Published ahead of print on February 25, 2003, doi:10.1164/rccm.200210-1175OC
© 2003 American Thoracic Society The Feasibility of Conducting Clinical Trials in Infants and Children with Acute Respiratory FailureDepartment of Anesthesia, Children's Hospital; Departments of Anesthesia and Pediatrics, Harvard Medical School, Boston, Massachusetts; Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan; Department of Pediatrics, Children's Hospital Oakland, Oakland, California; Department of Pediatrics, Children's Medical Center of Dallas, Dallas, Texas; Department of Pediatrics, Children's Hospital of Wisconsin, Milwaukee, Wisconsin; Department of Critical Care Medicine, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, Children's Hospital and Regional Medical Center, Seattle, Washington; Department of Critical Care Medicine, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; Clinical Research Center, Children's Hospital, Boston, Massachusetts; and Department of Pediatrics, Duke Children's Hospital, Durham, North Carolina Correspondence and requests for reprint should be addressed to Dr. Adrienne Randolph, M.D., M.Sc., Children's Hospital MICU, FA-108 300 Longwood Avenue, Boston, MA 02115. E-mail: adrienne.randolph{at}tch.harvard.edu
Designing robust clinical trials in critically ill, mechanically ventilated children requires an understanding of the epidemiology and course of pediatric respiratory failure. As part of a clinical trial, we screened all mechanically ventilated children in nine large pediatric intensive care units (ICUs) across North America for 6 consecutive months. Of 6,403 total ICU admissions, 1,096 (17.1%) required mechanical ventilator support for a minimum of 24 hours. Of these, 701 (64%) met one or more exclusion criteria for trial enrollment. Common reasons for exclusion were upper airway obstruction (13.5%) and cyanotic congenital heart disease (11.5%). Life support interventions were restricted for 9.7% of patients, and 5.5% were chronically ventilator dependent. In the patients who were eligible for respiratory failure studies, 62.4% had an acute primary diagnosis of pulmonary disease, 14.2% neurologic disease, and 8.9% cardiac disease. Chronic underlying conditions were present in 43.2% of the patients. The most common acute diagnosis was bronchiolitis in infants (43.6%) and pneumonia in children 1 year old and older (24.5%). Mortality was rare (1.6%), and the median duration of ventilation was 7 days. The design of clinical trials in critically ill children is feasible but must account for the diverse population, infrequent mortality, and short duration of mechanical ventilation.
Key Words: pediatric • respiratory failure • mechanical ventilation The management of children requiring mechanical ventilator support for acute respiratory failure should be based on strategies proven to be effective for treatment of the condition and prevention of related complications. To date, the three largest published randomized trials of management strategies for acute hypoxemic respiratory failure are a study of the effect of inhaled nitric oxide in 108 children (1), a crossover study of high-frequency ventilation in 70 children (2), and a pilot study of calf lung surfactant extract in 40 children (3). Objective evidence regarding the risks and benefits of most other interventions used for the treatment of acute respiratory failure in infants and children is lacking. Therefore, clinical practice is currently based on clinician experience and extrapolation from studies conducted in adults and newborns. Designing robust clinical trials in critically ill children on mechanical ventilator support requires a thorough understanding of the epidemiology and course of respiratory failure. Children with markedly different pathophysiology should be studied as separate diagnostic subgroups. This includes children with respiratory failure due to airway obstruction, cyanotic congenital heart disease, progressive neuromuscular weakness, and children with pulmonary hypoplasia or pulmonary vascular anomalies. Quantifying the number of patients potentially eligible for a given intervention is the first step in assessing the feasibility of a clinical trial. Clinically important outcome measures such as mortality or the length of critical illness must be identified, and baseline estimates of their frequency or duration should be obtained to ensure that a study has adequate statistical power to answer the clinical question posed. The objective of this observational study is to describe those children receiving mechanical ventilator support for a minimum of 24 hours across large pediatric referral centers in North American pediatric intensive care units (ICUs) to determine the feasibility of conducting clinical trials to improve the health outcomes of this population.
The Pediatric Acute Lung Injury and Sepsis Investigators Network is a consortium of investigators who collaborate to study therapies for acute lung injury and sepsis in children. As part of a randomized controlled clinical trial comparing three strategies for weaning patients from mechanical ventilator support (4), children less than 18 years of age who were mechanically ventilated for greater than 24 hours were screened between November 1, 1999, and April 30, 2001. Screening was performed to identify children who would be eligible for the weaning study. For the period of October 15, 2000 to April 15, 2001, all investigators screened rigorously, on a daily basis, for the purpose of describing the population of patients requiring prolonged mechanical ventilator support across pediatric ICUs. Diagnostic data collected from patients who were excluded from the weaning trial included the presence of prematurity with corrected gestational age less than 38 weeks, diaphragmatic hernia or paralysis, the need for mechanical ventilator support (including noninvasive) at baseline before admission, cyanotic congenital heart disease with unrepaired or palliated right to left intracardiac shunt, a history of single ventricle defect at any stage of repair, significantly diminished lung capacity where estimated resting tidal volume was less than 6 ml/kg, decreased lung vascularity, anatomic obstruction of lower airways, primary pulmonary hypertension or anticipated need for nitric oxide after extubation due to pulmonary hypertension, history of bone marrow or lung transplant, spinal cord injury above the lumbar region, tracheal reconstruction, upper airway obstructive conditions, status asthmaticus in patients over 2 years of age, and progressive neuromuscular weakness. Patients who had a do-not-resuscitate order or other restrictions on life support interventions were also excluded. Patients who were included in the weaning trial had new-onset (acute) respiratory failure from acute pulmonary, neurologic, or cardiac conditions, and no baseline need for mechanical ventilator support. Detailed data on acute and chronic diagnoses and clinical management were obtained from the subset of patients eligible for the weaning study. The institutional review board at each hospital approved the study. Informed consent was obtained from at least one parent or legal guardian before enrollment in the weaning study. At most sites, the institutional review board waived the informed consent requirement for collection of observational data. However, at some sites, the institutional review board did not allow observational data to be collected without informed consent. Data from these sites, with the exception of the exclusion screening form data, were only available on patients enrolled in the weaning study. Categorical data are expressed as absolute counts and percentages. Continuous data are expressed as the mean, SD, median, and range. Fisher's exact test was used for comparison of the proportions of demographic and diagnostic characteristics between groups.
The characteristics of the nine pediatric ICUs in which patients were screened for this study are listed in Table 1 . The ICUs included were large academic referral centers in the Northeast, South, Midwest, West, and one large site in Canada. Eight of the nine centers were designated pediatric trauma centers. The percentage of all children requiring mechanical ventilator support over 24 hours varied across ICUs from 12% to 24%. One site had a separate cardiac ICU that was not included in the screening sample.
A total of 26 weeks of screening data are included for each site. One site did not start screening until October 22nd, and their screening period was extended by 1 week. Two other sites missed 1 and 5 days, respectively, and their screening periods were extended for that interval to ensure that each site had a full 26 weeks of data. Out of 6,403 admissions, 1,096 infants and children (17.1%) required mechanical ventilator support for a minimum of 24 hours across the nine sites, with the number at each site varying from 70 to 202 patients (Table 1). The reasons for exclusion from the weaning trial and the percentage of patients in each exclusion category are listed in descending order in Table 2 . Common conditions resulting in mechanical ventilator support for over 24 hours across sites were intubation for upper airway obstruction (13.5%) and cyanotic congenital heart disease with unrepaired or palliated right to left intracardiac shunt (11.5%). There was marked variability in the patient populations across sites. This was partly because some sites did not screen cardiac surgery patients because they were managed in a separate ICU or because cardiothoracic surgeons were not able to enroll their patients in the protocol. Therefore, the number of patients with cyanotic congenital heart disease is most likely higher than we are reporting. Do-not-resuscitate orders or other limitations on life-support interventions were present in 9.7% of the children requiring mechanical ventilation over 24 hours. Children with a baseline need for invasive or noninvasive ventilator support accounted for 5.5% of excluded patients. Mechanical ventilation for status asthmaticus in children over 2 years of age was infrequent (1.9%). Exclusions making up the "other" category in Table 2 were progressive neuromuscular weakness (1.7%), anatomic obstruction of the lower airways (1.6%), primary pulmonary hypertension (1.6%), prematurity with a corrected gestational age of less than 38 weeks (1.1%), a history of lung transplant (0.8%), spinal cord injury above the 10th thoracic vertebrae (0.7%), and tracheal reconstruction (0.6%). Only seven patients (0.6%) were enrolled in another randomized controlled trial in which the intervention could potentially influence duration of ventilator support.
As shown in Figure 1 and Table 2, a total of 701 (64%) patients requiring mechanical ventilator support over 24 hours met at least one exclusion criterion, and 27 (2.5%) met multiple exclusion criteria. A total of 395 children (36%) on the ventilator over 24 hours met no exclusion criteria and were potentially eligible for studies of acute respiratory failure. Of these patients, we collected detailed data on 303 patients (76.7%) to describe the demographics, severity of illness, acute and chronic diagnoses, and clinical management. We were unable to collect data on 23.3% of the patients because of inability to obtain informed consent.
Table 3 lists the demographic characteristics and severity of illness of the 303 patients potentially eligible for inclusion in respiratory failure studies. Of these patients, 172 (56.7%) consented to enrollment in the weaning study, and 131 (43.2%) were not enrolled; detailed observational data were collected with informed consent or waiver of consent by the institutional review board. There were no significant differences between the age categories, sex, race, or severity of illness, as assessed by the Pediatric Risk of Mortality (PRISM) III (5) category scores of those patients enrolled and not enrolled in the clinical trial (Table 3; for Fisher's exact test, all p values were more than 0.1). Overall, 38 (13%) patients were neonates under 30 days of age; 121 (40%) were infants aged less than a year. One hundred three (34%) were children between the ages 1 and 12 years, and 41 (14%) were adolescents over 12 years of age. The median age was 327 days, with an interquartile range of 68 days to 7.3 years. The majority (55%) of patients were male. Most patients were white (47%), black (22%), or Hispanic (19%). The PRISM III scores for the population were relatively low, with 80% of patients having a score of 15 or less.
The mean duration of mechanical ventilation was 9.5 days (median, 7 days; SD, 8.8 days; range, 2 to 64 days). Blood gas and ventilator data were collected each morning as close as possible to 8 A.M. The PaO2/FIO2 ratio was 200 or less for at least 1 day in 52.5% of all patients in the study. In these patients, the PaO2/FIO2 ratio was 200 or less for a mean of 4.2 days (median, 2 days; SD, 5.48 days). The mean value of the lowest PaO2/FIO2 values was 107.4 (median, 110; SD, 48.9; 25th percentile, 65; 75th percentile, 145.7). An additional 15.2% of patients had a PaO2/FIO2 ratio of between 200 and 300 for at least 1 day. Table 4 lists the primary reason for mechanical ventilator support in patients eligible for the respiratory failure study broken down by categories of less than a year of age and 1 year of age and older. The diagnoses listed are the primary reason for mechanical ventilation as determined at study entry, although many patients had at least one secondary diagnosis. The most severe pulmonary diagnosis was assigned as the primary diagnosis. For example, patients with pneumonia progressing to acute respiratory distress syndrome (ARDS) and a patient with sepsis and ARDS would be categorized as ARDS with pneumonia and sepsis, respectively, as secondary diagnoses. Acute pulmonary conditions were the primary reason for mechanical ventilation in 62.4% of the patients. Bronchiolitis was the most common primary diagnosis present in 26.7% of patients, and pneumonia was the second most common in 15.8% of patients. As would be expected, 84% of patients with bronchiolitis were under a year of age. ARDS was defined as bilateral pulmonary infiltrates, acute onset, PaO2/FIO2 of 200 or less, and no suspicion of left heart failure (or a pulmonary capillary wedge pressure of 18 or less). ARDS was reported in 7.6% of patients as the primary reason for mechanical ventilator support at study entry. Although we did not collect chest radiograph reports in this study, we were able to confirm that the PaO2/FIO2 ratio was 200 or less for a minimum of 1 day in all of the patients diagnosed with ARDS. The median number of days that these patients met these criteria was 6, with an interquartile range of 3 and 9 days.
When combining primary and secondary diagnoses, 77 patients had a diagnosis of pneumonia (25.4%); 86 had a diagnosis of bronchiolitis (28.3%); and 16 had a diagnosis of pulmonary edema or effusion (5.3%). Gastrointestinal and hepatic diagnoses were reported in 37 patients (12.2%), including four liver transplants and nine diagnoses of bowel obstruction or bowel ischemia. Sepsis or "rule out" sepsis was reported in 48 patients (15.8%). Seizures were reported in 17 patients (5.6%). Trauma was reported in 30 patients (9.6%), and 25 had traumatic brain injury. Table 4 also lists the frequency and categories of chronic conditions in patients eligible for the weaning study. In this population, 131 of 303 (43.2%) patients had one or more chronic conditions. The frequency of chronic conditions was 23% higher in children over a year of age compared with neonates and infants. Chronic pulmonary conditions, oncologic or hematologic conditions, chronic neurologic conditions, and multiple chronic conditions were significantly more frequent in the older group. Infants and neonates were significantly more likely to have chronic cardiac conditions. Including those patients with multiple conditions, 40 patients (13.2%) had a chronic pulmonary condition, including 24 patients with asthma (7.9%), 9 patients with bronchopulmonary dysplasia (3.0%), 6 patients with restrictive lung disease (2%), and 1 patient with cystic fibrosis. Taking into account the patients excluded for diagnoses consistent with chronic health conditions and the 43.2% of eligible patients with one or more chronic health conditions, we estimate that a minimum of 70% of all of the patients requiring mechanical ventilator support in the ICU over 24 hours had one or more chronic health conditions. Patients requiring mechanical ventilator support for acute pulmonary conditions are most likely to be eligible for studies of therapeutic interventions for respiratory failure. Therefore, more detailed evaluation of the subset of patients with acute pulmonary conditions was performed and is shown in Table 5 . Of these 189 patients, 22 (11.6%) had at least one assistive or invasive device, with 3 children (1.6%) using home supplemental oxygen and only 1 patient with a tracheostomy. The majority (87.8%) of these patients were not postoperative, and of those who were, the major operative category was abdominal surgery (4.2%). The need for at least one chest tube was present in 10.6%, with 9.5% having a pleural effusion and 7.9% having airleak. The need for dopamine or dobutamine of 10 mcg/kg/minute or more or any epinephrine, norepinephrine, or phenylephrine was present in 25.4% of clinical trial patients. The mean PRISM III score was 8.3 (SD, 7.4; range, 0 to 52), and the median was 6. The mean length of mechanical ventilation in days is listed in Table 5 separately for the primary acute diagnoses of pneumonia, bronchiolitis, ARDS, and other acute pulmonary conditions.
We evaluated the secondary diagnoses and chronic conditions present in those patients with bronchiolitis, pneumonia, and ARDS. For the 81 patients with bronchiolitis, 75.3% were previously healthy, and 24.7% had one or more chronic conditions, with 4.9% having chronic pulmonary disease, 1.2% chronic cardiac disease, and 2.5% chronic neurologic disease. Pneumonia was a secondary diagnosis in 17.3% of the bronchiolitis patients. The mean age of the patients with bronchiolitis was 6.8 months (median, 2.6). Premature birth was recorded for 21% (n = 17) of the patients with bronchiolitis. For the 48 patients with a primary diagnosis of pneumonia, clinicians suspected aspiration in 13 patients (27%), but of these, only 2 had chronic neurologic conditions. Other secondary conditions listed in the 23 patients with ARDS were pneumonia (47.8%), bronchiolitis (30.4%), pneumonia and bronchiolitis (13%), and sepsis (17.4%). Chronic conditions were present in 39.1% of patients with ARDS, with 13% having chronic pulmonary disease, 8.7% having a chronic neurologic disorder, and 13% having an underlying hematologic or oncologic disorder. Patients in the weaning study were followed to hospital discharge even if they were transferred to another institution. Three patients out of the 189 enrolled in the weaning study died during their ICU stay for an overall ICU mortality rate of 1.6%. One patient had acute lymphoblastic leukemia with relapse with acute diagnoses of pneumonia and sepsis. One patient had liver failure and had a massive gastrointestinal hemorrhage. The third patient was a previously healthy 1-year-old male with pneumonia and ARDS who died on the ventilator and was never eligible for weaning. For those patients with an acute pulmonary diagnosis, the overall mortality rate was similar to that of the entire population in the trial 2 of 131 (1.5%). ICU mortality data were available for all patients reported as having ARDS whether or not they were enrolled in the weaning study. Only 1 of the 23 ARDS patients (4.3%) died during their ICU stay. The use of specific interventions in patients with the primary diagnosis of bronchiolitis, pneumonia, or ARDS is shown in Table 6 . These interventions included prone positioning, high-frequency ventilation, nitric oxide, extracorporeal life support, surfactant, and pulmonary artery catheters. Prone positioning was used in 17.1% of all patients and 43.5% of patients with ARDS at study entry. High-frequency ventilation was used in 52.2% of ARDS patients. Pulmonary artery catheters were rarely used.
This study highlights the challenges facing clinical investigators attempting to study therapeutic or support strategies for pediatric acute respiratory failure. Across nine large pediatric ICUs in North America, an average of 17.1% of all admissions required mechanical ventilator support for at least 24 hours, and the majority of these children would be ineligible for respiratory studies based on a very reasonable list of exclusion criteria. Therefore, 6% of all admissions to these pediatric ICUs were potentially eligible for clinical studies of therapies for acute respiratory failure during the 6-month winter season when respiratory infections are at their peak. Despite this small percentage, 395 patients were eligible in one 6-month period across nine ICUs for a study of mechanical ventilator management strategies. Approximately half of the eligible patients were infants, and a large percentage of the children had chronic health conditions. Mortality was a rare event, even for patients with a diagnosis of ARDS. The median length of mechanical ventilator support was 11 days for ARDS patients and 6 to 7 days for patients ventilated for other acute pulmonary diagnoses. Design of clinical trials in this population using traditional outcomes may be difficult as the population is heterogeneous, death is infrequent, and the average length of time on the ventilator is short. Outcomes such as functional status after hospital discharge, critical illness-related complications, and the need for rehospitalization may be more sensitive indicators of the effects of clinical interventions. Patients with acute respiratory failure from pulmonary causes are the population most likely to be studied in respiratory trials. The majority of the children in this study developed significant hypoxia during their ICU stay, with over half having a reported PaO2/FIO2 ratio of 200 or less. The most common acute respiratory conditions were bronchiolitis and pneumonia. Bronchiolitis was more prevalent in this cohort because the study took place over the annual respiratory syncytial virus season from November through March. However, bronchiolitis was also the most common diagnosis (29.6% of patients) in the published clinical trial that included the non–respiratory syncytial virus season (4). Despite the high percentage of infants with a diagnosis of bronchiolitis, there are currently no therapies of clear benefit in improving the clinical outcome of this population (6). Although there are sufficient numbers of bronchiolitis patients across centers to perform clinical trials, identification of a clinically important outcome measure is a necessary first step. We, as well as others, found mortality in this population to be rare. In the 12 clinical trials published to date in critically ill infants with bronchiolitis (7–18), a total of 358 infants were enrolled, and 8 died for a 2.2% mortality rate. These clinical trials each enrolled between 13 and 52 infants (mean 29 infants) and approximately 200 patients would be required to see a 1-day difference in duration of mechanical ventilator support (19). The incidence of recurrent wheezing in the first year of life (20) and the risk of chronic asthma (21) are potential long-term outcomes that have not been evaluated in infants and children who became critically ill from bronchiolitis. ARDS was diagnosed at study entry in only 7.6% of our patients. Because 52% of children met PaO2/FIO2 criteria for ARDS for at least one morning screening, it is possible that more patients developed ARDS during their ICU stay. However, the group of patients who were on the ventilator due to ARDS at study entry had the longest median duration of mechanical ventilator support, and their median duration of severe hypoxia was three times longer than the entire cohort (6 days versus 2 days). Although underlying oncologic diagnoses were uncommon in the overall population (less than 3.3%), they were disproportionately represented in this group of ARDS patients (13%). The mortality in this pediatric ARDS population was 4.3% compared with a reported 30 to 40% in adult ARDS patients (22). If ARDS was underdiagnosed in this study, the mortality may be even lower. Our mortality rate is consistent with that of Curley and colleagues (23), who reported a 28-day mortality rate of 4.8% (1 of 21) for children meeting acute lung injury or ARDS criteria who did not have a history of bone marrow transplant and 100% (4 of 4) for those with a history of bone marrow transplant. The low ARDS mortality rate in our population might be because 43% had a secondary diagnosis of bronchiolitis. Other studies have also reported that a significant proportion of infants with bronchiolitis will meet ARDS criteria but that ARDS triggered by bronchiolitis has a low mortality rate (24). Whether infants with bronchiolitis who meet clinical criteria for ARDS have histologic ARDS is unclear. Although mortality in this population may be low, the impact of ARDS on longer-term pulmonary function of these infants and children has not be studied and may be significant. Our study has limitations. Because of patient confidentiality and the need for informed consent, we were not able to collect detailed data on the clinical course of the ineligible patients outside of their primary diagnosis. Some of these patients may be eligible for clinical trials and may be at the highest risk of mortality. It is possible, but unlikely, that the 23.3% of eligible patients for whom data were not collected may differ markedly from the population we described. However, we found no demographic differences between the patients enrolled in the clinical trial and those in whom observational data were collected. It is also possible that certain patients with syndromes such as sepsis, pneumonia, or bronchiolitis could be misclassified. However, these were the clinical diagnoses given by the physicians caring for the patient. Given that over half of the children had PaO2/FIO2 ratios of 200 or less and that many infants with bronchiolitis and pneumonia have bilateral infiltrates, it is quite likely that ARDS was underdiagnosed and that the outcomes for ARDS may be even better than we are reporting. The clinical characteristics and outcome of patients requiring prolonged mechanical ventilator support in pediatric ICUs are very different from that described in critically ill adults and premature neonates. These findings have implications for the design of clinical trials in infants and children. Slightly over half of the patients in our eligible sample were under 1 year of age. The pulmonary mechanics of infants differ from older children and adults (25, 26). In addition, we found significant differences between the diagnoses and chronic conditions in children over and under 1 year of age. It is possible that studies of acute respiratory failure may need to analyze infants and neonates as a separate subgroup. As a way of improving clinical confidence in the ability to extrapolate therapies from adults to pediatric patients, the National Institutes of Health has mandated that investigators include children in adult trials unless exclusion has clear justification (27). However, the extremely low mortality rate in nonimmunocompromised children may decrease the power of trials with mortality endpoints. In contrast to adults, the length of mechanical ventilation is relatively short, and the need for mechanical ventilation over 28 days is rare. Management practices also differ, as over half of the patients with ARDS were supported with high-frequency ventilation. Therefore, we believe that the feasibility of enrolling pediatric patients with acute respiratory failure in adult clinical trials should be reexamined. The common strategy of extending eligibility criteria in adult trials down to the age of 12 years would not represent the great majority of children requiring mechanical ventilator support for acute respiratory failure. Although we are reassured that mortality in infants and children with acute respiratory failure who do not have underlying cyanotic heart disease, cancer, or pulmonary hypoplasia is low, the impact of mechanical ventilation on their long-term pulmonary function and neurocognitive development requires further study.
The study coordinator was Michelle Lilley, RRT (Children's Hospital, Boston, MA). The PALISI Network site coordinators were as follows: Linda Lynch, RN (Children's Hospital, Boston, MA); Jeanette Asselin, RRT, MS; Lori Blasi, RRT (Neonatal and Pediatric Research Group at Oakland Children's Hospital, CA); Tom George, RRT; Eddie Minton, RRT (Children's Medical Center of Dallas, TX); Sue Casinelli, RRT (Children's Hospital of Michigan, Detroit, MI); Donna Hamel, RRT; Michael Gentile, RRT (Duke Children's Hospital, Durham, NC); Kathy Murkowski, RRT (Children's Hospital of Wisconsin, Milwaukee, WI); Brad Kuch, RRT; Tiffany Nagy, RRT (Children's Hospital of Pittsburgh, PA); Helena Frndova (The Hospital for Sick Children, Toronto, ON, Canada); and Don Foubare, RRT (Children's Regional Medical Center, Seattle, WA).
Supported by Ronald McDonald House Charities, NIH NHLBI K23 Award HL04278 (A.G.R.), and the National Institutes of Health, Division of Research Resources to the General Clinical Research Center at Children's Hospital, Boston, Massachusetts (M01-RR02172). Received in original form October 14, 2002; accepted in final form February 12, 2003
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