Acute respiratory failure (ARF) is a common cause for admission to PICUs and the requirement of invasive mechanical ventilation (MV) (1,2). Single center cohort studies have shown a decline in function status (3) at discharge, in children with ARF (4) and with Pediatric Acute Respiratory Distress Syndrome (PARDS), a severe form of ARF (5). In a different cohort of PARDS survivors, parents had significantly lower perceived physical functioning and general health perceptions of the PARDS survivors compared with healthy children or children with chronic asthma (6). The importance of understanding the longer-term consequences of ARF on children is needed now more than ever as PICU mortality is decreasing and more children live with the consequences of critical illness (7).
Post-intensive care syndrome (PICS) is the combination of physical and mental health disabilities caused by critical illness (8). Preliminary work in pediatric PICS (PICS-p) has revealed nearly three-quarters of patients had functional disabilities 6 months after critical illness (9). Unfortunately, for both PICS and PICS-p, distinguishing the impacts of the distinct critical illness episode from patients’ underlying chronic illness has proved challenging. In pediatrics, conflicting data exists related to the impact of preexisting conditions and neurocognitive disabilities on functional outcomes after critical care (10). Reactive airway disease, including asthma, is the prototypical chronic pulmonary condition in children with both economic and developmental consequences (11–13). Although asthma is its own distinct entity, it provides insight into the potential for economical, developmental, and overall health consequences of a chronic pulmonary morbidity. Detailed study of the impact of an episode of ARF on previously healthy children’s long-term respiratory health and development of chronic illness has not been conducted.
Based on the limited data related to the impact of an index PICU admission for ARF on long-term outcomes, this study aimed to identify predictors of persistent respiratory morbidity at 6 and 12 months after an ARF episode in previously healthy children requiring invasive MV. By restricting this study to previously healthy children, we attempted to mitigate the contribution of preexisting comorbidities on the development of persistent respiratory morbidity. By identifying predictors of persistent respiratory morbidity, potential interventions could be aimed at attenuating this outcome. Therefore, we hypothesized that severity of ARF and MV course, as well as pulmonary dysfunction at discharge (PDAD), could predict persistent respiratory morbidity at 6- and 12-month follow-up.
MATERIALS AND METHODS
Study Design and Patient Selection
A multicenter cohort of previously healthy children 0–24 months requiring invasive MV for an index case of ARF from primary respiratory illness were prospectively enrolled at 10 participating PICUs over 5 consecutive years from 2005 to 2010 with follow-up data collection completing in 2012. Participating PICUs ranged from small, less than or equal to 10 beds, to large, greater than 30 beds and both centers with and without a critical care medicine fellowship were represented. Primary respiratory cause of ARF determined at the discretion of the site investigator and at least one of the following criteria: 1) chest radiograph with focal or diffuse infiltrative pulmonary process, 2) radiographic evidence of air trapping, or 3) clinical examination findings of lower respiratory tract illness. Children meeting inclusion criteria were enrolled consecutively within 12 hours of initiation of invasive MV or transfer to participating center if intubation occurred prior to PICU admission. Children with primary upper airway etiology of ARF, a primary aspiration as cause of ARF or a preexisting condition were excluded (Exclusion Criteria supplement, Supplemental Digital Content 1, http://links.lww.com/CCM/F471). Institutional Review Board approval obtained at each site and consent obtained from parent or legal guardian.
Demographic information and past medical and social history were obtained from patient’s caregivers. Data related to hospital course, duration of MV, supplemental oxygen duration, and PICU duration was recorded. Severity of illness at PICU admission was assessed using the Pediatric Risk of Mortality (PRISM) III score at 12 hours. Daily, ventilator data including mode of ventilation, peak inspiratory pressure (PIP), positive end-expiratory pressure (PEEP), mean airway pressure, and tidal volume was recorded at time of worst blood gas (defined by lowest pH) or, if no blood gas was performed, at 0800. Daily blood gas data was also recorded when collected per clinical care, as well as end tidal carbon dioxide data and oxygen saturation via pulse oximetry. Oxygenation was recorded as oxygenation index (OI) or oxygen saturation index (OSI). For analysis all OSI were converted to OI using accepted formula (14). Subjects’ medications, use of inhaled nitric oxide or extracorporeal membrane oxygenation support was recorded. The 3-day average ventilator parameters were calculated from up to the first 3 days of MV data. If a patient only had 1 day of MV, their MV data was included only in the “highest ventilator parameters” analysis.
PDAD defined a priori, as requiring at least one of the following at 28 days or hospital discharge: MV, supplemental oxygen, bronchodilators or steroids. This information was recorded as well as other discharge medications. Six and 12-month follow-up was conducted via telephone interview from centralized location with designated parent about subjects’ health status. Questions included the 11 item PedsQL (Mapi Research Trust; ePROVIDE, Lyon, France; http://www.pedsql.org) asthma module health-related quality of life symptom scale (15–18) recorded from never = 0 to almost always = 4. Parents were also asked the subjects prescribed medications and frequency of use as well as if child had been diagnosed with asthma, had visits to physician office or emergency department for “breathing problems” or readmitted to hospital, PICU for “breathing problems” and finally if the child had required MV post index admission.
The primary outcome was persistent respiratory morbidity at 6 and 12 months after discharge. Persistent respiratory morbidity defined a priori as children meeting one of the following: 1) diagnosis of asthma, 2) bronchodilator use, 3) inhaled corticosteroid use, 4) representation to care for a respiratory related complaint, or 5) asthma module PedsQL score greater than or equal to 5.
Analyses were conducted in Stata 14 and 15.1 (StataCorp, College Station, TX). Continuous variables were compared using Wilcoxon rank-sum or Kruskal-Wallis tests and categorical variables compared using Pearson chi-square or Fisher exact test analysis. PDAD was considered both an outcome and a predictor. Variables with a univariate association with PDAD were entered into a multivariate logistic regression model, with iterative removal of variables and assessment of Akaike information criterion (AIC), with continued removal until AIC was minimized. Variables were assessed for colinearity both during model building, and after using variance inflation factors. This final model described a parsimonious, limited set of independent predictors for PDAD. Subsequently, PDAD, in addition to the previous variables, was tested as a candidate predictor variable for separate multivariable logistic models testing for independent predictors of persistent respiratory morbidity at 6 and 12 months.
The study enrolled a total of 259 children. After excluding two patients with incomplete data and two patients whom were later found to have an underlying chronic genetic disease during index course, the presence or absence of pulmonary dysfunction was determined for 255 patients, with PDAD present in 87 of 255 patients (34.1%; 95% CI, 28.3–40.3%) (Fig. 1). Patients with PDAD were older, but otherwise the PDAD and non-PDAD groups were demographically similar (Table 1). There were no differences in admission diagnosis or PRISM III scores between the two groups. Patients with PDAD had worse oxygenation, by worst OI (OI 9.7 vs 6.6; p = 0.014), as well as higher 3-day average PIP and PEEP, compared with patients that did not have PDAD (Table 1; and Supplemental Table 1, Supplemental Digital Content 2, http://links.lww.com/CCM/F472), but no difference in tidal volume was noted between the two groups. Patients with PDAD were significantly more likely to have a positive respiratory bacterial culture (p = 0.009). There were no differences between length of PICU stay, ventilator days, or duration of supplemental oxygen for patients that did and did not have PDAD. There was a total of six mortalities (2%) from the cohort, four due to sepsis, one from complications of pneumonia, and one due to pulmonary hemorrhage.
In the 87 patients meeting criteria for PDAD, requiring bronchodilator therapy was most common (67 patients, 77%) with inhaled or oral corticosteroid use the second most frequent therapy (36 patients, 41%). (Table 1)
Multivariable analyses suggested the strongest predictors of PDAD were admission for pneumonia (odds ratio [OR], 4.72; 95% CI, 1.64–13.56) as well as having a positive respiratory bacterial culture (OR, 4.38; 95% CI, 1.66–11.56) (Table 2). Worst OI was the only ventilator characteristic or severity of illness measure that was found to be a predictor of PDAD (OR, 1.07; 95% CI, 1.02–1.12).
Of the 249 hospital survivors, response rate for follow-up questionnaires was 63.5% (158 patients) and 52.2% (130 patients) at 6 and 12 months, respectively. Persistent respiratory morbidity was present in 66 patients (42%; 95% CI, 34–50%) at 6 months and 57 patients (44%; 95% CI, 35.2–52.8%) at 12 months (Supplemental Table 2, Supplemental Digital Content 3, http://links.lww.com/CCM/F473). Bronchodilators were the most commonly prescribed respiratory medication at both time points. At 6 months, 26% of respondents (41/158) had represented to care, with eight children requiring readmission for a respiratory diagnosis. At 12 months, a similar percentage of respondents had represented to care (25%), with seven being readmitted (Supplemental Table 2, Supplemental Digital Content 3, http://links.lww.com/CCM/F473; and Supplemental Table 3, Supplemental Digital Content 4, http://links.lww.com/CCM/F474). Children who did not contribute follow-up data were similar to those who were evaluated for persistent respiratory morbidity with no differences in demographics, severity of illness, or ventilator characteristics based on follow-up status (Supplemental Table 4, Supplemental Digital Content 5, http://links.lww.com/CCM/F475). A higher proportion of patients with positive bacterial cultures (84.1% vs 62.1%) and who required reintubation (18.8% vs 7.1%), did not participate in follow-up.
In comparing patients with persistent respiratory morbidity at 6 months to those that did not have persistent respiratory morbidity, there were no differences in severity of illness, ventilator characteristics, ventilator days, or PICU length of stay (Table 3; and Supplemental Table 5, Supplemental Digital Content 6, http://links.lww.com/CCM/F476). Patients with persistent respiratory morbidity had more severe oxygenation failure. Additionally, more patients with persistent respiratory morbidity were found to have a positive bacterial respiratory culture compared with those patients without persistent respiratory morbidity. Having PDAD at discharge was strongly associated with persistent respiratory morbidity at 6 months (47% vs 21%; p = 0.001). At 12 months, in addition to no differences in severity of illness, ventilator characteristics and ventilator days, no difference was seen in degree of oxygenation failure (Table 3). The presences of persistent respiratory morbidity at 6 months was strongly associated with persistent respiratory morbidity at 12 months (Table 3).
Using a multivariable model to determine predictors of persistent respiratory morbidity at both 6 and 12 months, positive bacterial respiratory culture was found to predict persistent respiratory morbidity at both time points (Table 4). Degree of oxygenation failure independently predicted 6-month persistent respiratory morbidity, while presence of persistent respiratory morbidity at 6 months strongly predicted persistent respiratory morbidity at 12 months (OR, 18.58; 95% CI, 6.68–52.67) (Table 4).
In this study of previously healthy children, of those responding at 6 and 12 months, persistent respiratory morbidity after an index episode of ARF requiring MV is common, occurring in up to 44% of children. To our knowledge, this is the first estimate of prevalence of persistent respiratory morbidity attributable entirely to an episode of ARF in children, as the cohort was selected to lack preexisting comorbidities. The presence of persistent respiratory morbidity throughout 1-year follow-up was predicted by the presence of a positive bacterial respiratory culture during the index illness. Although associated with persistent respiratory morbidity at 6 months in univariate analysis, PDAD, as defined a priori, was not an independent predictor of persistent respiratory morbidity at either follow-up time point. In patients that developed persistent respiratory morbidity by 6 months, there was a strong association with persistent respiratory morbidity at 12 months. The strongest predictor of persistent respiratory morbidity at 12 months was the presence of persistent respiratory morbidity at the previous follow-up time point, suggesting that the pulmonary sequela these children possess does continue up to a year after discharge. Importantly, severity of illness measures and patient ventilator characteristics were not predictive of persistent respiratory morbidity throughout the entire 1-year period.
The association of positive bacterial respiratory culture, during ARF course and long-lasting detrimental effect on pulmonary health, to our knowledge, has not been reported before. Cultures from patients were considered positive only if there was growth of a single bacteria; patients with mixed flora were considered negative. This is an approximation of the gold standard for bacterial pneumonia that has been used previously (19). The presence of a culture positive bacterial pneumonia in multivariable modeling predicted pulmonary morbidity at both discharge and throughout the 1-year follow-up period. The pathophysiology of bacterial respiratory infection is likely to be distinctively different from viral-induced illness, as no viral infection was associated with either PDAD or persistent respiratory morbidity. There are several possible explanations to this finding. It is known that both the alveolarization process and the lungs microvascular supply continue to mature after birth and through teenage years (20). Animal models point to complex interactions between lipofibroblasts, myofibroblasts, vascular endothelial cells, and alveolar endothelial cells and their associated growth factors in this ongoing alveolarization process, as well as, recovery from injury (21). Bacteria may be more locally destructive to alveoli, alter the local inflammatory cascade in the short term and long term, or impart a change on the alveolarization and healing process of lung parenchyma by altering these interactions and the production of local growth factors. To better understand this association, future investigations into the differences in alveolarization and alveolar cytokine profiles after bacterial and viral infections in combination with MV may help to shed light on the pathophysiology of this association.
Alternatively, it is possible that a positive bacterial culture is not causal for PDAD or persistent respiratory morbidity at either 6- or 12-month follow-up. Rather, a positive culture may be colinear with an unmeasured confounder. The timing of obtaining bacterial respiratory culture was based on clinical care, and not standardized. A number of patient cultures were sent at admission and be related the underlying cause of ARF. Alternatively, cultures may have been obtained due to a clinical deterioration during the course of a patient’s ARF and these positive respiratory cultures may represent patients that had a worse or more complicated course of ARF. However, severity of illness measures were not associated with PDAD or persistent respiratory morbidity, and the association with PDAD and persistent respiratory morbidity persisted after adjustment for OI. Additionally, presence of a positive respiratory culture as a sole finding may not represent bacterial pneumonia. The presence of a focal infiltrate on imaging, fever, or patients’ immunologic response to the presence of the bacteria were not captured. Therefore, the association that was found is not clearly understood. Future work examining children with ARF with the clinical diagnosis of pneumonia and bacterial respiratory cultures along with prospectively collected clinical and antibiotic treatment data are required.
The ability to identify those at risk for persistent respiratory morbidity is a crucial first step in potentially augmenting the long-term pulmonary morbidity for these patients. Additionally, financial and quality-of-life considerations exist with the individual components that define persistent respiratory morbidity (11,22). The presence of persistent respiratory morbidity may impart a significant burden on the patient and their family. In this cohort, patients with PDAD had at least one of our predefined predictors of persistent respiratory morbidity. Although PDAD was associated with having persistent respiratory morbidity at 6 months in univariate analysis, it was not independently predictive of persistent respiratory morbidity at 6 months in multivariable modeling. By 12 months, the association between PDAD and persistent respiratory morbidity was no longer present. In examining our a priori definition of PDAD, this definition may have captured both children truly at risk for long lasting dysfunction of their respiratory system, but also included children in a convalescent phase of their acute illness who are still healing. In essence, PDAD encompassed all patients that were still experiencing pulmonary dysfunction at this discreet time point, but a separate definition of patients at risk for persistent respiratory morbidity and the elements that make up this entity is needed. A potential second explanation of why PDAD did not independently predict persistent respiratory morbidity is the over or inappropriate prescription of bronchodilators after bronchiolitis. Bronchodilator use was the most common reason for a child to be designated as having PDAD and prescriptions may have been carried over even if the bronchodilator did not work during acute illness or the child was not having any current respiratory symptoms to warrant these medications at time of discharge. In contrast, it appears that the functional, structural, and developmental changes to lung parenchyma that are imparted by the index episode of ARF are likely more long lasting in patients that have persistent respiratory morbidity at 6 months, as this finding was strongly associated with persistent respiratory morbidity at 12 months.
Most importantly, this was a cohort without known comorbidities or preexisting conditions, which makes it unique in the present literature. Previous studies showing functional decline and lasting impacts of critical illness have included children with preexisting comorbidities (10). These chronic conditions have influenced the ability to detect the impact of the critical illness’ contribution on post discharge and longer-term health. This cohort lacked preexisting comorbidities, so development of persistent respiratory morbidity was more directly related to the impact of ARF. The question of genetic predisposition to lung disease still exists. Children may be born with a predisposition to lung disease and this index episode of ARF may be the first in the at-risk subject. On the other hand, the episode of ARF in-and-of-itself or from the MV needed to support the index case may induce or cause lasting changes in the lungs that lead to chronic dysfunction.
Previous studies in children with bronchiolitis have shown short-term, 30 day, readmission rates of nearly 4% (23) and ongoing wheezing for as long as 2 years (24); although the outcomes of interest in this cohort were not independently associated with bronchiolitis, we may have identified covariates that were surrogates for severity of bronchiolitis course.
Our study has several strengths. It was a multicenter, prospective cohort of previously healthy children followed for up to 12 months. Data collection was detailed and consistent across multiple institutions. There are, however, several limitations of this study. Bacterial respiratory cultures were obtained in a large proportion of this cohort, but it was not and remains not universal practice to obtain bacterial respiratory cultures in ARF. The timing of obtaining respiratory culture was at the discretion of the clinical team. The method of obtaining respiratory cultures was not recorded. As the study reflected usual care, respiratory cultures, antibiotic use, and MV were not protocolized, limiting the potential predictive value of respiratory cultures for the development of persistent respiratory morbidity in practice.
Other limitations of this study include the lack of inflammatory marker data, limiting the ability to determine the immunologic response to the respiratory cultures. Response rates in this study were 64% and 52% at 6 and 12 months, respectively, which is within a large range of previously reported response rates for telephone ICU follow-up studies (25–27). Children who did not have follow-up data available were similar to responders in terms of demographics, severity of illness, ventilatory support, and hospitalization characteristics, but nonresponders may have been children that were generally healthier at follow-up time points, leading to nonresponse bias in the outcome metrics of interest. At least 130 patients were available for evaluation of their post discharge pulmonary health which has previously not been done on this scale for a cohort of exclusively previously healthy children. Recall of beta-agonist and inhaled corticosteroid use was a component of determining the presence of persistent respiratory morbidity in subjects making recall bias a potential limitation in determining the presence of persistent respiratory morbidity in subjects (28,29). Previously healthy was defined by the lack of any of the specific conditions listed in the exclusion criteria and through parental interview. Recall bias of a health condition or outpatient diagnosis possible. There is a potential for misclassification of persistent respiratory morbidity due to either over-prescription of bronchodilators or over diagnosis of asthma. Patient’s had to have used bronchodilator in the last month to meet persistent respiratory morbidity definition, making it not just prescription, but also use that classified the patient as having the outcome of interest, strengthening the validity of persistent respiratory morbidity as true respiratory dysfunction during follow-up period. Additionally, bronchodilator use and asthma diagnosis alone as the criteria to define patients as having persistent respiratory morbidity was rare in this cohort. We considered persistent respiratory morbidity only as a binary outcome, but a continuous measurement of respiratory morbidity may provide greater insight into the subtleties of respiratory morbidity after ARF. Last, this cohort contained children less than or equal to 24 months old. The inciting causes of ARF in this age group differ from older children who develop ARF and the potential mechanisms of persistent respiratory morbidity discussed here may not apply to older children. Caution should be taken before generalizing these results to other age groups that develop ARF requiring MV in the PICU.
In an effort to better delineate the acute illness and its convalescent stage from early pulmonary dysfunction and persistent respiratory morbidity, follow-up studies focused in the initial weeks to months after hospital discharge are needed. This would allow for refinement of in the predictors of persistent respiratory morbidity. In addition, the novel association of bacterial respiratory infections and persistent respiratory morbidity deserves further exploration, both mechanistically in models of ARF and validation in future cohorts of patients with ARF.
In previously healthy children less than or equal to 24 months old following an episode of ARF requiring MV, development of persistent respiratory morbidity is common, occurring in potentially up to 44% of patients. The presence of PDAD predicted persistent respiratory morbidity at 6 months, and persistent respiratory morbidity at 6 months in turn strongly predicted persistent respiratory morbidity at 12 months. This is the first study to our knowledge to show an association between the presence of a bacterial respiratory culture positive pneumonia and persistent respiratory morbidity to at least 12 months after index episode of ARF.
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