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The Outcomes of Children With Pediatric Acute Respiratory Distress Syndrome: Proceedings From the Pediatric Acute Lung Injury Consensus Conference

Quasney, Michael W. MD, PhD1; López-Fernández, Yolanda M. MD2; Santschi, Miriam MD3; Watson, R. Scott MD, MPH4

doi: 10.1097/PCC.0000000000000438
PARDS Supplement
Free

Objective: To provide additional details and evidence behind the recommendations for outcomes assessment of patients with pediatric acute respiratory distress syndrome from the Pediatric Acute Lung Injury Consensus Conference.

Design: Consensus conference of experts in pediatric acute lung injury.

Methods: A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. The outcomes subgroup comprised four experts. When published data were lacking, a modified Delphi approach emphasizing strong professional agreement was used.

Results: The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the topics related to pediatric acute respiratory distress syndrome, seven of which related to outcomes after pediatric acute respiratory distress syndrome. All seven recommendations had strong agreement. Children with acute respiratory distress syndrome continue to have a high mortality, specifically, in relation to certain comorbidities and etiologies related to pediatric acute respiratory distress syndrome. Comorbid conditions, such as an immunocompromised state, increase the risk of mortality even further. Likewise, certain etiologies, such as non–pulmonary sepsis, also place children at a higher risk of mortality. Significant long-term effects were reported in adult survivors of acute respiratory distress syndrome: diminished lung function and exercise tolerance, reduced quality of life, and diminished neurocognitive function. Little knowledge of long-term outcomes exists in children who survive pediatric acute respiratory distress syndrome. Characterization of the longer term consequences of pediatric acute respiratory distress syndrome in children is vital to help identify opportunities for improved therapeutic and rehabilitative strategies that will lessen the long-term burden of pediatric acute respiratory distress syndrome and improve the quality of life in children.

Conclusions: The Consensus Conference developed pediatric-specific recommendations for pediatric acute respiratory distress syndrome regarding outcome measures and future research priorities. These recommendations are intended to promote optimization and consistency of care for children with pediatric acute respiratory distress syndrome and identify areas of uncertainty requiring further investigation.

1Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI.

2Division of Pediatric Critical Care Medicine, Department of Pediatrics, Cruces University Hospital, Bizkaia, Spain.

3Division of Pediatric Critical Care, Department of Pediatrics, Universite de Sherbrooke, Sherbrooke, QC, Canada.

4Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington and Center for Child Health, Behavior, and Development, Seattle Children’s Research Institute, Seattle, WA.

The Pediatric Acute Lung Injury Consensus Conference Group is listed in Appendix 1.

Supported, in part, by Department of Pediatrics, The Pennsylvania State University College of Medicine; Health outcome axis—Ste Justine research center, Montreal, Canada; Respiratory research network of Fonds de Recherche du Québec-Santé, Québec, Canada; Mother and children French-speaking network; French-speaking group in pediatric emergency and intensive care (Groupe Francophone de Réanimation et Urgences Pédiatriques), French-speaking intensive care society (Société de Réanimation de Langue Française); European Society for Pediatric and Neonatal Intensive Care Society for the travel support of European expert. Financial support for publication of the supplement in Pediatric Critical Care Medicine is from the Children’s Hospital Foundation of Children’s Hospital of Richmond at Virginia Commonwealth University, the Division of Pediatric Critical Care Medicine, C.S. Mott Children’s Hospital at the University of Michigan, and the Department of Anesthesia and Critical Care, Children’s Hospital of Philadelphia.

Dr. Jouvet received grants from the respiratory research network of Fonds de Recherche du Québec-Santé, Réseau mère enfant de la francophonie, and Research Center of Ste-Justine Hospital related to the submitted work; and received equipment on loan from Philips and Maquet outside the submitted work. Dr. Thomas served on the Advisory Board for Discovery Laboratories and Ikaria outside the submitted work; received a grant from United States Food and Drug Administration Office of Orphan Product Development outside the submitted work. Dr. Willson served on the Advisory Board for Discovery Laboratories outside the submitted work. Drs. Khemani, Smith, Dahmer, and Watson received grants from the National Institutes of Health (NIH) outside the submitted work. Dr. Zimmerman received research grants from the NIH, Seattle Children’s Research Institute, and ImmuneXpress outside the submitted work. Drs. Flori and Sapru received grants from the NIH related to the submitted work. Dr. Cheifetz served as a consultant with Philips and Hill-Rom outside the submitted work; and received grants from Philips, Care Fusion, Covidien, Teleflex, and Ikaria outside the submitted work. Drs. Rimensberger and Kneyber received travel support from the European Societiy of Pediatric and Neonatal Intensive Care related to this work. Dr. Tamburro received a grant from United States Food and Drug Administration Office of Orphan Product Development outside the submitted work. Dr. Emeriaud received a grant from Respiratory Health Network of the Fonds de la Recherche du Québec–Santé outside the submitted work. Dr. Newth served as a consultant for Philips Medical outside the submitted work. Drs. Erickson, Quasney, Curley, Nadkarni, Valentine, Carroll, Essouri, Dalton, Macrae, Lopez-Cruces, Santschi, and Bembea have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: Michael Quasney, MD, PhD, Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan, 1500 East Medical Center Drive, F6790/5243, Ann Arbor, MI 48109. E-mail: mquasney@med.umich.edu

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ACUTE LUNG INJURY AND ACUTE RESPIRATORY DISTRESS SYNDROME IN CHILDREN ARE SIGNIFICANT PROBLEMS: THE SCOPE OF THE PROBLEM

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common diagnoses in critically ill children and account for a significant proportion of all pediatric ICU (PICU) admissions. For every 1,000 children admitted to PICUs, nine to 16 meet the criteria for either ALI or ARDS. Several pediatric studies have used the American European Consensus Conference criteria (1) for ARDS to determine the incidence rates to be from 1.4 cases/100,000/yr to 9.5 cases/100,000/yr (2–7). Although the mortality in children with ARDS is high, upward of 90% in some cohorts, it has been steadily decreasing over the past several years. Significant long-term effects including decreased lung function and exercise tolerance, reduced quality of life, and diminished neurocognitive functioning are reported in adult survivors of ALI/ARDS. However, the significance and consequences of severe lung injury in terms of pulmonary function, quality of life, and neurocognitive functioning in the pediatric population are unknown, and, thus, ALI/ARDS may pose a significant personal, social, and economic burden. It is important that there is an understanding of the basic epidemiology of any disease in children, including its long-term outcomes, not only to direct care of children with the disease but also for designing any new potential therapeutic and rehabilitative strategies to improve the quality of life in children.

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ALI/ARDS IN CHILDREN RESULTS IN SIGNIFICANT MORTALITY

Since the 1990s, ARDS in children has been associated with significant but highly variable mortality rates (Table 1) although there appears to be an overall decrease in the mortality over time (Fig. 1). These variable mortality rates reflect populations of children with differing etiologies of ARDS, some of which are associated with higher mortalities, comorbid conditions that influence the severity of ARDS and, perhaps, as well, changing ventilatory strategies and other general care in the ICU. In general, large observational and epidemiological studies of children with ALI/ARDS suggest mortality rates of 15–50% (2, 5–27). This compares with mortality rates of 35–45% in adults (28). A systematic review of 53 observational studies found that the pooled mortality for ARDS in adults from 1994 to 2006 was 44% (28), being slightly lower in randomized controlled trials (RCTs) (36%) (29). In a more recent study that enrolled 255 adult patients with ARDS, the ICU mortality rate was 43% (30).

TABLE 1

TABLE 1

Figure 1

Figure 1

A few of these studies in children are worth mentioning in more detail because they begin to shed light on potential opportunities for further study. In a prospective multicenter observational study, overall mortality was 35%, and risk factors for mortality included comorbid conditions such as immunosuppression and older age (5), as well as subsequent development of additional organ failure. In a large, prospective population cohort study, the in-hospital mortality rate for ALI in children aged 0.5 to 15 years was 18% (2), but age, gender, and other known risk factors were not associated with mortality. A large retrospective review of ventilated children demonstrated an overall mortality of 23% for ALI, with higher oxygenation index, lower PaO2/FIO2 ratio, and higher lung injury score at baseline being risk factors for mortality (26). In a single-site study that examined children over a longer period of time, mortality rates for pediatric ALI appear to decrease over time from 35% to 21% (24). Using multivariable logistic regression analysis, this study demonstrated that high tidal volumes, PRISM III, and immunodeficiency were associated with increased mortality. Three large national epidemiological studies reported 28-day mortality rates between 25% and 45% with children meeting less severe ALI criteria, fairing a little better than those meeting ARDS criteria (6, 7, 27).

Although some cohorts in other observational studies have somewhat lower mortality rates (11–17%) (31, 32), other cohorts do poorly. For example, children who had hematologic malignancies or who have undergone bone marrow transplants have some of the highest mortality rates (10, 12–14, 33–35), with over 90% mortality in some series. Likewise, children with disseminated intravascular coagulation also have high mortality rates (36). Taken together, these studies demonstrate that mortality for pediatric ARDS (PARDS) remains significant, that children with immunodeficiencies fair much worse, and that there has been some decline in mortality rates during the past 20 years. Whether this reduction in mortality is the result of specific ventilation strategies or improved care in the PICU in general or a combination of both is not clear.

The etiology of ARDS also influences outcomes; in a prospective multicenter observational study, of all etiologies of ALI, non–pulmonary sepsis was associated with the highest mortality; 65% of those with non–pulmonary sepsis died compared with 38% of those with ARDS caused by bacterial pneumonia (5). Other studies have also reported higher mortality rates in children with sepsis-induced ARDS (37, 38), with some studies reporting as high as 70% for non–pulmonary sepsis-induced ARDS (39, 40). Some specific infectious causes of ARDS are associated with very high mortality rates as well. For example, all children with leptospirosis and ARDS died in a small series in India (41), and the recent outbreaks of influenza, especially H1N1, led to children developing ARDS that resulted in poorer outcomes, with mortality rates ranging from 40% to 50% (42–53). In contrast, in a 10-center study, children with RSV had lower mortality rates than all other subgroups (54). This is consistent with the 10–24% mortality in children with no comorbid conditions who develop ARDS after a drowning event, trauma, burns, or RSV infections. Children with neurologic injury who develop ARDS also have somewhat lower mortality rates of 23% (55).

A challenge in interpreting variations in outcomes over time is that treatment approaches for children with ARDS have also varied over time. We refer readers to other sections in the supplement for detailed information and conclusions about the efficacy of specific therapies, and we present here several important examples of how outcomes are undoubtedly confounded by interactions between both patient and treatment factors.

Changing ventilatory strategies over the past 25 years, such as the use of higher positive end-expiratory pressures and permissive hypercapnea, have been associated with somewhat lower mortality rates (11–37%) (17, 24, 56, 57) although determining the impact of the etiology of the ARDS and various comorbid conditions on mortality is difficult in these studies. As high-frequency oscillatory ventilation has been used more frequently, reported mortality rates have ranged from 26% to 67% (7, 37, 58, 59). In a multicenter observational study of children on high-frequency oscillatory ventilation and a mean PaO2/FIO2 less than 100, mortality of 36% was observed among children without a history of lung disease whereas mortality of 51% was observed among children with a history of lung disease (54), further supporting the notion that pre-existing conditions influence the outcome of children with PARDS. Results from studies of surfactant have included a wide range of mortality, from 27% to 56% (60–65). Mortality for children with respiratory failure progressing to extracorporeal membrane oxygenation in one study was about 25% if no systemic infection was found compared with 90% if systemic infection was present (66) although whether the children specifically met PARDS criteria cannot be ascertained in this study. In a retrospective review of ECLS Database in the United Kingdom, mortality from children undergoing extracorporeal membrane oxygenation for ARDS approached 50% (67), which is similar to other studies (57–66%) (7, 38, 68, 69). Studies of prone positioning also had wide ranges of mortality rates, as high as 48% in an observational study (70) to 4.8% (71) in a multicenter RCT of prone positioning. A small number of children with ARDS enrolled in a large, multicenter ventilator weaning trial (72) had a better mortality rate of only 4.3%. The reasons behind these lower mortality rates in RCTs may reflect strict protocolization of various care modalities and/or exclusions of known high-risk groups from those enrolled in the trials.

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FACTORS ASSOCIATED WITH MORTALITY IN CHILDREN WITH PARDS

Many studies have tried to identify factors during the acute period of the disease that will predict mortality in children. Multiorgan dysfunction syndrome and degree of hypoxia appear to be the main early factors predicting mortality. In a small retrospective study of children meeting ARDS criteria, having greater than or equal to four organ failures was correlated to a higher mortality (73), and in a larger study, the presence of multiorgan system failure was associated with an increased risk of mortality (17). Likewise, a mortality rate of 7.7% was observed in a cohort of children without additional organ failure compared with a mortality rate of 66.7% in those children who exhibited more than three organ failures (7). A PaO2/FIO2 ratio of less than 80 predicted mortality with a sensitivity of 62% and a specificity of 64% in a cohort of nonimmunosuppressed children (74). A somewhat better early predictor was the alveolar-arterial oxygen tension difference (PA–aO2) greater than 420 (9). More recently, a higher oxygen index at 24 hours was found to be associated with increased mortality in a cohort of immunocompromised children with severe hypoxemic respiratory failure (54).

Various biomarkers are also being evaluated for their value in predicting mortality in children with ARDS. These include plasminogen activator inhibitor-1 (75), soluble receptor for advanced glycation end products and S100A12 (76), and soluble intracellular adhesion molecule and the high molecular weight glycoprotein expressed on apical borders of alveolar epithelial cells, Krebs von den Lungen [KL]-6 (59). The value in such biomarkers is that if biomarkers can be found that will identify those children at greater risk for more severe disease, and then physicians will be able to develop different therapeutic modalities that may lessen the longer term complications of PARDS. In addition, the use of early, rapidly assayed biomarkers identifying those children with greatest risk for mortality may identify patients best suited for new therapeutic trials. Hopefully, additional biomarkers will be evaluated for their early predictive values for more severe disease in children.

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PARDS IN CHILDREN RESULTS IN SIGNIFICANT LENGTH OF PICU AND HOSPITAL LENGTH OF STAY

Over the years, several studies have reported other short-term outcome measures in children with ARDS. Fifteen to 20 years ago, several studies reported that the duration of mechanical ventilation ranged from 8 ± 9.3 to 36 ± 9 days (9, 10, 16, 56, 57, 73, 77–80), whereas the mean length of stay ranged from 9 ± 10 to 31 ± 5 days (9, 10, 12, 56, 78, 80–82). However, more recently in a large, prospective cohort study, mean mechanical ventilation duration was 5.7 ± 3.9 days, PICU length of stay was 8.6 ± 6.6 days, and hospital length of stay was 22.2 ± 29.3 days (2).

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Long-Term Pulmonary Function in Children Who Survive PARDS

Recommendations

9.1.1 We recommend screening for pulmonary function abnormalities within the first year after discharge, including a minimum of respiratory symptom questionnaires and pulse oximetry for all children with PARDS who undergo invasive mechanical ventilation. Strong agreement

9.1.2 We recommend that, for all children with PARDS who undergo invasive mechanical ventilation and are of sufficient developmental age and capabilities, spirometry should also be performed for the screening for pulmonary function abnormalities within the first year after discharge. Strong agreement

9.1.3 We recommend that, when deficits in pulmonary function are identified, patients should be referred to a pediatric pulmonologist for further assessment, treatment, and long-term pulmonary follow-up. Strong agreement

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Rationale.

Despite resounding evidence that there are significant long-term consequences in adults survivors of ARDS, the long-term consequences of PARDS remain largely unknown. The few pediatric studies published to date examining pulmonary function in PARDS survivors are small series, and pulmonary function test (PFT) assessments were performed at highly variable times after hospital discharge (Table 2) (83–88). Deficits in PFTs have been reported up to 12 years after hospital discharge (87). In another small series, five of five children demonstrated deficits in pulmonary function (84). Three of five confirmed improvement, and this recovery had occurred by 6 to 12 months after illness. Beyond this interval, two of five children demonstrated prolonged deficits in pulmonary function up to 4 years after the lung injury (84). Another study confirmed this observation (89). These studies suggest that a relatively large percentage of children who survive PARDS demonstrate abnormal pulmonary function representing both obstructive and restrictive disease. However, the studies performed thus far are small case series with high variability in the ages of the children and the time of PFT. In addition, these did not, or were unable to, control for potential confounders.

TABLE 2

TABLE 2

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Neurocognitive Development Children Who Survive PARDS

Recommendations

9.2.1 We recommend that physical, neurocognitive, emotional, family and social function be evaluated within 3 months of hospital discharge for children who survive moderate to severe PARDS. Strong agreement

9.2.2 We recommend that, for younger patients (infants and toddlers), additional evaluation of physical, neurocognitive, emotional, family, and social function should be performed prior to entering school. Strong agreement

9.2.3 We recommend that, when abnormalities are identified, children should be treated or referred for more in-depth assessment and treatment by appropriate subspecialists and educators (e.g., when learning deficits are identified). Strong agreement

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Rationale.

Few other assessments of the long-term consequences of PARDS have been conducted. In a multicenter trial of prone positioning in children with ALI, the Pediatric Overall Performance Category (90) scale worsened from admission to discharge in 16% of survivors, whereas the Pediatric Cerebral Performance Category scale worsened in 11% of survivors (71), but these outcomes were only up to the time of discharge and did not reflect potential longer term consequences.

Recent studies have begun to focus on long-term consequences in children requiring intensive care in general, particularly on acquisition of new physical deficits and effects on quality of life, mental health, and family functioning (91–94). For example, over half of the children who had a PICU stay demonstrated new, additional morbidities 3 months after hospital discharge including neurological disabilities (92). Parents also reported more lung problems and worse liveliness in a group of 1–6-year olds 3–6 months after discharge from the PICU, and older children reported worse motor functioning (93). Quality of life measures were also reduced at 6 and 24 months in a significant percentage of PICU survivors (94). Post-traumatic stress disorder (PTSD) has been found in up to 30% of PICU survivors and is associated with severity of illness, invasive procedures, and length of stay (95–97). Worse adverse outcomes in the areas of physical sequelae, neurological impairment, problem behavior, and total intelligence quotient were associated with longer length of PICU stay and higher PRISM scores in a cohort of children who survived meningococcemia (98). Parents of patients who survived PICU care report significant and persistent post-PICU distress and symptoms of PTSD (99, 100). In addition, poor parental mental health has ramifications for children. It can have negative effects on childhood development (101, 102) setting up a cycle in which child morbidity contributes to caregiver depression which then impedes developmental recovery. However, it is difficult to ascertain in these studies whether any of the children met PARDS criteria. Thus, long-term outcomes in children who survive PARDS have not yet been adequately examined.

Neurocognitive impairment has also been found in several other populations of critically ill children. Using general measures without detailed testing, some studies report cognitive deterioration or difficulties in up to 25% of children who are discharged from the PICU (103, 104). Likewise, cognitive difficulties were self-reported in up to 42% of 50 children who recovered from septic shock (105), and deficits in spatial memory, verbal memory, and attention have been documented (106). Patients surviving sepsis demonstrate particular difficulty with pattern recognition. Cognitive impairment has been well documented after premature birth (107–112) and in asymptomatic children who underwent birth resuscitation at term (113) or had low Apgar scores (114). Children with congenital heart disease demonstrate problems with visual-motor integration, inattention, hyperactivity, planning, executive function, behavior, and handwriting (115–123). In addition, children undergoing corrective heart surgery as infants demonstrate to have IQ results inversely proportional to ICU length of stay at 8 years, with particular deficits in verbal IQ even when adjusting for perioperative and sociodemographic factors (124). Neurological morbidity may improve over time (125), but some get worse with age (125, 126).

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ALI/ARDS RESULTS IN LONG-TERM ADVERSE SEQUELAE IN ADULTS

In contrast to the paucity of studies reporting long-term outcomes of children after PARDS, multiple studies of adult survivors of ARDS reported adverse long-term effects, including decreased lung function, reduced quality of life, and diminished neurocognitive functioning that impacts daily living. For example, many adults demonstrate a significantly diminished forced expiratory volume in 1 second, forced vital capacity, total lung capacity, and diffusion capacity after ARDS, and many adults remain impaired up to 1 year or more after hospital discharge (127–132). Although these measures may improve over the first year of discharge from the hospital, they remain below predicted values (131, 133). Forced expiratory volume in 1 second and forced vital capacity are significantly reduced (134, 135), and exercise limitations are well documented (136, 137), including tests of the distance walked over 6 minutes (136). In contrast, other studies suggest that the diminished long-term pulmonary function in adult survivors of ALI/ARDS is not universal, and that many adults have relatively preserved pulmonary function (128, 136–138).

A significant overall reduction in quality of life has also been reported in adult survivors of ALI/ARDS (137, 139, 140), which is worse with worse postdischarge pulmonary function (141). A persistent decrease in overall quality of life appears to be associated not only with residual physical deficits and limitations (142, 143) but also with impairment of cognitive function and mental health (143, 144). Depressive symptoms have been noted at a higher rate in adult survivors of ALI compared with the general adult population (145, 146). PTSD has been demonstrated in 21%–44% of adult survivors of ARDS (147, 148) as have the deficits in mental function that are risk factors for the development of PTSD (149–152), and rates of PTSD were higher than those both in patients undergoing surgery and in United Nations soldiers serving in Cambodia (149). A recent meta-analysis of 13 studies evaluating health-related quality of life in 557 adult survivors of ALI/ARDS demonstrated that all eight health-related quality of life domains of the Short Form-36 assessment were below the age- and sex-matched normative values regardless of the etiology of the lung injury (153). In addition, quality of life after ARDS was significantly worse than age-matched controls of adults living with cystic fibrosis and other chronic illness (142). Improvement in quality of life appears to be both time and domain specific, providing a better understanding of the needs of the patient at various times through their acute illness and recovery (154, 155).

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ALI/ARDS RESULTS IN DIMINISHED NEUROCOGNITIVE FUNCTIONING IN ADULTS

Long-term neurocognitive deficits have also been demonstrated in adult survivors of ALI/ARDS (155, 156). Up to 75% of adults evaluated with validated formal tests of neurocognitive function demonstrate neurocognitive deficits up to 6 years after discharge from the ICU (154). These included the domains of mental processing speed, memory, attention, executive functioning, intellectual functioning, and visual spatial ability, and the severity of neurocognitive deficits depended, in part, on the specific domain. With regards to memory dysfunction, 8% of adults had scores that were greater than 2 SDs below age-adjusted norms reflecting moderately severe memory impairment whereas 20% had scores greater than 1 SD below age-adjusted norms reflecting mild memory impairment. This memory impairment appears to be a common finding in adult survivors of ALI/ARDS (143, 144, 154, 156–160), and hypoxemia alone places patients at particular risk of memory loss (161–166). In addition to hypoxemia, multiple other mechanisms have been related to neurocognitive dysfunction after critical illness in adults, including inflammation, sedative and analgesic medications, hypotension, hypoglycemia or hyperglycemia, and delirium (167–174). Although adults are notably different from children, the insults thought likely to be related to cognitive impairment are comparably frequent in critically ill children and are therefore relevant. Thus, the assessment of neurocognitive function in children who survive PARDS may be especially important for children.

Of particular importance is that although neurocognitive deficits have been reported in adult survivors of ALI/ARDS, some improvements were noted within the first year of discharge from the hospital, suggesting that while some deficits persist, improvement can be seen (154). This raises the intriguing possibility that whether similar deficits in neurocognitive functioning are observed in children who survive PARDS, then perhaps aggressive targeted therapies might lessen these long-term neurocognitive deficits in this vulnerable population.

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ALI/ARDS RESULTS IN DIMINISHED NEUROMUSCULAR FUNCTIONING IN ADULTS

Long-term neuromuscular function in adult survivors of ARDS also is depressed for up to 24 months after discharge (175). Nearly half of the adults in this small series demonstrated mononeuropathies and sensory complaints. Whether these findings contribute to the complaints of weakness and reduced exercise intolerance in adult ARDS survivors is unknown, as are the implications for pediatric survivors.

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Outcome Measures

Recommendation

9.3.1 Given decreasing mortality among children with PARDS, we recommend research into the following potential alternative end points for clinical trials: longer term mortality (e.g., 90 d), rates of new or progressive organ dysfunction, organ failure– or treatment-free days, ventilator-free days (with and without noninvasive ventilation), duration of oxygen therapy (or a higher concentration of oxygen for subjects on chronic supplemental oxygen), risk-adjusted hospital and PICU lengths of stay, hospital, and PICU readmissions (e.g., within 30 days of discharge), quality of life, neurocognitive function, emotional health. Strong agreement

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Rationale.

If long-term measures were routinely included in even a subset of patients in observational and interventional studies of PARDS, we would develop a much more thorough understanding of the relationships between traditional outcomes assessed during hospitalization with longer term, patient-centered outcomes. Commonly studied outcomes measures include mortality, organ function, resource use, and patient-centered outcomes (which include long-term health-related quality of life, physical function, and psychological, cognitive, and family outcomes). All of these measures can be evaluated at different points in time (e.g., during hospitalization, i.e., short term, or post discharge). Each outcome has strengths and weaknesses (Table 3). Understanding the relationships between short- and long-term outcomes would provide a framework that could be used to examine the influence of multiple factors on long-term recovery, growth, development, and quality of life of children surviving PARDS. Ultimately, such a framework would facilitate clinical trials and inform clinical care to optimize the long-term health of children surviving PARDS.

TABLE 3

TABLE 3

Given the widespread evidence of long-term impairment across multiple domains in adults who survive ALI/ARDS and emerging results in other populations of critically ill children, there is an urgent need to assess and understand the multidimensional, postdischarge outcomes in children surviving PARDS. Children who have undergone mechanical ventilation for PARDS are at high risk of impairment in multiple domains and merit thorough evaluation and, when abnormalities are found, early intervention or referral for specialized care. In general, we recommend that comprehensive clinical evaluation be conducted soon after hospital discharge and no later than 3 months post discharge. In infants and toddlers, some abnormalities, particularly those related to cognitive function, may not be reliably identified at such a young age. Therefore, we recommend a second evaluation later in childhood, prior to starting school. Providers should also keep in mind that certain aspects of PARDS and its treatment increase risk of specific problems. For example, hypoxemia may place children at higher risk of neurocognitive impairment. The use of steroids and neuromuscular blockade, as well as many other aspects of critical illness, places children at risk of weakness and impaired physical function. Central venous catheters and coagulopathies place children at risk of deep venous thrombosis.

In addition, research must be undertaken to understand risk factors, preventative strategies, and treatment for long-term post-PARDS abnormalities. Finally, given decreasing mortality among children with PARDS, we recommend research into potential alternative end points for clinical trials. If long-term measures were routinely included in even a subset of patients in observational and interventional studies of PARDS, we would develop a much more thorough understanding of the relationships between traditional outcomes assessed during hospitalization with longer term, patient-centered outcomes. Commonly studied outcomes measures include mortality, organ function, resource use, and patient-centered outcomes (which include long-term health-related quality of life, physical function, and psychological, cognitive, and family outcomes). All of these measures can be evaluated at different points in time (e.g., during hospitalization, i.e., short term, or post discharge). Each outcome has strengths and weaknesses (Table 3). Understanding the relationships between short- and long-term outcomes would provide a framework that could be used to examine the influence of multiple factors on long-term recovery, growth, development, and quality of life of children surviving PARDS. Ultimately, such a framework would facilitate clinical trials and inform clinical care to optimize the long-term health of children surviving PARDS.

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SUMMARY

Children with PARDS continue to have a high mortality. Comorbid conditions, such as an immunocompromised state, increase the risk of mortality even further. Likewise, certain diseases such as non–pulmonary sepsis, also place children at a higher risk of mortality. Significant long-term effects on lung function and exercise tolerance, reduced quality of life, and diminished neurocognitive functioning are reported in adult survivors of ALI/ARDS. Little knowledge of long-term outcomes exists in children with PARDS. We need to characterize the longer term consequences of PARDS to help identify opportunities for improved therapeutic and rehabilitative strategies that will lessen the long-term burden of PARDS and improve the quality of life in children.

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                                                  APPENDIX 1. Pediatric Acute Lung Injury Consensus Conference Group

                                                  Organizing Committee: Philippe Jouvet, University of Montreal, Canada; Neal J. Thomas, Pennsylvania State University; Douglas F. Willson, Medical College of Virginia.

                                                  Section 1, Definition, incidence, and epidemiology: Simon Erickson, Princess Margaret Hospital for Children, Australia; Robinder Khemani, University of Southern California; Lincoln Smith, University of Washington; Jerry Zimmerman, University of Washington.

                                                  Section 2, Pathophysiology, comorbidities and severity: Mary Dahmer, University of Michigan; Heidi Flori, Children’s Hospital & Research Center Oakland; Michael Quasney, University of Michigan; Anil Sapru, University of California San Francisco.

                                                  Section 3, Ventilatory support: Ira M. Cheifetz, Duke University; Peter C. Rimensberger, University Hospital of Geneva, Switzerland.

                                                  Section 4, Pulmonary specific ancillary treatment: Martin Kneyber, University Medical Center Groningen, Netherlands; Robert F. Tamburro, Pennsylvania State University.

                                                  Section 5, Non-pulmonary treatment: Martha A. Q. Curley, University of Pennsylvania; Vinay Nadkarni, University of Pennsylvania; Stacey Valentine, Harvard University.

                                                  Section 6, Monitoring: Guillaume Emeriaud, University of Montreal, Canada; Christopher Newth, University of Southern California.

                                                  Section 7, Noninvasive support and ventilation: Christopher L. Carroll, University of Connecticut; Sandrine Essouri, Université Pierre et Marie Curie, France.

                                                  Section 8, Extracorporeal support: Heidi Dalton, University of Arizona; Duncan Macrae, Royal Brompton Hospital, England.

                                                  Section 9, Morbidity and long-term outcomes: Yolanda Lopez, Cruces University Hospital, Spain; Michael Quasney, University of Michigan; Miriam Santschi, Université de Sherbrooke, Canada; R. Scott Watson, University of Pittsburgh.

                                                  Literature Search Methodology: Melania Bembea, Johns Hopkins University.

                                                  Keywords:

                                                  acute lung injury; pediatrics; pediatric acute respiratory distress syndrome; outcomes

                                                  ©2015The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies