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Caring for the Critically Ill Patient |

Effect of Prone Positioning on Clinical Outcomes in Children With Acute Lung Injury:  A Randomized Controlled Trial FREE

Martha A. Q. Curley, RN, PhD; Patricia L. Hibberd, MD, PhD; Lori D. Fineman, RN, MS; David Wypij, PhD; Mei-Chiung Shih, PhD; John E. Thompson, RRT; Mary Jo C. Grant, RN, PhD; Frederick E. Barr, MD, MS; Natalie Z. Cvijanovich, MD; Lauren Sorce, RN, MS; Peter M. Luckett, MD; Michael A. Matthay, MD; John H. Arnold, MD
[+] Author Affiliations

Caring for the Critically Ill Patient Section Editor: Deborah J. Cook, MD, Consulting Editor, JAMA.

Author Affiliations: Children’s Hospital Boston, Boston, Mass (Drs Curley, Wypij, Shih, and Arnold, and Mr Thompson); Tufts-New England Medical Center, Boston, Mass (Dr Hibberd); University of California, San Francisco (Dr Matthay and Ms Fineman); Primary Children’s Medical Center, Salt Lake City, Utah (Dr Grant); Vanderbilt Children’s Hospital, Nashville, Tenn (Dr Barr); Children’s Hospital Oakland, Oakland, Calif (Dr Cvijanovich); Children’s Memorial Hospital, Chicago, Ill (Ms Sorce); and Children’s Medical Center of Dallas, Dallas, Tex (Dr Luckett).

More Author Information
JAMA. 2005;294(2):229-237. doi:10.1001/jama.294.2.229.
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Published online

Context In uncontrolled clinical studies, prone positioning appeared to be safe and to improve oxygenation in pediatric patients with acute lung injury. However, the effect of prone positioning on clinical outcomes in children is not known.

Objective To test the hypothesis that at the end of 28 days infants and children with acute lung injury treated with prone positioning would have more ventilator-free days than those treated with supine positioning.

Design, Setting, and Patients Multicenter, randomized, controlled clinical trial conducted from August 28, 2001, to April 23, 2004, of 102 pediatric patients from 7 US pediatric intensive care units aged 2 weeks to 18 years who were treated with supine vs prone positioning. Randomization was concealed and group assignment was not blinded.

Intervention Patients were randomized to either supine or prone positioning within 48 hours of meeting acute lung injury criteria, with those patients in the prone group being positioned within 4 hours of randomization and remaining prone for 20 hours each day during the acute phase of their illness for a maximum of 7 days, after which they were positioned supine. Both groups were treated using lung protective ventilator and sedation protocols, extubation readiness testing, and hemodynamic, nutrition, and skin care guidelines.

Main Outcome Measure Ventilator-free days to day 28.

Results The trial was stopped at the planned interim analysis on the basis of the prespecified futility stopping rule. There were no differences in the number of ventilator-free days between the 2 groups (mean [SD], 15.8 [8.5] supine vs 15.6 [8.6] prone; mean difference, −0.2 days; 95% CI, −3.6 to 3.2; P = .91). After controlling for age, Pediatric Risk of Mortality III score, direct vs indirect acute lung injury, and mode of mechanical ventilation at enrollment, the adjusted difference in ventilator-free days was 0.3 days (95% CI, −3.0 to 3.5; P = .87). There were no differences in the secondary end points, including proportion alive and ventilator-free on day 28 (P = .45), mortality from all causes (P>.99), the time to recovery of lung injury (P = .78), organ-failure−free days (P = .88), and cognitive impairment (P = .16) or overall functional health (P = .12) at hospital discharge or on day 28.

Conclusion Prone positioning does not significantly reduce ventilator-free days or improve other clinical outcomes in pediatric patients with acute lung injury.

Figures in this Article

Acute lung injury is a major cause of acute respiratory failure in patients who are critically ill and is associated with several clinical disorders, including sepsis, pneumonia, and aspiration.1 Although lifesaving, traditional ventilation strategies with higher tidal volumes and airway pressures can exacerbate lung inflammation and injury.2 Acute lung injury produces parenchymal lung damage that is heterogeneous and may place the patient at risk for ventilator-associated lung injury. When patients are supine, the reduced volume of the nondependent-aerated lung is at risk for alveolar overdistention,3 and the cyclical ventilation of the dependent lung at low volumes can cause recruitment-derecruitment with subsequent mechanical strain.4 Prone positioning, as first suggested by Bryan,5 is a maneuver that can improve ventilation-to-perfusion matching6 and lung mechanics7 in both adult and pediatric patients with severe impairment of gas exchange.813 The improved oxygenation and regional changes in ventilation may result in decreased ventilator-associated lung injury14 and facilitate patient recovery.

Although prone positioning is frequently used in the management of pediatric patients with acute lung injury,15 there are no data that suggest improved clinical outcomes. Gattinoni et al16 showed no effect of 7 hours per day of prone positioning with survival in adult patients with acute lung injury. Prone positioning improved oxygenation and a post hoc analysis suggested improved outcomes in those patients with severe acute lung injury. Using a similar study design, Guerin et al17 extended the study population to include all adult patients with acute hypoxemic respiratory failure and found improved oxygenation but no difference in survival or ventilator days between the prone and supine groups. Both trials used prone positioning for relatively short periods each day, did not require a lower tidal volume approach, and did not include children. Therefore, we examined prolonged periods of prone ventilation combined with a lower tidal volume approach in children aged 2 weeks to 18 years with acute lung injury. We tested the hypothesis that children with acute lung injury treated with prone positioning would have more ventilator-free days than those treated with supine positioning.

Patients were enrolled from August 28, 2001, to April 23, 2004, at 7 US pediatric intensive care units that participate in the Pediatric Acute Lung Injury and Sepsis Investigators network. The study design was approved by the institutional review board of each hospital. Written informed consent was obtained from the parent or legal guardian of each patient.

Patients

Inclusion criteria were pediatric patients aged 2 weeks to 18 years who were intubated and mechanically ventilated with a ratio of partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FIO2) of 300 or less (adjusted to 253 in Salt Lake City, Utah, because of altitude), bilateral pulmonary infiltrates, and no clinical evidence of left atrial hypertension.18 Patients were excluded if they were younger than 2 weeks of age (newborn physiology), less than 42 weeks postconceptual age (considered preterm), unable to tolerate a position change (persistent hypotension, cerebral hypertension), had respiratory failure from cardiac disease, had hypoxemia without bilateral infiltrates, had received a bone marrow or lung transplant, were supported with extracorporeal membrane oxygenation, had a nonpulmonary condition that could be exacerbated by the prone position, had participated in other clinical trials within the preceding 30 days, or if there was a decision to limit life support. Randomization was performed by using a permuted blocks design, stratified by center, with random block sizes. Allocation was concealed; each center received serially numbered, opaque, sealed envelopes containing study assignments.

Treatment Procedures

Eligible patients were randomized within 48 hours of meeting study criteria to either supine or prone positioning. The clinical and research teams were not blinded to treatment assignment. Patients randomized to the supine group remained supine. Patients randomized to the prone group were positioned prone within 4 hours of randomization and remained prone for 20 hours each day during the acute phase of their illness for a maximum of 7 days of treatment, after which they were positioned supine. When prone, individually sized cushions were used to splint the most compliant aspect of the chest wall over the sternum and unrestrain the diaphragmatic-abdomen component of the chest wall.7

The acute phase of illness was defined as the time interval between randomization and the time at which extubation readiness criteria were met; specifically, spontaneous breathing, oxygenation index (mean airway pressure/[PaO2:FIO2 ratio] × 100) of less than 6, and a decrease in ventilator support over the previous 12 hours.19 Patients in both groups were assessed each morning while in the supine position. Thus, the length of prone positioning could be less than 20 hours on day 1. Other than positioning, both groups were treated with specific care algorithms, which included ventilator and sedation protocols, extubation readiness testing, as well as hemodynamic, nutrition, and skin care guidelines during the 28-day period.

Data Collection

At enrollment, admission functional health20 and Pediatric Risk of Mortality III (PRISM III)21 data were recorded. Race and ethnic group were categorized by the investigators. Circulatory, pulmonary, coagulation, hepatic, renal, and neurological system function was also monitored daily for 28 days.

Patients randomized to prone positioning had their physiological values and arterial blood gases assessed before and 1 hour after each supine-to-prone and prone-to-supine turn. Days in which a patient exhibited an increase in the PaO2:FIO2 ratio of at least 20 or a decrease in oxygenation index of at least 10% after a supine-to-prone turn were classified a priori as responder days.22 Patients who experienced more responder days than nonresponder days over the entire study period were considered overall responders; when equal, the patient’s overall response was categorized by the day 1 response.9

Outcome Measures

The primary outcome measure was ventilator-free days, which were defined as the number of days a patient breathed without assistance for at least 48 consecutive hours from day 1 to day 28 after randomization.23 Secondary end points included alive and ventilator-free on day 28, mortality from all causes, the time to recovery of lung injury, organ-failure−free days, and functional health. Time to recovery of lung injury was defined as the number of days from randomization to meeting extubation readiness testing criteria for 24 consecutive hours through day 28. Organ-failure−free days were defined as the number of days from day 1 to day 28 in which a patient was without clinically significant nonpulmonary organ dysfunction. The Paediatric Logistic Organ Dysfunction score parameters24 were used to define pediatric organ dysfunction. Functional health was defined as differences in cognitive impairment and overall functional health from intensive care admission to hospital discharge or day 28, whichever occurred first, using the Pediatric Cerebral Performance Category score and Pediatric Overall Performance Category score.20

Statistical Analysis

To ensure adequate power for the interim and final analyses, we conservatively based our sample estimate on a dichotomous outcome—the proportion of patients who were alive and ventilator-free at the end of 28 days. We used data from our phase 1 study9 in which 25 consecutive prone-positioned patients were matched (on acute lung injury trigger, age, and closest PRISM III score on admission and oxygenation index at enrollment) 1:2 to a historical control group derived from the pediatric acute respiratory distress syndrome data set.19 After we excluded bone marrow transplant recipients from the analysis, 18 (90%) of 20 prone-positioned patients were alive and ventilator-free on day 28 compared with 26 (65%) of 40 matched supine-positioned patients. Prone-positioned patients also experienced more ventilator-free days (mean [SD], 15 [9] days) than supine-positioned patients (mean [SD], 8 [9] days). Assuming 10% noncompliance in each group, we calculated that a sample size of 90 patients per group was required to yield 90% power to detect the noncompliance-adjusted difference of 87.5% [(90% × 90%) + (65% × 10%)] vs 67.5% [(65% × 90%) + (90% × 10%)] in the proportion of patients alive and ventilator-free on day 28, using a fixed sample size χ2 test (nQuery Advisor 3.0, Statistical Solutions, Boston, Mass).

A single interim analysis was planned after 50% of patients had completed their participation in the study using the O’Brien-Fleming stopping rule,25 with a priori boundaries of P<.006 (|Z|>2.74) to reject the null hypothesis (efficacy boundary, if large treatment differences appear before the end of the study) and P>.52 (|Z|<0.70) to accept the null hypothesis (futility boundary, if there is little chance of finding a significant difference between groups). Allowing for this interim analysis with possible early stopping, a sample size of 90 patients per group provided 88% power to detect the difference of 87.5% vs 67.5% in proportion of patients alive and ventilator-free on day 28 between treatment groups using a χ2 test, and 82% power to detect a difference of at least 4 ventilator-free days between treatment groups via a t test, assuming a common SD of 9 days for each group (East 3.1, Cytel Software Corporation, Cambridge, Mass). Thus, this study was adequately powered to detect the hypothesized difference of at least 4 ventilator-free days or a 20% or more difference in the proportion of patients who were ventilator-free and alive on day 28.

The primary analyses were performed on an intention-to-treat basis. We used the 2-sample t test, χ2 test, or Fisher exact test to compare baseline characteristics. The t test was used to compare the number of ventilator-free days between the 2 groups. Multiple linear regression analysis was then used to control for age, PRISM III score, mode of mechanical ventilation at enrollment, and direct vs indirect cause of lung injury. Center was not included in regression models because it did not appreciably affect treatment group comparisons and center effects were not statistically significant. No lack of fit, deviation from the homoscedasticity assumption, or outliers were indicated in the residual plots against variables in the model or against selected variables not in the model. A quantile normal plot of the residuals revealed no clear deviation from normality. The secondary outcomes and adverse events were compared using the 2-sample t test for continuous variables and χ2 test or Fisher exact test for categorical variables, except that the time to recovery of lung injury was analyzed using the log-rank test. Although 2-sample t tests are known to be robust for deviation from normality for the sample sizes in the current study, Wilcoxon rank sum tests were also performed because they may be more powerful than t tests for nonnormal data. The P values for Wilcoxon rank sum tests were not reported unless the significance result differed from t tests. All analyses were performed with SAS software version 9.0 (SAS Institute, Cary, NC). A 2-sided P<.05 indicated statistical significance.

The data and safety monitoring board stopped the trial at the interim analysis, after 102 patients had been enrolled, on the basis of the prespecified futility stopping rule. At this time, based on the 94 patients who had completed the 28-day study period (47 in the prone group and 47 in the supine group), comparison of the primary outcome variable (ventilator-free days) either via t test (P = .87) or multiple linear regression (P = .55) crossed the a priori futility boundary for early stopping with acceptance of the null hypothesis of no difference between groups. An identical conclusion was reached using the comparison between proportions of patients alive and ventilator-free on day 28 (χ2 test P = .60). At the interim analysis, it was calculated that if the study had continued to the planned enrollment of 180 patients, the probability of demonstrating a difference in ventilator-free days between treatment groups was less than 1% under the alternative hypothesis based on the observed unadjusted ventilator-free day treatment group differences. Analyses report on data from all 102 patients enrolled.

Study Population

Of the 8017 pediatric patients who were intubated, ventilated, and screened for the study, 184 met acute lung injury criteria and 102 were enrolled and randomized, 51 patients to each group (Figure 1). The baseline characteristics and respiratory variables at enrollment were similar between the 2 groups (Table 1 and Table 2). More patients in the prone-positioned group were initially supported on high-frequency oscillatory ventilation (12% supine and 29% prone; χ2 test P = .03). This difference was no longer significant after the implementation of study protocols when patients in both groups with an oxygenation index of more than 20 were transitioned to high-frequency oscillatory ventilation.

Figure 1. Patient Flow Through Clinical Trial
Graphic Jump Location

*Prone positioning alone was stopped on day 2 in a patient with sickle cell disease because of splenic sequestration.

Table Graphic Jump LocationTable 1. Patient Characteristics at Enrollment*
Table Graphic Jump LocationTable 2. Respiratory Values at Baseline, Study Day 1, and Average in Acute Phase*
Outcomes

The primary outcome, number of ventilator-free days, was not significantly different between the 2 groups (mean [SD], 15.8 [8.5] for supine and 15.6 [8.6] for prone; 2-sample t test P = .91; prone-to-supine mean difference, −0.2 days; 95% confidence interval [CI], –3.6 to 3.2) (Table 3 and Figure 2). After controlling for age, PRISM III score, direct vs indirect cause of acute lung injury, and mode of mechanical ventilation at enrollment in a multiple linear regression analysis, the adjusted prone-to-supine mean difference was 0.3 days (95% CI, –3.0 to 3.5; Wald test P = .87). In addition, we found no evidence that age was a confounder (when excluding age from model, prone-to-supine mean difference was 0.4 days, similar to that when age was included in the model; 95% CI, −2.9 to 3.7) or effect modifier of the association between prone vs supine positioning and ventilator-free days (F test for position by age interaction P = .53). In particular, the mean (SD) ventilator-free days for patients in the supine and prone position for the 3 age groups were for less than 2 years, 18.7 (7.1) vs 18.6 (7.6) days (mean difference, −0.1 days; 95% CI, −4.4 to 4.1); for 2 to 8 years, 14.6 (8.3) vs 11.5 (8.3) days (mean difference, −3.1 days; 95% CI, −10.4 to 4.1); for more than 8 years, 12.2 (9.4) vs 14.0 (9.2) days (mean difference, 1.8 days; 95% CI, −5.3 to 9.0).

Table Graphic Jump LocationTable 3. Primary and Secondary Outcome Variables*
Figure 2. Number of Ventilator-Free Days in the Supine- and Prone-Positioned Groups
Graphic Jump Location

No significant differences were found between the 2 groups (2-sample t test P = .91).

The proportion of patients alive and ventilator-free on day 28 was 86% in the supine and 80% in the prone group (risk ratio [RR], 0.93; 95% CI, 0.78-1.11; χ2 test P = .45). The mortality rate was 8% in both groups (RR, 0.98; 95% CI, 0.26-3.71; Fisher exact P>.99). There were no significant differences in the other secondary end points of time to recovery of lung injury, organ-failure−free days, and functional outcomes (Table 3) or sedative use (Table 4) between the 2 groups. There were also no significant differences in the number of survivors who were oxygen dependent on day 28 (20% supine and 26% prone, χ2 test P = .49).

Table Graphic Jump LocationTable 4. Sedation Use During the Acute Phase*
Prone Positioning and Oxygenation

Patients who were randomized to the prone-positioned group were positioned within a median 28 hours of meeting study criteria (interquartile range, 18-39 hours) and within a median 2.3 hours of randomization (interquartile range, 1.6-3.5 hours). Patients remained prone for a mean 18 (SD, 4) hours per day for 4 days (range, 1-7 days), which accounted for a mean 79% (SD, 9%) of the acute phase of illness. The PaO2:FIO2 ratio and oxygenation index response to positioning are shown in Figure 3.

Figure 3. Mean PaO2:FIO2 Ratio and Oxygenation Index During the Acute Phase
Graphic Jump Location

Baseline reflects supine values in both groups before the implementation of ventilator protocols. Each calculation includes data from all patients, regardless of how many measurements were available from each patient on that day. The number of patients who contributed at least 1 measurement to the calculation are included. The morning supine PaO2:FIO2 ratio and oxygenation index were not significantly different between the 2 groups for any of the acute phase days (2-sample t test P≥.15). Error bars indicate SE.

Sixty-four percent of 202 daily pronation procedures resulted in a PaO2:FIO2 ratio increase of at least 20 mm Hg, or an oxygenation index decrease of at least 10%. Based on the patient’s multiple day oxygenation response, 90% of patients in the prone group were categorized as overall responders to prone positioning. The number of ventilator-free days was not significantly different between overall responders and nonresponders to prone positioning (2-sample t test P = .85).

Protocol Deviations and Adverse Events

All positioning and adjunctive therapy protocols were stopped during the acute phase in 4 patients (3 in the prone group and 1 in the supine group) (Figure 1). In the prone group, 1 patient became hemodynamically unstable after consent had been obtained (day 1), 1 patient did not respond to conventional therapies and was cannulated for extracorporeal membrane oxygenation (day 2), and 1 patient demonstrated persistent hypercarbia in the prone position (day 3). One parent in the supine group withdrew consent on day 1. Prone positioning alone was stopped on day 2 in a patient with sickle cell disease because of splenic sequestration. Except for 1 patient in the supine group for whom parental consent was withdrawn, all patients were included in the intention-to-treat analysis.

Position-Related Complications

All position-related adverse events are listed in Table 5. Five patients experienced serious study-related events, 4 in the prone group and 1 in the supine group (Fisher exact P = .36). In the prone group, 3 patients experienced hypercarbia and 1 patient’s endotracheal tube was twisted and partially obstructed during a head turn while prone. All 4 of these patients were on high-frequency oscillatory ventilation at the time of the event and all 4 survived. The single study-related serious adverse event in the supine group was a stage IV pressure ulcer28,29; the patient did survive.

Table Graphic Jump LocationTable 5. Position-Related Adverse Events

In this randomized trial of 102 pediatric patients with acute lung injury, there were no significant differences in the number of ventilator-free days, mortality, time to recovery of lung injury, organ-failure−free days, or functional outcome between the prone and supine groups. Although we examined prolonged periods of prone ventilation combined with a lower tidal volume approach in children with acute lung injury, our results are similar to previously reported studies in the adult population.16,17

As described in several nonrandomized studies,9,10,12 most of our patients who were positioned prone did exhibit an improvement in oxygenation; however, these improvements were not associated with a decrease in the duration of ventilator support. Our 20-hour per day protocol was much longer than the 7- and 8-hour protocols that were previously tested in adult patients.16,17 This study was designed so that patients could be afforded the potential lung-protective effects of prone ventilation early and throughout the acute phase of illness. This goal was achieved as patients were positioned prone on average 28 hours after meeting eligibility criteria and were treated in the prone position for 79% of the acute phase of illness. Although patients in this trial received early and prolonged use of the prone position, we were unable to demonstrate beneficial effects on clinical outcomes.

Ninety percent of prone-positioned patients were categorized as responders by some improvement in oxygenation efficiency. The mechanism by which prone positioning leads to an improvement in oxygenation is not fully understood, especially in a patient who is developmentally immature. In infancy, chest wall compliance is nearly 3 times that of the lung.30 By the second year of life, the increase in chest wall stiffness is such that the chest wall and lung have similar compliance as in adults. By 8 years, the height of the chest wall is similar to that of an adult. Pelosi et al7 reported that thoracoabdominal compliance decreases in the prone position and the magnitude of this change is associated with the observed change in oxygenation; that is, the greater the decrease in thoracoabdominal compliance, the greater the improvement in oxygenation with prone positioning. Given the demonstration that improved oxygenation with prone positioning is associated with the magnitude of supine-prone difference in chest wall compliance in adults,7 we predicted that prone positioning would be more effective for improving oxygenation and clinical outcomes in the younger patients enrolled in our clinical trial. Our results did not support this prediction.

The primary outcome for this study was ventilator-free days, a composite outcome that reflects both survival and duration of mechanical ventilation.23 We selected this outcome variable because we hypothesized that prone positioning would simultaneously reduce mortality and shorten the duration of ventilation. Compared with previous studies investigating acute lung injury in adult patients,2,16,17,3133 we report lower mortality and more ventilator-free days. Aside from age and excluding patients after bone marrow transplant, our patient population was similar to previous studies investigating prone positioning in adult patients.16,17

To evaluate the nonpulmonary effects of the prone position, a number of secondary outcomes were analyzed. Nonpulmonary organ-failure−free days, an outcome that provides insight into the lethal multiple organ dysfunction related to acute lung injury,34 were not significantly different between the 2 groups. This may be related to the small number of patients who were septic in our study, a population that consistently manifests the largest number of organ failures in clinical trials.1 Furthermore, the use of a lung-protective ventilator protocol limited the potential for differences in treatment outside of the positioning protocols.

Our study design also included assessment of functional health, which provided additional insights. Not all pediatric patients who survived acute lung injury returned to their previous level of function. Specifically, 11% of survivors experienced worsening cerebral function and 16% of survivors had worsening overall functional ability. To our knowledge, this is the first study of acute lung injury describing the impact of acute lung injury on functional outcomes in the pediatric population.

Little is known about the relationship between acute phase management (specifically, optimal levels of oxygenation in the acute phase) and functional outcomes in patients with acute lung injury. In pediatrics, several functional outcome and quality of life measures are now available. Future interventional studies should concentrate on looking past the immediate outcome of the episode of illness and focus on the patient’s functional capacity and quality of survival.35

There are limitations to this clinical trial. First, it was not possible to blind clinicians to group assignment, so observer bias may have been introduced. However, several aspects of the trial design should have limited this potential bias, including the use of algorithms for most aspects of clinical care as well as the use of objective outcome measures (available from the authors upon request). Second, this study was not designed to show equivalence between prone and supine positioning. Our trial design included a futility stopping boundary because we thought it would be inappropriate to continue to randomize patients into a study in which there was little chance of finding statistically significant differences in the main clinical outcomes. Stopping the study for futility at the planned interim analysis could have caused a type II error (false-negative result); that is, failing to detect a prone positioning possible benefit of 3.5 ventilator-free days or possible harm of 3.0 ventilator-free days as indicated from the 95% CI. Third, given the smaller total sample size induced by stopping early, we might not have observed a rare position-related complication in the study.

Shortcomings of previous clinical studies of prone positioning have included the lack of treatment algorithms for adjunctive care of study patients that might impact primary or secondary study outcomes. In this trial, carefully designed protocols to define ventilator management, extubation readiness, and the use of sedative agents were implemented to minimize variation in the daily management of both groups. Despite careful control of these cointerventions, pediatric patients positioned prone did not demonstrate improved clinical outcomes. Although we can rule out a large beneficial treatment effect, we cannot exclude a small treatment effect, including a small negative effect. However, based on the interim analysis performed at the study midpoint, the results of this trial do not support the continued use of prone positioning as a therapeutic intervention to improve the outcomes in pediatric patients with acute lung injury.

Corresponding Author: Martha A. Q. Curley, RN, PhD, Children’s Hospital Boston, Medical-Surgical Intensive Care Unit, 300 Longwood Ave, Boston, MA 02115 (martha.curley@childrens.harvard.edu).

Advisory Board: David Bihari, MD; Christian Brun-Buisson, MD; Timothy Evans, MD; John Heffner, MD; Norman Paradis, MD; Adrienne Randolph, MD.

Author Contributions: Dr Curley had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Curley, Hibberd, Wypij, Thompson, Matthay, Arnold.

Acquisition of data: Curley, Fineman, Grant, Barr, Cvijanovich, Sorce, Luckett.

Analysis and interpretation of data: Curley, Hibberd, Wypij, Shih, Thompson, Arnold.

Drafting of the manuscript: Curley, Hibberd, Wypij, Shih, Matthay, Arnold.

Critical revision of the manuscript for important intellectual content: Curley, Hibberd, Fineman, Wypij, Shih, Thompson, Grant, Barr, Cvijanovich, Sorce, Luckett, Matthay, Arnold.

Statistical analysis: Curley, Hibberd, Wypij, Shih.

Obtained funding: Curley, Thompson, Hibberd, Wypij.

Administrative, technical, or material support: Curley, Fineman, Wypij, Grant, Barr, Cvijanovich, Sorce.

Study supervision: Curley.

Financial Disclosures: None reported.

Funding/Support: This study was supported by grants RO1NR05336 from the National Institutes of Health/National Institute of Nursing Research (NIH/NINR) and RR00064 and RR00054 from the NIH/National Center for Research Resources (NCRR). Novametrix Medical Systems, Medical Ventures, and i-STAT Corporation contributed equipment for this study.

Role of the Sponsor: The NIH/NINR, NIH/NCRR, Novametrix Medical Systems, Medical Ventures, and i-STAT Corporation were not involved in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Participants in the Pediatric Prone Study Group:Children's Hospital Boston, Boston, Mass: J. H. Arnold, R. Johnson, M. LaBrecque, J. E. Thompson; Children's Memorial Hospital, Chicago, Ill: L. Sorce, D. Steinhorn; Primary Children's Medical Center, Salt Lake City, Utah: M. J. Chellis Grant, C. Maloney; University of California, San Francisco: L. D. Fineman, J. Gutierrez, M. A. Matthay; Vanderbilt Children's Hospital, Nashville, Tenn: F. E. Barr, J. Forlidas, A. Johnson; Children's Medical Center of Dallas, Dallas, Tex: P. M. Luckett, S. Molitor-Kirsch; Children's Hospital Oakland, Oakland, Calif: N. Cvijanovich, L. Wertz. Data Coordination Center: P. L. Hibberd, P. Hopkins, M. McCarthy, A. Netson, M. C. Shih, S. Wong, D. Wypij. Project Director: M. LaBrecque. External Quality Monitor: R. Lebet. Data and Safety Monitoring Board: K. Stone (chair), R. Clark, R. M. Kacmarek, D. A. Schoenfeld.

Acknowledgment: We thank the pediatric critical care nurses, respiratory therapists, physicians, and our patients and their families who supported this clinical trial, and our colleagues in the Pediatric Acute Lung Injury and Sepsis Investigators network who helped sustain this clinical trial.

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Numa AH, Hammer J, Newth CJ. Effect of prone and supine positions on functional residual capacity, oxygenation, and respiratory mechanics in ventilated infants and children.  Am J Respir Crit Care Med. 1997;156:1185-1189
PubMed   |  Link to Article
Casado-Flores J, Martinez de Azagra A, Ruiz-Lopez MJ, Ruiz M, Serrano A. Pediatric ARDS: effect of supine-prone postural changes on oxygenation.  Intensive Care Med. 2002;28:1792-1796
PubMed   |  Link to Article
Fridrich P, Krafft P, Hochleuthner H, Mauritz W. The effects of long-term prone positioning in patients with trauma-induced adult respiratory distress syndrome.  Anesth Analg. 1996;83:1206-1211
PubMed
Broccard AF Sr, Schmitz LL, Ravenscraft SA, Marini JJ. Influence of prone position on the extent and distribution of lung injury in a high tidal volume oleic acid model of acute respiratory distress syndrome.  Crit Care Med. 1997;25:16-27
PubMed   |  Link to Article
Randolph AG, Meert KL, O'Neil ME.  et al.  The feasibility of conducting clinical trials in infants and children with acute respiratory failure.  Am J Respir Crit Care Med. 2003;167:1334-1340
PubMed   |  Link to Article
Gattinoni L, Tognoni G, Pesenti A.  et al.  Effect of prone positioning on the survival of patients with acute respiratory failure.  N Engl J Med. 2001;345:568-573
PubMed   |  Link to Article
Guerin C, Gaillard S, Lemasson S.  et al.  Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial.  JAMA. 2004;292:2379-2387
PubMed   |  Link to Article
Bernard GR, Artigas A, Brigham KL.  et al.  The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination.  Am J Respir Crit Care Med. 1994;149:818-824
PubMed   |  Link to Article
Curley MAQ, Fackler JC. Weaning from mechanical ventilation: patterns in young children recovering from acute hypoxemic respiratory failure.  Am J Crit Care. 1998;7:335-345
PubMed
Fiser DH. Assessing the outcome of pediatric intensive care.  J Pediatr. 1992;121:68-74
PubMed   |  Link to Article
Pollack M, Patel K, Ruttimann U. The Pediatric Risk of Mortality III–Acute Physiology Score (PRISM III-APS): a method of assessing physiologic instability for pediatric intensive care unit patients.  J Pediatr. 1997;131:575-581
PubMed   |  Link to Article
Curley MAQ. Prone positioning of patients with acute respiratory distress syndrome: a systematic review.  Am J Crit Care. 1999;8:397-405
PubMed
Schoenfeld DA, Bernard GR.Network ARDS.  Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome.  Crit Care Med. 2002;30:1772-1777
PubMed   |  Link to Article
Leteurtre S, Martinot A, Duhamel A.  et al.  Validation of the Paediatric Logistic Organ Dysfunction (PELOD) score: prospective, observational, multicentre study.  Lancet. 2003;362:192-197
PubMed   |  Link to Article
O'Brien P, Fleming T. A multiple testing procedure for clinical trials.  Biometrics. 1979;35:549-556
PubMed   |  Link to Article
Gattinoni L, Pelosi P, Suter PM, Pedoto A, Vercesi P, Lissoni A. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease: different syndromes?  Am J Respir Crit Care Med. 1998;158:3-11
PubMed   |  Link to Article
Randolph AG, Wypij D, Venkataraman ST.  et al.  Effect of mechanical ventilator weaning protocols on respiratory outcomes in infants and children: a randomized controlled trial.  JAMA. 2002;288:2561-2568
PubMed   |  Link to Article
The National Pressure Ulcer Advisory Panel (NPUAP).  Stage I assessment in darkly pigmented skin. Available at: http://www.npuap.org/positn4.html. Accessibility verified June 7, 2005
The National Pressure Ulcer Advisory Panel.  Pressure ulcers prevalence, cost and risk assessment: consensus development conference statement.  Decubitus. 1989;2:24-28
PubMed
Papastamelos C, Panitch HB, England SE, Allen JL. Developmental changes in chest wall compliance in infancy and early childhood.  J Appl Physiol. 1995;78:179-184
PubMed
ARDS Clinical Trials Network.  Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome.  N Engl J Med. 2004;351:327-336
PubMed   |  Link to Article
Taylor RW, Zimmerman JL, Dellinger RP.  et al.  Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial.  JAMA. 2004;291:1603-1609
PubMed   |  Link to Article
Spragg RG, Lewis JF, Walmrath HD.  et al.  Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome.  N Engl J Med. 2004;351:884-892
PubMed   |  Link to Article
Plotz FB, Slutsky AS, van Vught AJ, Heijnen CJ. Ventilator-induced lung injury and multiple system organ failure: a critical review of facts and hypotheses.  Intensive Care Med. 2004;30:1865-1872
PubMed   |  Link to Article
Curley MAQ, Zimmerman JJ. Alternative outcome measures for pediatric clinical sepsis trials.  Pediatr Crit Care Med. 2005;6:(suppl 3)  S150-S156
PubMed   |  Link to Article

Figures

Figure 1. Patient Flow Through Clinical Trial
Graphic Jump Location

*Prone positioning alone was stopped on day 2 in a patient with sickle cell disease because of splenic sequestration.

Figure 2. Number of Ventilator-Free Days in the Supine- and Prone-Positioned Groups
Graphic Jump Location

No significant differences were found between the 2 groups (2-sample t test P = .91).

Figure 3. Mean PaO2:FIO2 Ratio and Oxygenation Index During the Acute Phase
Graphic Jump Location

Baseline reflects supine values in both groups before the implementation of ventilator protocols. Each calculation includes data from all patients, regardless of how many measurements were available from each patient on that day. The number of patients who contributed at least 1 measurement to the calculation are included. The morning supine PaO2:FIO2 ratio and oxygenation index were not significantly different between the 2 groups for any of the acute phase days (2-sample t test P≥.15). Error bars indicate SE.

Tables

Table Graphic Jump LocationTable 1. Patient Characteristics at Enrollment*
Table Graphic Jump LocationTable 2. Respiratory Values at Baseline, Study Day 1, and Average in Acute Phase*
Table Graphic Jump LocationTable 3. Primary and Secondary Outcome Variables*
Table Graphic Jump LocationTable 4. Sedation Use During the Acute Phase*
Table Graphic Jump LocationTable 5. Position-Related Adverse Events

References

Ware LB, Matthay MA. The acute respiratory distress syndrome.  N Engl J Med. 2000;342:1334-1349
PubMed   |  Link to Article
ARDS Clinical Trials Network.  Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.  N Engl J Med. 2000;342:1301-1308
PubMed   |  Link to Article
Dreyfuss D, Soler P, Basset G, Saumon G. High inflation pressure pulmonary edema: respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure.  Am Rev Respir Dis. 1988;137:1159-1164
PubMed   |  Link to Article
Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury.  Am J Respir Crit Care Med. 1994;149:1327-1334
PubMed   |  Link to Article
Bryan AC. Comments of a devil's advocate.  Am Rev Respir Dis. 1974;110:143-144
PubMed
Lamm WJ, Graham MM, Albert RK. Mechanism by which the prone position improves oxygenation in acute lung injury.  Am J Respir Crit Care Med. 1994;150:184-193
PubMed   |  Link to Article
Pelosi P, Tubiolo D, Mascheroni D.  et al.  Effects of the prone position on respiratory mechanics and gas exchange during acute lung injury.  Am J Respir Crit Care Med. 1998;157:387-393
PubMed   |  Link to Article
Chatte G, Sab JM, Dubois JM, Sirodot M, Gaussorgues P, Robert D. Prone position in mechanically ventilated patients with severe acute respiratory failure.  Am J Respir Crit Care Med. 1997;155:473-478
PubMed   |  Link to Article
Curley MAQ, Thompson JE, Arnold JH. The effects of early and repeated prone positioning in pediatric patients with acute lung injury.  Chest. 2000;118:156-163
PubMed   |  Link to Article
Murdoch IA, Storman MO. Improved arterial oxygenation in children with the adult respiratory distress syndrome: the prone position.  Acta Paediatr. 1994;83:1043-1046
PubMed   |  Link to Article
Numa AH, Hammer J, Newth CJ. Effect of prone and supine positions on functional residual capacity, oxygenation, and respiratory mechanics in ventilated infants and children.  Am J Respir Crit Care Med. 1997;156:1185-1189
PubMed   |  Link to Article
Casado-Flores J, Martinez de Azagra A, Ruiz-Lopez MJ, Ruiz M, Serrano A. Pediatric ARDS: effect of supine-prone postural changes on oxygenation.  Intensive Care Med. 2002;28:1792-1796
PubMed   |  Link to Article
Fridrich P, Krafft P, Hochleuthner H, Mauritz W. The effects of long-term prone positioning in patients with trauma-induced adult respiratory distress syndrome.  Anesth Analg. 1996;83:1206-1211
PubMed
Broccard AF Sr, Schmitz LL, Ravenscraft SA, Marini JJ. Influence of prone position on the extent and distribution of lung injury in a high tidal volume oleic acid model of acute respiratory distress syndrome.  Crit Care Med. 1997;25:16-27
PubMed   |  Link to Article
Randolph AG, Meert KL, O'Neil ME.  et al.  The feasibility of conducting clinical trials in infants and children with acute respiratory failure.  Am J Respir Crit Care Med. 2003;167:1334-1340
PubMed   |  Link to Article
Gattinoni L, Tognoni G, Pesenti A.  et al.  Effect of prone positioning on the survival of patients with acute respiratory failure.  N Engl J Med. 2001;345:568-573
PubMed   |  Link to Article
Guerin C, Gaillard S, Lemasson S.  et al.  Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial.  JAMA. 2004;292:2379-2387
PubMed   |  Link to Article
Bernard GR, Artigas A, Brigham KL.  et al.  The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination.  Am J Respir Crit Care Med. 1994;149:818-824
PubMed   |  Link to Article
Curley MAQ, Fackler JC. Weaning from mechanical ventilation: patterns in young children recovering from acute hypoxemic respiratory failure.  Am J Crit Care. 1998;7:335-345
PubMed
Fiser DH. Assessing the outcome of pediatric intensive care.  J Pediatr. 1992;121:68-74
PubMed   |  Link to Article
Pollack M, Patel K, Ruttimann U. The Pediatric Risk of Mortality III–Acute Physiology Score (PRISM III-APS): a method of assessing physiologic instability for pediatric intensive care unit patients.  J Pediatr. 1997;131:575-581
PubMed   |  Link to Article
Curley MAQ. Prone positioning of patients with acute respiratory distress syndrome: a systematic review.  Am J Crit Care. 1999;8:397-405
PubMed
Schoenfeld DA, Bernard GR.Network ARDS.  Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome.  Crit Care Med. 2002;30:1772-1777
PubMed   |  Link to Article
Leteurtre S, Martinot A, Duhamel A.  et al.  Validation of the Paediatric Logistic Organ Dysfunction (PELOD) score: prospective, observational, multicentre study.  Lancet. 2003;362:192-197
PubMed   |  Link to Article
O'Brien P, Fleming T. A multiple testing procedure for clinical trials.  Biometrics. 1979;35:549-556
PubMed   |  Link to Article
Gattinoni L, Pelosi P, Suter PM, Pedoto A, Vercesi P, Lissoni A. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease: different syndromes?  Am J Respir Crit Care Med. 1998;158:3-11
PubMed   |  Link to Article
Randolph AG, Wypij D, Venkataraman ST.  et al.  Effect of mechanical ventilator weaning protocols on respiratory outcomes in infants and children: a randomized controlled trial.  JAMA. 2002;288:2561-2568
PubMed   |  Link to Article
The National Pressure Ulcer Advisory Panel (NPUAP).  Stage I assessment in darkly pigmented skin. Available at: http://www.npuap.org/positn4.html. Accessibility verified June 7, 2005
The National Pressure Ulcer Advisory Panel.  Pressure ulcers prevalence, cost and risk assessment: consensus development conference statement.  Decubitus. 1989;2:24-28
PubMed
Papastamelos C, Panitch HB, England SE, Allen JL. Developmental changes in chest wall compliance in infancy and early childhood.  J Appl Physiol. 1995;78:179-184
PubMed
ARDS Clinical Trials Network.  Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome.  N Engl J Med. 2004;351:327-336
PubMed   |  Link to Article
Taylor RW, Zimmerman JL, Dellinger RP.  et al.  Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial.  JAMA. 2004;291:1603-1609
PubMed   |  Link to Article
Spragg RG, Lewis JF, Walmrath HD.  et al.  Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome.  N Engl J Med. 2004;351:884-892
PubMed   |  Link to Article
Plotz FB, Slutsky AS, van Vught AJ, Heijnen CJ. Ventilator-induced lung injury and multiple system organ failure: a critical review of facts and hypotheses.  Intensive Care Med. 2004;30:1865-1872
PubMed   |  Link to Article
Curley MAQ, Zimmerman JJ. Alternative outcome measures for pediatric clinical sepsis trials.  Pediatr Crit Care Med. 2005;6:(suppl 3)  S150-S156
PubMed   |  Link to Article

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