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Department of Critical Care, Children's Hospital and Research Center at Oakland, Oakland
Department of Epidemiology and Biostatistics, University of California, San Francisco
Department of Pediatrics
Departments of Medicine and Anesthesia and the Cardiovascular Research Institute, University of California, San Francisco Medical Center, San Francisco, California
ABSTRACT
Rationale: The 1994 American European Consensus Committee definitions of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) have not been applied systematically in the pediatric population. Objectives: The purpose of this study was to evaluate prospectively the epidemiology and clinical risk factors associated with death and prolonged mechanical ventilation in all pediatric patients admitted to two large, pediatric intensive care units with ALI/ARDS using Consensus criteria. Methods: All pediatric patients meeting Consensus Committee definitions for ALI were prospectively identified and included in a relational database. Measurements and Main Results: There were 328 admissions for ALI/ARDS with a mortality of 22%. Multivariate logistic regression analyses revealed (1) the initial severity of oxygenation defect, as measured by the PaO2/FIO2 ratio; (2) the presence of nonpulmonary and noneCcentral nervous system (CNS) organ dysfunction; and (3) the presence of CNS dysfunction were independently associated with mortality and prolonged mechanical ventilation. A substantial fraction of patients (28%) did not require mechanical ventilation at the onset of ALI; 46% of these patients eventually required intubation for worsening ALI. Conclusions: Mortality in pediatric ALI/ARDS is high and several risk factors have major prognostic value. In contrast to ALI/ARDS in adults, the initial severity of arterial hypoxemia in children correlates well with mortality. A significant fraction of patients with pediatric ALI/ARDS can be identified before endotracheal intubation is required. These patients provide a valuable group in whom new therapies can be tested.
Key Words: acute lung injury acute respiratory distress syndrome mortality, pediatric
In 1994, the American European Consensus Conference on ARDS was convened to bring clarity and uniformity to the definition of acute lung injury (ALI) and ARDS (1). The Conference defined ALI as the acute onset of bilateral infiltrates on chest radiograph without evidence of left atrial hypertension and with a partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FIO2) ratio of less than 300 and ARDS as the acute onset of bilateral infiltrates without left atrial hypertension and a PaO2/FIO2 ratio of less than 200. The Consensus included a return to the use of acute rather than adult as an acknowledgment that ARDS is not limited to the adult population, as we recommended previously (2), and an acknowledgment that mechanical ventilation was not a requirement for defining ALI or ARDS.
The recommendations of this conference have been widely used in adults with ALI or ARDS for both clinical investigations and clinical trials, but they have not been as widely accepted for use in critically ill pediatric patients, perhaps in part because of the lack of a large, prospective epidemiologic study using these definitions in this population. Most pediatric studies to date have been confined to single-center investigations with small numbers of patients (3eC10). Several investigators have used the term acute hypoxemic respiratory failure rather than a uniform definition of ALI or ARDS (3, 11eC13). Without uniform definitions, comparison of the various studies is difficult at best. In addition, most studies have been confined to retrospective reviews rather than prospective cohort studies (3eC9, 11, 14eC16). One large, prospective, observational study of pediatric patients with acute respiratory failure identified 23 patients with ARDS as measured by PaO2/FIO2 less than 200. Unfortunately, 64% of patients screened for this study were excluded from the analysis (17). Despite these issues, it has been estimated that ARDS accounts for 1 to 4% of all pediatric ICU admissions, approximately 8 to 10% of patients requiring mechanical ventilation (10, 17), and carries an estimated mortality between 20 and 75% (4, 7, 8, 10, 12eC15, 18eC22).
This study was designed to use the 1994 American European Consensus Conference definition to identify prospectively all pediatric patients with ALI in both an academic university setting and a major community children's hospital to examine (1) the epidemiology and natural history of pediatric ALI, with particular emphasis on those patients who fulfilled ALI criteria but did not initially require endotracheal intubation and mechanical ventilation at the time of diagnosis; and (2) to study the clinical risk factors associated with two major clinical outcomes, mortality in the pediatric intensive care unit (PICU) and the duration of mechanical ventilation.
METHODS
Patients
All pediatric patients admitted to the Pediatric Intensive Care Unit (PICU) at Children's Hospital and Research Center at Oakland between July 1996 and May 2000, and all pediatric patients admitted to the PICU at the University of California Medical Center, San Francisco between July 1996 and July 1998, were prospectively evaluated. All patients meeting the 1994 American European Consensus Committee definition of ALI (PaO2/FIO2 < 300 with acute onset of bilateral infiltrates on chest radiograph and no evidence of left atrial hypertension [1]) were included in a Microsoft Access relational database management system. Patients were excluded if they were less than 36 weeks corrected gestational age or more than 18 years of age at the onset of ALI, had evidence of left atrial hypertension either clinically or by echocardiogram, or had any echocardiographic evidence of intracardiac shunt. All patients had at least one arterial blood gas supporting the PaO2/FIO2 less than 300 requirement. All arterial blood gases were obtained as standard of patient care; none were obtained for the purposes of this research study. Patients received echocardiograms at the discretion of the intensive care team based on clinical need. All echocardiograms were interpreted by attending cardiologists on staff at each institution who were blinded to the investigation. Patients with evidence of moderate to severe left ventricular dysfunction and/or left atrial hypertension based on independent attending cardiologist interpretation were excluded from this study. Radiographic interpretation was confirmed by independent readings from attending radiologists at each institution who were blinded to the study.
The study was approved by the Institutional Review Board at Children's Hospital and Research Center at Oakland and the Committee on Human Research at the University of California Medical Center at San Francisco.
Definitions
For patients who were not mechanically ventilated, the FIO2 was calculated according to the American Association of Respiratory Care guidelines (23).
Nonpulmonary end-organ dysfunction was divided into the following groups: cardiovascular, renal, hepatic, hematologic, neurologic, and gastrointestinal. Definitions for each category were derived from published, peer-reviewed standards (18, 24eC26). To be used in statistical analyses, organ dysfunction was required to be present within the first 24 hours after the onset of ALI. Organ dysfunction that occurred before the onset of ALI, but was no longer present at the onset of ALI, was not included. In-depth descriptions of each of the individual organ system definitions are available in the online supplement.
The primary outcome was mortality in the PICU. The secondary outcome was the duration of unassisted mechanical ventilation, defined as the number of days the patient was alive and not mechanically ventilated in the 28 days after onset of ALI, as defined in prior studies (27). Because this outcome was not normally distributed, the duration of unassisted mechanical ventilation was categorized into "greater than" or "less than or equal to" 14 ventilator-free days, as we have done previously (28). All patients who died while still mechanically ventilated were assigned a value of zero and included in the less than or equal to 14 category; all patients not requiring mechanical ventilation were assigned a value of 28 and included in the greater than 14 category.
Statistical Analysis
Statistical analysis was completed using Stata6 software (StataCorp LP, College Station, TX) (29). A p value less than 0.05 was considered statistically significant. Assessment of individual clinical risk factors associated with all-cause PICU mortality was completed using chi-squared and logistic regression analyses. All variables with a p value less than 0.1 and with specific clinical relevance were included in backward, stepwise multivariate models. All assumptions of multiple logistic regression modeling were met and the overall fit of the model was checked with the Hosmer-Lemeshow test. No data were transformed. As the amount of missing data was minimal for both multivariate analyses (1% for mortality and 2% for duration of mechanical ventilation), model-based methods like imputation were neither required nor used. Assessment of individual clinical risk factors associated with duration of mechanical ventilation was completed using rank sum analyses. Logistic regression was applied to the dichotomized duration of mechanical ventilation outcome described above.
RESULTS
A total of 320 patients were enrolled. Eight patients were readmitted to the PICU for second episodes of acute lung injury, thus totaling 328 admissions for ALI during the 4-year time period. Table 1 shows the patient characteristics for the entire cohort. The primary diagnoses associated with ALI were pneumonia 35%, aspiration 15%, sepsis 13%, near drowning 9%, concomitant cardiac disease 7%, and other 21% (Figure 1). Infectious causes, specifically sepsis and pneumonia, accounted for about 50% of all clinical disorders associated with ALI. Overall PICU mortality was 22%. The majority of patients (93%) died with two or more nonpulmonary organ system failures in addition to ALI. Fourteen percent were declared brain dead, 11% had a "do not resuscitate" order or "no escalation of care" orders instituted before death, and 31% had support withdrawn for medical futility.
A total of 237 patients (72%) required endotracheal intubation and mechanical ventilation before the diagnosis of ALI was made. The initial modes of mechanical ventilation at the onset of ALI included volume control in 181 (76%), pressure control in 48 (20%), high frequency oscillatory ventilation in 6 (3%), and extracorporeal membrane oxygenation in 2 (1%).
There were 91 (28%) patients who did not require endotracheal intubation and mechanical ventilation at the onset of ALI. Of the 91 patients not requiring mechanical ventilation at the onset of ALI, 54 (59%) required supplemental oxygen by mask, 31 (34%) by nasal cannula, and only 6 (7%) by bi-level or continuous positive airway pressure (BIPAP or CPAP, respectively). Of these 91 patients, 42 (46%) patients eventually required intubation and mechanical ventilation as a result of worsening ALI. Of those patients who required intubation and mechanical ventilation at the onset of ALI, 30% presented with a PaO2/FIO2 ratio between 200 and 300 and 70% with a PaO2/FIO2 ratio less than 200, a similar ratio for those in the nonintubated, noneCmechanically ventilated group in whom 38% presented with less severe hypoxemia (PaO2/FIO2 ratio 200eC300) and 62% with more severe hypoxemia (PaO2/FIO2 < 200).
Clinical Variables Associated with Increased Mortality: Univariate Analyses
The highest mortality rates occurred in patients with near drowning (54%), associated cardiac disease (39%), and sepsis (31%) (Table 2), with lower mortality rates in patients with pneumonia (11%), aspiration (12%) and other associated disease (23%) groups. There was no relationship between mortality and age (odds ratio [OR],1.0; confidence interval [95% CI], 0.99, 1.0; p = 0.5), male sex (OR, 0.86; 95% CI, 0.51, 1.46; p = 0.58) or past medical history (p = 0.6). Table 2 shows the clinical variables assessed in univariate logistic regression analyses that were associated with mortality and prolonged mechanical ventilation.
Mortality was twice as high (26%) in patients presenting with ARDS (PaO2/FIO2 < 200) compared with those presenting with ALI who did not meet ARDS criteria (13%) (p < 0.01, Figure 2). Mortality was also higher in those patients with either ALI (18%) or ARDS (29%) who required mechanical ventilation at the onset of ALI compared with those with ALI (3%) or ARDS (18%) who did not require mechanical ventilation at the onset of ALI (p = 0.03).
Evaluation of the respiratory indices as continuous variables showed that decreasing PaO2/FIO2 (per 20-point decrease: OR, 1.13; 95% CI, 1.05, 1.22; p = 0.001), and increasing FIO2 (OR, 9.66; 95% CI, 3.33, 28.04; p < 0.001), mean airway pressure (OR, 1.10; 95% CI, 1.03, 1.17; p = 0.004), and the level of positive end-expiratory pressure (PEEP) (OR, 1.22; 95% CI, 1.09, 1.38; p = 0.001) were associated with mortality. In addition to these respiratory variables, other variables were associated with mortality by the univariate analysis including a lower arterial pH, greater base excess, and the calculated oxygenation index (Table 2).
Mortality was greater in patients presenting with two or more nonpulmonary organ system failures (47%, 60/128) compared with those who presented with one or no other nonpulmonary organ system failures (6%, 11/200, p < 0.001). Mortalities associated with individual organ system failures were: cardiovascular 41% (55/133), hematologic 39%(37/94), central nervous system 61% (43/70), hepatic 49% (33/67), gastrointestinal 45% (22/49), renal 49% (23/47), none 2% (3/131).
Airleak was present in 8% of patients at ALI onset with an associated mortality of 37% (10/27) compared with 21% (62/301) among patients presenting without airleak (p = 0.049). There were 11% of patients who presented with neutropenia, and mortality in this cohort (35%, 13/37) was greater than in patients presenting without neutropenia (20%, 59/291, p = 0.040).
Forty-seven percent (157/328) of patients received inhaled eCadrenergic agonists on the first day of ALI, although only four patients were diagnosed as having status asthmaticus in addition to ALI. Patients who received aerosolized -agonists had a lower mortality than those who did not receive -agonists (10% versus 33%, p < 0.001). As expected, patients requiring epinephrine or other vasoactive medications had much higher mortalities (epinephrine: 52%, other vasoactive medications: 42%) compared with those that did not receive those medications (17% no epinephrine, 10% no other vasoactive medications, p < 0.001). No association with mortality was found with the use of diuretics or corticosteroids.
Clinical Variables Associated with Increased Mortality: Multivariate Analyses
A multivariate logistic regression analysis was performed for the entire cohort of patients to determine which variables had an independent association with mortality. Several potential interactions were examined but none reached statistical significance (data not shown). Three variables were independently associated with mortality: (1) the initial severity of oxygenation defect, as measured by PaO2/FIO2 ratio; (2) the presence of nonpulmonary and non-CNS organ dysfunction; and (3) the presence of CNS dysfunction (see Table 3). When nonpulmonary organ system dysfunction was dichotomized into patients with one no other nonpulmonary organ system dysfunction compared with those with dysfunction in two or more nonpulmonary organ systems, these relationships also held true. In addition, when the PaO2/FIO2 was dichotomized into PaO2/FIO2 of 200 to 300 or PaO2/FIO2 less than 200, the relationship to mortality also was true.
Medical therapies and modes of mechanical ventilation were not included in the multivariate models because these therapies were non-randomized and therefore not interpretable for prognostic value. The unadjusted PRISMIII score (30) was not included in subgroup analyses both because scores were unadjusted and there was insufficient power to include both presence of multiple organ system dysfunction and PRISMIII score into these models with the mortality rate of 22%.
Clinical Risk Factors Associated with Duration of Mechanical Ventilation
The secondary outcome measure for this study was the duration of unassisted mechanical ventilation (or ventilator-free days). All the individual clinical risk factors (Table 2) that were associated with increased mortality were similarly associated with prolonged mechanical ventilation on rank sum analysis (data not shown). Univariate and multivariate analyses using the ventilator-free days in a dichotomized fashion showed similar associations between PaO2/FIO2 and presence of nonpulmonary organ system dysfunction (see Tables 2 and 3).
DISCUSSION
In adult patients with ALI/ARDS, mortality remains high (31). However, the mortality in pediatric ALI/ARDS has not been established. To analyze the pediatric population accurately and with the most power requires large, prospective studies that use standardized, internationally accepted definitions. To date, this has been particularly difficult to achieve in pediatric critical care. Therefore, the primary purpose of this study was to identify prospectively all pediatric patients with ALI admitted to two major pediatric medical centers over 4 years. We identified patients using the 1994 American European Consensus Committee definitions, which have been only variably used in pediatric critical care. By adopting a uniform definition, both pediatric and adult clinicians and researchers alike can interpret and discuss incidence and mechanisms of pediatric ALI and ARDS as well as potential therapeutic options in a more scientifically rigorous manner.
The major findings of this study can be summarized as follows: (1) Pediatric ALI has a high mortality (22%) compared with the overall mortality of pediatric intensive care unit patients (30). (2) Several clinical risk factors contribute independently to an increased risk of death and prolonged mechanical ventilation, including the initial oxygenation defect, as measured by the PaO2/FIO2 ratio, the presence of nonpulmonary, non-CNS organ system dysfunction (hepatic, renal, hematologic, or gastrointestinal dysfunction), and the presence of CNS dysfunction, all of which are identifiable and interpretable in the clinical and research settings. (3) A significant proportion of pediatric patients with acute lung injury do not require mechanical ventilation at the time of diagnosis. (4) There are important similarities and differences in specific prognostic factors between adult and pediatric patients with ALI.
By including over 300 patients in this database, this project made possible a more comprehensive analysis of the general characteristics of pediatric patients with ALI and ARDS and the generation of multivariate models to describe independent predictors of death and prolonged mechanical ventilation. Three independent predictors of death were identified. Two of the three represent clinical factors (presence of renal, hepatic, hematologic, or gastrointestinal dysfunction, and presence of CNS dysfunction) and the third is an objective physiologic measure of lung dysfunction (decreasing PaO2/FIO2). All of the predictors are easily identifiable, whether the patient requires mechanical ventilation at the onset of ALI or ARDS or not, and whether the patient has evolving ALI or ARDS in the emergency department, ward or intensive care settings. By identifying patients earlier in the course of ALI/ARDS, therapeutic strategies may be tested and applied earlier, thus potentially decreasing patient morbidity and mortality.
By identifying patients whether mechanically ventilated or not, this study further underscores the value of identifying patients at the earliest phases of ALI and ARDS. The 1994 American European Consensus Committee definition does not require mechanical ventilatory support to be in place for the definition of ALI or ARDS to be applied (1). In this study, 28% of the patients did not require endotracheal intubation and mechanical ventilation at the onset of ALI. Approximately one-half of these patients ultimately required intubation and mechanical ventilatory support. Interestingly, in adults with acute respiratory failure from cardiogenic pulmonary edema, CPAP has been demonstrated to result in improved clinical outcomes compared with intubation and mechanical ventilation (32eC34). These data are also underscored by recent literature in pediatric oncology patients also supporting noninvasive ventilation as a method of avoiding intubation and mechanical ventilation in pediatric patients with ARDS (35). Given these results, a clinical trial could be organized to randomize pediatric patients with ALI to a noninvasive ventilation strategy with BIPAP or CPAP versus supplemental oxygen to determine if clinical outcomes, such as the need for endotracheal intubation and mechanical ventilation, or even mortality, can be decreased by noninvasive ventilatory support.
By identifying pediatric patients with ALI and ARDS using the Consensus Committee definitions, this study allows for direct comparisons to be made between the adult and pediatric populations. This study has identified four important similarities between adults and pediatric patients with ALI. First, the top three diagnoses associated with ALI or ARDS are similar in both children and adults (pneumonia, aspiration, and sepsis). Second, the presence of nonpulmonary organ system dysfunction shares a markedly increased risk of death in both children and adults. Third, as in adult studies, (26, 36) presence of airleak at the onset of ALI does not seem to have independent predictive value for mortality.
One last similarity between children and adults with ALI is the lack of influence of gender on duration of mechanical ventilation or mortality. This is an interesting finding as male newborns, in particular premature infants, share independently increased risk of death, respiratory distress syndrome and bronchopulmonary dysplasia in multivariate analyses (37eC40). One recent evaluation of the ESPNIC ARDS database showed a male preponderance in prepubertal children with ARDS and sepsis compared with ARDS and no sepsis (M/F: 1.7 sepsis, 1.0 no sepsis) (41). Similarly, a recent pediatric trial comparing modes of weaning from mechanical ventilation indicated that males had a significantly higher rate of failed extubation (OR, 7.86; p < 0.001) (42). Although one evaluation of Multiple-Cause Mortality Files suggested an increased mortality rate in African American men (43), our finding is supported by the largest studies on clinical risk factors associated with death in adults with ALI (44eC46). Given these data, one can speculate that the ultimate outcome from ALI in both adults and children is determined in part perhaps by genetic differences that are not autosomally related but that contribute instead to the increased inflammation, fibrosis, and coagulation causing refractory multiple organ system failure and death.
These data also point to two major differences between pediatric and adult patients with ALI. First, the overall mortality of pediatric patients with ALI or ARDS was significantly lower than that reported in adults (22% versus 35eC45%) (46). Second, and perhaps most importantly, in pediatric patients with ALI the initial severity of hypoxemia has predictive value for identifying patients at high risk of prolonged mechanical ventilation and death. In fact, the relationship to mortality can be appreciated by observing the progressive increase in mortality in patients who presented with a PaO2/FIO2 ratio in the lowest, intermediate, and highest tertiles (Figure 3). The prognostic value of the initial PaO2/FIO2 ratio in children contrasts with most adult studies in which the initial oxygenation defect has not been found to be an independent predictor of either outcome (45eC47). The better prognostic value of the initial PaO2/FIO2 in children may indicate that arterial hypoxemia is a more accurate indicator of the magnitude of acute lung injury in pediatric patients, perhaps correlating with the extent of initial injury to the alveolar epithelium. In adults, the severity of the initial arterial hypoxemia in ALI may have less predictive value because older adults have a significantly higher mortality, an important risk factor that may have no relationship to the original oxygenation defect in adults (48).
Several variables were significant only in a univariate analysis (Table 2). Although most of these variables were not robust enough to demonstrate independent predictive value, some may still have clinical significance and warrant additional study. Because this was an observational study, no therapies were protocolized for research purposes. Therefore, all therapies were instituted based on clinical need. Given these constraints, the widespread use of -agonists at the onset of ALI and the univariate association of -adrenergic agonist use with a better outcome is intriguing. Some investigations, both experimental and clinical, have indicated that aerosolized 2-adrenergic agonists can reach clinically relevant concentrations in the airspaces such that clearance of alveolar edema can be accelerated (49eC55). Given that 47% of all patients with ALI in our series received -agonists while only 1% were concomitantly diagnosed to have status asthmaticus, it is apparent that many pediatric intensivists at these two institutions thought that this therapy might be of clinical benefit in the early phases of ALI as well. Together, these data suggest that the at the mechanism of clinical improvement noted after 2-agonist administration is not fully understood and is not limited to the presence or absence of asthma-like symptoms. These data support the development of prospective clinical studies to test the therapeutic potential of 2-agonists in the treatment of ALI, in children and perhaps also in adults (56).
This study has some limitations. First, controversy still exists regarding accurate interpretation of the actual FIO2 received in patients requiring noninvasive support. To account for this, standardized ratios were used with maximal fraction of inspired oxygen for simple mask application limited at 0.5 (23). Second, due to logistical difficulties, the study was performed for 4 years at one institution and 2 years at another. To account for this, we analyzed the mortality, age, diagnosis, and ethnicity data for the patients enrolled before July 1998 and those enrolled after July 1998 and found no differences based on date of enrollment. Third, although this study involved two separate PICUs with differing patient characteristics, it is possible that local practices may not be the same in these institutions compared with other institutions across the country. Fourth, because this study was an observational cohort study, it cannot be used to examine questions of treatment effects. Lastly, the study likely underestimates the number of patients with ALI after cardiopulmonary bypass, because patients with intracardiac shunt of any kind were excluded. This last group should be assessed in future studies as an intermediate group with a modified definition of ALI.
In summary, the results of this prospective study provide new epidemiologic information and clinical risk data regarding pediatric ALI that should be useful for both future clinical research and clinical trials. Mortality in pediatric ALI/ARDS is 22%, and several risk factors have major prognostic value. In contrast to ALI/ARDS in adults, the initial severity of arterial hypoxemia in children correlates well with mortality. Because a significant fraction of patients with pediatric ALI/ARDS can be identified before intubation is required, these patients provide a valuable group in whom new therapies can be tested.
Acknowledgments
The authors acknowledge the assistance of the UCSF GCRC Database Management Center, the CHRCO Pediatric Clinical Research Center, and the CHRCO Neonatal Pediatric Research Group for their support in the completion of this study.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournal.org
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