Fewer arterial blood gases are obtained in PICUs compared with adult units, and the use of NRS has resulted in increasing number of patients with lung injury that are cared for outside of ICUs (10, 23, 96, 97). Therefore, it is imperative to create a definition for PARDS that does not rely on the subjective decision to obtain an arterial blood gas (9). Given the strong linear relationship between OSI ([FIO2 × Mean airway pressure × 100]/SpO2) and OI when the SpO2 is less than or equal to 97%, we have established OSI cut points to correspond with the OI cut points proposed above (88) (Fig. 1). The SF ratio also has a strong relationship with PF ratio, and as a screening tool, the use of an SF ratio has moderate positive likelihood ratios to identify patients with PF ratios less than 300 or less than 200, but very high posttest probability for patients who are invasively ventilated (88, 89, 98). As such, if a mechanically ventilated patient meets SF criteria, he or she will very likely meet PF criteria, allowing for its use for consideration for inclusion in a clinical trial. It may not, however, fully capture all patients that may meet PF criteria of less than 300, and therefore may not be adequate for all epidemiologic studies. It is unclear how well SF ratio performs in relation to PF ratio for children receiving noninvasive ventilation, given difficulties in calculating FIO2, and the potential effect modification based on the degree of ventilatory support. For this reason, we do not recommend applying SF ratios for nonintubated patients (or those not on full face mask noninvasive ventilation) to grade severity, but rather creating guidelines based on combinations of SpO2 and minimal delivered oxygen to establish who is at risk for PARDS (see below).
Next, we sought to explore whether a measure of dead space would be relevant for further risk stratification. Volumetric capnography remains the most accepted way to measure dead space, but there are no studies examining the association between volumetric capnography and mortality in PARDS. In a study by Ghuman et al (7), alveolar dead space fraction (AVDSF) combined with OSI was shown to have a nonstatistically significant increase in risk stratification of mortality when compared with OSI alone for children with ARDS. Secondary analysis of that dataset is shown in the electronic supplement (Supplemental Table 3, Supplemental Digital Content 3, http://links.lww.com/PCC/A163; Supplemental Table 4, Supplemental Digital Content 4, http://links.lww.com/PCC/A164). Patients with AVDSF greater than 0.23 had an overall mortality of 46%, whereas mortality was 13% in patients with AVDSF less than or equal to 0.23. AVDSF appears to add to the predictive ability regardless of the degree of hypoxemia, whether stratified by PF ratio or OI. Because these are limited data from a small sample and a single center, there is insufficient evidence to recommend a measure of dead space in the definition of PARDS. However, it appears that increased dead space (as measured by AVDSF) may be useful for additional risk stratification in clinical trials for children with PARDS, and further study is warranted. Furthermore, the combination of severe hypoxemia and elevated dead space may represent a particularly high-risk group, with mortality of over 50%. Given difficulties in accurate measurement of tidal volume in children (see below), we elected not to consider corrected minute ventilation, in defining PARDS.
Several unique issues for measurement of tidal volume in children limit the applicability of measurements of respiratory system compliance. Tidal volume cannot be calculated accurately if: 1) there is a significant air leak around the endotracheal tube, a problem that may be minimized in patients with severe ARDS as most will have cuffed endotracheal tubes; 2) the measurement of ideal body weight is more complicated in children, particularly those with severe scoliosis in which an accurate measurement of height to calculate predicted body weight is difficult; and 3) the device and location of the device (proximal airway vs at the ventilator) to measure tidal volume may result in different values for tidal volume, based on the type of ventilator, circuit tubing used, compliance of the patient, compliance of the tubing, and size of the patient (96). For these reasons, we have elected to omit compliance from the definition of PARDS. It may be used for study-specific risk stratification, with detailed instruction and standardization of measurements.
NRS is being used with increasing frequency for acute respiratory failure in adult ICUs and PICUs (see section on noninvasive ventilation ), and there are an increasing number of patient interfaces available. Nasal modes of NRS allow for entrainment of room air during inspiration, making calculation of SF or PF ratios difficult. In order to determine the incidence of ARDS in adults and children by capturing patients cared for out of ICUs where suspicion of ARDS may be low, NRS is common, and arterial blood sampling is uncommon, an estimation of FIO2 is necessary for calculation of SF ratio (9, 96, 97). Conventional methods of estimating the fraction of delivered oxygen (FdO2) may over- or underestimate FIO2 depending on the rate of flow delivered to the patient, the patient’s minute ventilation, and whether the flow is warmed or humidified. The published guidelines for the calculation of FIO2 by the American Association of Respiratory Care suggest that regular nasal cannula do not provide an FIO2 greater than 0.40 (101–104). Consider a 5-kg infant with a minute ventilation of 240 mL/kg/min (1.2 L/min) who is treated with 100% oxygen via nasal cannula at 4 L/min. What is the fraction of room air that this infant can entrain? An average adult with a minute ventilation of 6 L/min has a much greater chance of entraining room air if treated with the same 100% oxygen via nasal cannula at 4 L/min. Nasal interfaces to deliver BiPAP, CPAP, or high-flow nasal cannula (HFNC) may provide enough flow to washout anatomic oropharyngeal dead space as well as prevent entrainment of room air during inspiration. The minute ventilation demands of an individual patient, the flow delivered by the device, as well as the presence of an oral leak may affect the FdO2 for a given patient. Unfortunately, there are no published studies reporting the effective FdO2 by nasal modes of NRS. Therefore, in the absence of data to generate a nomogram for estimation of FIO2, we propose a simple screening algorithm based on normal resting minute ventilation (VE) of an average patient and a predicted FIO2 = 0.40 when the flow is approximately equal to VE (Table 7).
We have elected not to stratify patients receiving NRS into risk severity groups based on hypoxemia criteria due to variability in how noninvasive ventilation is used, paired with the difficulty in estimating delivered FIO2 and mean airway pressure. Therefore, we recommend that children who are on full face mask modes of NRS with a minimum CPAP of 5 cm H2O who have PF ratios less than or equal to 300 or SF ratios less than or equal to 264 have PARDS. Patients who are on full face mask CPAP or BiPAP but do not fulfill all the criteria for PARDS should be considered at risk for PARDS.
Interpretation of the diagnostic criteria of ARDS in children has varied since the AECC criteria were finalized, and the acceptance and application of the Berlin criteria (2) is unlikely to clarify the issue of exclusion criteria in PARDS. In particular, a number of exclusion criteria have been applied in children by various studies. These have included gestational age, preexisting chronic lung disease, cyanotic congenital heart disease, and coexisting LV failure/dysfunction. However, these preexisting comorbidities do not exclude the potential for these patients to develop PARDS, and these comorbidities represent important at-risk patient populations. Therefore, we believe these must be addressed in a definition of PARDS.
The Berlin criteria define ARDS occurring within 1 week of a known clinical insult or new/worsening symptoms, providing clarity regarding the occurrence of ARDS on a background of chronic lung disease. Infants and children with chronic lung disease are at risk of developing PARDS, and many authors have included children with chronic lung disease in ARDS cohorts. Santschi et al (23) found that 36.4% of cases of PARDS involved underlying chronic pulmonary disease and 25.5% of their cohort were also ex-preterm infants. Other authors have found high proportion of children presenting with ARDS with underlying chronic lung disease (Flori et al—11% , Erickson et al—10% ) and history of prematurity (Flori et al—24% ).
In order to develop criteria to define PARDS in children with chronic lung disease, the spectrum of chronic lung disease, ranging from oxygen dependence to various forms of noninvasive ventilation to long-term invasive ventilation, were considered. Since this is a diverse population with some patients with chronic bilateral densities on CXR and others chronically supported with invasive ventilation that at baseline meet hypoxemia criteria for moderate to severe PARDS, it became clear that criteria for degree of change would be arbitrary. Patients that are chronically supported with supplemental oxygen or noninvasive positive pressure mechanical ventilation that require intubation and invasive mechanical ventilation can be stratified into mild to severe PARDS criteria. However, there are no data to support applying severity criteria to patients chronically treated with invasive mechanical ventilatory support. In order to determine whether severity criteria can be applied to these patients, future studies will need to include these patients in the enrollment criteria.
The most important factor in the diagnosis of PARDS in patients with preexisting lung disease is the acute deterioration in oxygenation, in response to a known clinical trigger. Future studies are required to determine whether changes in chest imaging that are consistent with new parenchymal disease will be of diagnostic and prognostic value.
Patients with cyanotic congenital heart disease have not been addressed in either the AECC or the Berlin criteria. In general, the presence of cyanotic congenital heart disease has been considered an exclusion criterion for the diagnosis of PARDS in children. This is understandable as intracardiac mixing or right-to-left shunting of blood affects the PF ratio and other indices of oxygenation. However, it is clear that the pathologic processes described by Ware and Matthay (105) can occur in children with cyanotic congenital heart disease. Hence, worsening hypoxemia with pulmonary parenchymal disease on CXR in the absence of changes in the underlying cardiac disease may be consistent with a diagnosis of PARDS. Patients with uncorrected cyanotic congenital heart disease may be at high risk of PARDS for a number of reasons: frequent hospitalization, instrumentation, risk of endocarditis, immune compromise, need for palliative procedures and cardiopulmonary bypass, and other associated congenital defects.
Review of the literature is largely unhelpful in defining the association between cyanotic congenital heart disease and ARDS as cyanotic congenital heart disease is listed as an exclusion in most epidemiological studies (5, 8, 11, 18, 23). Of the patients screened by Santschi et al (23) who fulfilled ARDS criteria (a known acute cause of ARDS, significant hypoxemia and bilateral CXR changes), 73 of 414 (17.6%) were excluded due to presence of cyanotic congenital heart disease.
Children with chronic cardiac disease, both cyanotic congenital cardiac disease and noncyanotic disease, are likely to be an important group of patients with high morbidity and mortality from PARDS. The diagnosis of PARDS in these children will require individual providers to exclude new changes in intracardiac shunt/mixing or worsening LV dysfunction as the cause of worsening hypoxemia. Children with a known acute clinical insult, chest imaging consistent with parenchymal lung disease, and an acute deterioration in oxygenation not explained by changes in underlying cardiac disease should be considered to have PARDS.
Echocardiography is not ideal for assessment of changes in intracardiac shunt or mixing. However, echocardiography may be useful in excluding selected cardiac causes of acute deterioration in oxygenation (e.g., systemic-pulmonary shunt thrombosis or narrowing, increasing right ventricular outflow tract obstruction, and increasing pulmonary hypertension). More invasive modalities, such as cardiac catheterization, CT angiography, and MRI, while useful in defining intracardiac shunts, pose significant risks in children with PARDS.
Given the difficulties in ascribing the contribution to hypoxemia from acute lung disease versus intracardiac shunt, future studies will need to include patients with cyanotic congenital heart disease to determine whether PARDS severity criteria can be applied to these patients.
1.9.4. We recommend that future studies of PARDS should endeavor to include children with preexisting pulmonary and cardiac disease. Strong agreement
This has allowed us to arrive at the preceding draft definition of PARDS (Figs. 1 and 2).
We have attempted to create a pediatric-specific definition for ARDS that builds on the adult-based Berlin definition, but has been modified to account for the unique epidemiology, practice patterns, comorbidities, and differences in outcome between adults and children with ARDS. The definition is largely based on consensus opinion, supported by existing literature when available, and specific aspects of the definition have been tested with available empirical data.
Several aspects of the PARDS definition are identical to the Berlin Definition of ARDS: namely, timing of ARDS after a known risk factor and the potential for ARDS to coexist with LV dysfunction. We elected to stay consistent with the Berlin definition for these elements because pediatric literature and practice patterns support similarities with adult literature and practice. In addition, although there are age-related differences in lung morphogenesis that may modify incidence, outcome, and severity of ARDS in children compared with adults, there are insufficient data to support any specific age for “adult” or “pediatric” ARDS. On the other end of the age spectrum, there are clear differences in the pathobiology of PARDS and hypoxemic respiratory failure that occur in the perinatal period, justifying specific exclusion of these patients from the definition of PARDS. Larger departures from the Berlin Definition surround 1) the elimination of the requirement of bilateral infiltrates on chest imaging; 2) the use of OI and OSI instead of PF ratio with a minimum PEEP level (51); 3) the specific inclusion of children with preexisting chronic lung disease or cyanotic congenital heart disease; and 4) the creation of “at-risk” criteria to facilitate future epidemiologic studies of PARDS, and assist with earlier identification of patients, as consistent with the adult NIH PETAL initiative.
The goal of a pediatric-specific definition for ARDS is to provide the basis for consistent identification of a heterogeneous syndrome with a variety of causes. The definition may facilitate future epidemiological research as well as evaluation of specific therapies and prevention strategies. On a population level, our hope is that stratification of severity groups will allow robust evaluation of the risks and benefits of potential therapies. However, caution must be used when applying this definition to individual patients given the multitude of pulmonary and extrapulmonary factors that contribute to outcome for children with PARDS.
There are certainly limitations with our definition. First, there were insufficient data to test several of the recommendations. We hope future research will target some of these aspects of the definition, and we advocate iterative improvements and revision of the definition as more data become available. Second, much of the data available for analysis were generated as part of clinical investigations conducted by members of the PALICC group. Given that most of these data were from larger academic PICUs, it is possible that the cut points used for the risk groups are not as generalizable to the global management of PARDS. This should be tested with external data. Third, we have included OSI in the definition of PARDS when OI is not available. Although there has been a recent retrospective study examining the relationship between OSI and mortality (90), studies validating the use of OSI in PARDS are sparse and there are not sufficient data to examine whether the risk severity groups generated from OSI result in similar mortality rates as those generated with OI. This should be tested in a future study.
In conclusion, we have developed a pediatric-specific definition of ARDS based largely on consensus opinion from established investigators in PARDS, with some validation using data from existing PARDS studies. We propose using this definition for future investigations and clinical care of children with PARDS and encourage external validation with the hope for continued iterative refinement of the definition.
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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, The Netherlands; Robert F. Tamburro, Pennsylvania State University
Section 5, Nonpulmonary 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, United Kingdom
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