeine or placebo, until drug therapy for apnea of prematurity was no longer needed. We evaluated the short-term outcomes before the first discharge home. RESULTS: Of 963 infants who were assigned to caffeine and who remained alive at a postmenstrual age of 36 weeks, 350 (36 percent) received supplemental oxygen, as did 447 of the 954 infants (47 percent) assigned to placebo (adjusted odds ratio, 0.63; 95 percent confidence interval, 0.52 to 0.76; P<0.001). Positive airway pressure was discontinued one week earlier in the infants assigned to caffeine (median postmenstrual age, 31.0 weeks; interquartile range, 29.4 to 33.0) than in the infants in the placebo group (median postmenstrual age, 32.0 weeks; interquartile range, 30.3 to 34.0; P<0.001). Caffeine reduced weight gain temporarily. The mean difference in weight gain between the group receiving caffeine and the group receiving placebo was greatest after two weeks (mean difference, -23 g; 95 percent confidence interval, -32 to -13; P<0.001). The rates of death, ultrasonographic signs of brain injury, and necrotizing enterocolitis did not differ significantly between the two groups. CONCLUSIONS: Caffeine therapy for apnea of prematurity reduces the rate of bronchopulmonary dysplasia in infants with very low birth weight. (ClinicalTrials.gov number, NCT00182312.).

Positive end-expiratory pressure above lower inflection point minimizes influx of activated neutrophils into lung.

OBJECTIVES: To compare the effects of low vs. high tidal volume (Vt) with three positive end-expiratory pressure (PEEP) strategies on activated neutrophil influx into the lung. DESIGN: Prospective, randomized controlled animal study. SETTING: Animal laboratory in a university hospital. SUBJECTS: Newborn piglets. INTERVENTIONS: Surfactant-depleted piglets were randomized in littermate pairs; to PEEP of either 0 (zero end-expiratory pressure [ZEEP]; n = 6), 8 cm H2O (PEEP 8; n = 5), or 1 cm H2O above the lower inflection point (LIP) (PEEP>LIP; n = 6). Within each pair piglets were randomized to a low VT (5-7 mL/kg) or high VT strategy (17-19 mL/kg). After 4 hrs of mechanical ventilation, 18-fluorodeoxyglucose (18FDG) was injected and positron emission tomography scanning was performed. MEASUREMENTS AND MAIN RESULTS: VT and PEEP changes on influx constants of 18FDG were assessed by analysis of variance. A within-litter comparison of Vt was nonsignificant (p = .50). A between-litter comparison, ordered in linear trend rank, from ZEEP, to PEEP 8, to PEEP>LIP, showed a strong effect of PEEP on influx constant (p = .019). CONCLUSIONS: PEEP set above the LIP on the inspiratory limb of the pressure-volume curve affords a stronger lung protection than VT strategy.

Why cancer patients enter randomized clinical trials: exploring the factors that influence their decision.

PURPOSE: Few interventions have been designed and tested to improve recruitment to clinical trials in oncology. The multiple factors influencing patients' decisions have made the prioritization of specific interventions challenging. The present study was undertaken to identify the independent predictors of a cancer patient's decision to enter a randomized clinical trial. METHODS: A list of factors from the medical literature was augmented with a series of focus groups involving cancer patients, physicians, and clinical research associates (CRAs). A series of questionnaires was developed with items based on these factors and were administered concurrently to 189 cancer patients, their physicians, and CRAs following the patient's decision regarding trial entry. Forward logistic regression modeling was performed using the items significantly correlated (by univariate analysis) with the decision to enter a clinical trial. RESULTS: A number of items were significantly correlated with the patient's decision. In the multivariate logistic regression model, the patient's perception of personal benefit was the most important, with an odds ratio (OR) of 3.08 (P < .05). CRA-related items involving supportive aspects of the decision-making process were also important. These included whether the CRA helped with the decision (OR = 1.71; P < .05), and whether the decision was hard for the patient to make (OR = 0.52; P < .05). CONCLUSION: Strategies that better address the potential benefits of trial entry may result in improved accrual. Interventions or aids that focus on the supportive aspects of the decision-making process while respecting the need for information and patient autonomy may also lead to meaningful improvements in accrual.