Comorbidities and Assessment of Severity of Pediatric ARDS
Comorbidities and Assessment of Severity of Pediatric ARDS
Assessing the severity of disease in patients with PARDS has been much more widely studied in adults than in children. Disease severity measures can be subdivided into 1) measures that can be made at the bedside, 2) measures requiring more in-depth calculation, 3) biochemical measurements, and 4) early responsiveness to therapy.
Despite inconsistency in the optimal timing of the measurement, both oxygenation defect and ventilation defect have been demonstrated in multiple studies to be associated with outcome. Some studies report measurements of oxygenation and ventilation defects at the onset of ALI/ARDS, whether the patient is invasively or noninvasively ventilated at the time. By contrast, other studies report these measurements within the first hours to days of ALI/ARDS onset, whereas others report the association of these measures with outcome based on the "worst" measurement during the patient's entire PICU stay.
Measurements of Oxygenation Indices. Of the oxygenation measures, both P/F ratio and oxygenation index (OI) have been fairly consistent and robust predictors of disease severity and outcomes. Given the decrease in use of arterial catheters and, hence, arterial blood gases in the pediatric population and the increased use of noninvasive respiratory support strategies, SpO2/FIO2 and oxygen saturation index (OSI) have been shown to be valid substitutions for the arterial blood gas–based measurements. These findings are critically important in allowing earlier identification of patients for clinical purposes as well as appropriate identification of patients for inclusion in future PARDS research. The reader is encouraged to review the article on definitions, incidence, and epidemiology for additional details on oxygenation defect measurement and defining PARDS severity (64).
Timing of Measuring Oxygenation Indices. When assessing the timing of these measurements in the course of PARDS, strong predictive ability in measurements made at the onset of or perhaps more accurately at the time that PARDS is diagnosed has been reported. Specifically, the P/F ratio at the onset of ALI/ARDS has been shown to be an independent predictor of mortality and duration of mechanical ventilation. This finding was confirmed in a more recent pediatric cohort. Certainly, this finding is multifactorial and may be related to earlier diagnosis of the patient and institution of lung-protective management strategies rather than the measure itself being causative of the outcome.
The utility of measurements reflecting persistence of oxygenation defect after the onset (or diagnosis) of ALI/ARDS in predicting outcome has been well demonstrated. Children with persistently elevated P(A-a)O2 greater than 420 mm Hg from day 2 to day 5 after diagnosis demonstrate an increased risk of death with an OR of 26.7 (95% CI, 4.7–183) in a study of 60 patients with ARDS. P/F ratio after 24 hours of ARDS onset was able to predict mortality (p < 0.001) in a cohort of children stratified into four categories (severe ARDS, moderate ARDS, ALI, and acute respiratory failure) (Fig. 3). Increased mortality has been observed in children with lower P/F ratio after 24 hours of ALI/ARDS. In addition, both maximum oxygen index (OI) and minimum P/F ratio are good predictors of mortality; a minimum P/F ratio of less than 53 predicted risk of death greater than 70.5% with specificity of 92% and maximum OI greater than 53.5 predicted risk of death greater than 80% with specificity of 97%. Lower P/F ratio during hospital stay has also been observed to predict mortality.
(Enlarge Image)
Figure 3.
Reclassification of 146 children at 24 hr of acute respiratory distress syndrome (ARDS) onset after reassessment of oxygenation under standard ventilatory settings. AECC = American-European Consensus Conference, PEEP = positive end-expiratory pressure. Reprinted with permission from López-Fernández et al (7). Copyright 2014 Walter Kluwer Health.
Measurements of Ventilation Indices. Oxygenation reflects only a portion of the physiological deficits in PARDS. Recent pediatric studies have demonstrated the predictive value of CO2 exchange, and thereby lung perfusion, on outcomes just as has been seen in the adult population. Worse lung perfusion is thought to be due to dysregulated coagulation and vascular endothelial injury in the lungs of PARDS patients. Abnormal ventilation indices (VI = PaCO2 × peak airway pressure × respiratory rate/1,000) at the onset of disease in children with ARDS have been reported. Furthermore, significant discriminative ability of VI in predicting death was observed in those children whose VI did not improve by study day 3 (survivors exhibited VI between 30 and 35 throughout this time period, whereas nonsurvivors exhibited VI rising over 57 on day 3). The importance of the severity of VI on day 3 of lung injury was also demonstrated in a study of children with malignancy and ARDS. End-tidal alveolar dead space fraction (AVDSf) has also been shown to be independently predictive of mortality within the first day in children with acute hypoxemic respiratory failure even after controlling for severity of illness with Pediatric Risk of Mortality (PRISM) III (OR, 1.83; 95% CI, 1.23–2.7; p = 0.003).
Measurements of Simultaneous Oxygenation and Ventilation Indices. As our understanding of PARDS pathophysiology improves, it is important to recognize the incremental improvement in outcome prediction by measures that include both oxygenation and ventilation indices. The use of OSI or OI and AVDSf together can improve discrimination with area under the curve greater than 0.7, and the discriminative ability when using P/F or SaO2FIO2 and AVDSf is also quite acceptable (Fig. 4).
(Enlarge Image)
Figure 4.
The receiver operating characteristic plots for oxygen saturation index (OSI) and OSI + end-tidal alveolar dead space fraction (AVDSf). The area under the receiver operating characteristic plot (area under the curve [AUC]) increases when the AVDSf is added to OSI; however, this increase is not statistically significant (p = 0.1). Reprinted with permission from Ghuman et al (11). Copyright 2014 Walter Kluwer Health.
Going forward, however, PARDS investigators should examine and report findings at similar time periods through the course of PARDS using all of the above-mentioned indices. Specifically, we recommend studying indices at the onset of PARDS and at 24, 48, and 72 hours after onset of the disease as the utility of these measures in predicting outcome for clinical purposes as well as risk stratification for research studies is most salient at these time points. Furthermore, assessing patients after these time points likely eliminates the "extremes" of the patient populations, that is, those patients that survived and were discharged from the PICU or those that died.
Recommendations:
2.2.1 Of the measures available at the bedside, both oxygenation defect and ventilation defect have generally been found to be associated with outcome. There is great inconsistency in the literature, however, concerning the optimal timing of these measurements. We recommend evaluating respiratory indices and biomarkers at the onset of PARDS, within the first 24 hours of onset, as well as serial measures beyond that as indicated according to treatment and/or clinical studies. Strong agreement
2.2.2 For disease severity measures that can be made at the bedside, we recommend that future research studies evaluating both trajectory of illness and recovery should use standardized, minimal datasets with adequately explicit definitions. Strong agreement
2.2.3 Recent adult studies evaluating the effect of dead space ventilation, thereby reflecting lung perfusion, have been highly predictive of outcome. We recommend that future multicenter studies should examine the association of dead space and outcome of PARDS. Strong agreement
Measurements of Ventilator Parameters. Various ventilator parameters, including peak inspiratory pressures (PIP), positive end-expiratory pressures (PEEP), mean airway pressures (MAP), and tidal volume (TV) have been reported to have predictive value in children with ARDS. As these measures are decidedly clinician dependent and can be considered therapies rather than independent predictors, their utility in multivariate regression analyses is limited. An increased risk of death has been reported in those patients with increased PIP, PEEP, and MAP on univariate analysis and multivariate regression independent of severity of illness. Interestingly, Khemani et al studied 398 intubated patients with P/F ratio less than 300, of which 192 had bilateral infiltrates on chest radiograph. TV between 6 and 10 mL/kg was not associated with mortality on multivariate analysis, but higher TVs on day 1 were associated with greater ventilator-free days (OR, 0.88; 95% CI, 0.78–0.98); however, this did not reach statistical significance in the group with bilateral infiltrates (OR, 0.82; 95% CI, 0.70–0.96). Zhu et al also found no association between TVs less than 6 mL/kg to more than 10 mL/kg and mortality or ventilator-free days in a recent study of 345 children with acute hypoxemic respiratory failure. Although seemingly intuitive, most studies do not report associations of ventilation variables and barotrauma; one recent study reported an association between TV and increased risk of barotrauma.
Recommendation:
2.2.4 Studies examining the relationship between TV, peak airway pressures, PEEP, or MAPs with mortality or length of mechanical ventilation have resulted in conflicting results; some studies exhibit associations with outcomes while others do not. We recommend that future studies incorporating variables such as TV, peak and plateau airway pressures, PEEP, or MAP use explicit protocols and definitions such that these measures can be more robustly evaluated. Strong agreement
PRISM III and PIM-2. Other robust measures exist. However, these measures require a much greater collection of patient data and assessment of factors at ICU admission or over the first 12–24 hours of ICU and, therefore, these measures may not necessarily be relevant to the patient in whom PARDS develops 24 hours or more after admission. Specifically, PRISM III and PIM-2 are widely used and validated at predicting outcome, both in children who have ALI/ARDS and in the pediatric critical care population in general. The Pediatric Respiratory Failure Score was proposed to identify the highest risk children with ARDS who might benefit with treatment with extracorporeal membrane oxygenation. This score had a positive predictive value for mortality of 0.72 at onset and 0.7 between 0 and 132 hours. These measures essentially assess the extent of multiple organ system dysfunction. Unfortunately, these composite scores include respiratory variables and thereby instill confounding or colinearity in any multivariable analyses intended to dissect out the association of respiratory failure independent of other nonpulmonary organ system failures.
Multiple Organ System Dysfunction. Of the few studies large enough to allow for multivariate analyses, multiple organ system dysfunction has been the single most important independent clinical risk factor for mortality in children at the onset of ALI/ARDS. As expected, progressive increases in the number of failing nonpulmonary organ systems, often termed "new and progressive multiple organ dysfunction," in the days prior to the onset of ALI/ARDS all indicate progressively increased risk of mortality (Table 1). These findings have been cited to justify the use of noninvasive ventilatory support for ALI/ARDS in children as safest in those children with single organ system failure.
Various studies evaluate individual organ system failures. However, comparison is challenging given that there is no consensus to the exact definition of each individual organ system among these studies. For example, renal dysfunction is defined as an elevation in creatinine in some studies compared with the need for renal replacement therapy in other studies; renal dysfunction has been demonstrated to be a strong independent risk factor for mortality in the pediatric oncology population even on multivariable analysis. Given the variability in these definitions and the importance of evaluating their association with mortality, we believe there should be great effort in explicitly defining and validating these nonpulmonary organ failures in critically ill children, particularly, in future studies of PARDS.
Recommendation:
2.2.5 Among measures requiring more in-depth calculation, we recommend that the use of an estimate of multiple organ system failure should be included in any studies of clinical risk factors associated with outcome in PARDS patients. Strong agreement
2.2.6 While evaluating risk factors related to organ failure in research related to PARDS, caution should be exercised in the use of organ failure scoring systems that include indices of respiratory failure. We recommend the development of a validated, nonpulmonary organ failure definition for use in PARDS research. Strong agreement
Many biochemical markers have been measured in critically ill children, though to a lesser degree than those measured in adults, and few studies have focused on children with PARDS. Elevations of von Willebrand factor antigen and endothelin-1, reflecting endothelial injury; elevation of soluble intercellular adhesion molecule-1, reflecting macrophage activation and endothelial cell injury; and elevation in plasminogen activation inhibitor, reflecting dysregulated coagulation, resulting in alveolar fibrin deposition (Table 2), have all been associated with increased risk of mortality and prolonged need for mechanical ventilation in children. Elevations of beta natriuretic peptide have also been demonstrated to correlate with worse clinical outcome, but the magnitude of the elevation is to a far lesser degree than that seen in patients with myocardial dysfunction. Unlike studies in adult ARDS and pediatric sepsis, the use of various combinations of biomarkers in providing even stronger prediction of outcome has not been adequately examined in PARDS.
One of the potential values of the study of these biomarkers is in the development of diagnostic testing with greater sensitivity and specificity. If such testing were available as point of care testing, it could help in the risk stratification of patients since these markers are elevated at the onset of PARDS and may better predict outcomes. Elevations of these markers in the earliest days of lung injury also indicate that the pathophysiological process of PARDS is well underway often by the time that the clinician has recognized the extent of disease and certainly before these patients are approached for participation in clinical trials. This latter scenario is relevant given that most therapeutic trials are tested in animal studies within hours after the insult leading to the development of ARDS; by contrast, human subjects enrolling in clinical therapeutic trials are often consented and the investigational therapy is begun often days after the onset of the pathophysiological processes in PARDS. Insomuch as oxygenation defect, dead space ventilation and biomarker changes can be surrogates for the extent of lung tissue damage, the greater these measures deviate from "normal," the greater the extent of lung injury and, by extension, greater risk of mortality or prolonged mechanical ventilation.
Recommendation:
2.2.7 We recommend further research into the potential use of combinations of biomarker levels in providing a stronger prediction outcome. Strong agreement
Early response to therapy has been demonstrated to predict outcome, although the definition of "early" has not been standardized in either clinical practice or research, therefore making comparison of studies difficult. An inability to rapidly reduce FIO2 is a simple, yet sensitive prognostic indicator of poor outcome. In addition, a significant association between response to inhaled nitric oxide treatment and outcome (r = 0.43; p < 0.02) has also been demonstrated; all children with a less than 15% improvement in OI did not survive in contrast to 61% of children with a more than 30% improvement in OI surviving.
Improvement in oxygenation indices within 24 hours of initiation of high-frequency oscillatory ventilation (HFOV) has also been associated with improved outcome. Conversely, failure of patients to improve after initiation of HFOV has been predictive of mortality. A combination of initial OI greater than 20 and failure to decrease this OI by greater than 20% within 6 hours of start of HFOV predicted death with 86% sensitivity and 83% specificity. P(A-a)O2 at 6 hours, oxygenation indices at 24 hours, and MAPs at 36 hours were significantly different in survivors compared with nonsurvivors after initiation of HFOV. Persistently high OI after 24 hours of HFOV is also predictive of increased mortality in children receiving HFOV.
Certainly, the early management of children with severe lung injury can directly influence their long-term outcome. There is general consensus that lung-protective mechanical ventilation and judicious management of both protein-rich blood product transfusions, especially plasma and platelets, and fluid therapy with the target of attaining euvolemia are associated with improved outcome. Importantly, disregard for these strategies has been associated with worse outcome with a clear association between TV and prevalence of barotrauma. These strategies are discussed in further detail later in this PARDS Consensus document (83).
Recommendation:
2.2.8 We recommend that early response to therapy should not be used as a primary outcome measure in phase III clinical research trials. Future research should explore the relationship of early response to therapy as an intermediate process variable linked to more clinically relevant, long-term outcomes (e.g., ventilator-free days and mortality). Strong agreement
Assessing Disease Severity
Assessing the severity of disease in patients with PARDS has been much more widely studied in adults than in children. Disease severity measures can be subdivided into 1) measures that can be made at the bedside, 2) measures requiring more in-depth calculation, 3) biochemical measurements, and 4) early responsiveness to therapy.
Measures That can be Made at the Bedside
Despite inconsistency in the optimal timing of the measurement, both oxygenation defect and ventilation defect have been demonstrated in multiple studies to be associated with outcome. Some studies report measurements of oxygenation and ventilation defects at the onset of ALI/ARDS, whether the patient is invasively or noninvasively ventilated at the time. By contrast, other studies report these measurements within the first hours to days of ALI/ARDS onset, whereas others report the association of these measures with outcome based on the "worst" measurement during the patient's entire PICU stay.
Measurements of Oxygenation Indices. Of the oxygenation measures, both P/F ratio and oxygenation index (OI) have been fairly consistent and robust predictors of disease severity and outcomes. Given the decrease in use of arterial catheters and, hence, arterial blood gases in the pediatric population and the increased use of noninvasive respiratory support strategies, SpO2/FIO2 and oxygen saturation index (OSI) have been shown to be valid substitutions for the arterial blood gas–based measurements. These findings are critically important in allowing earlier identification of patients for clinical purposes as well as appropriate identification of patients for inclusion in future PARDS research. The reader is encouraged to review the article on definitions, incidence, and epidemiology for additional details on oxygenation defect measurement and defining PARDS severity (64).
Timing of Measuring Oxygenation Indices. When assessing the timing of these measurements in the course of PARDS, strong predictive ability in measurements made at the onset of or perhaps more accurately at the time that PARDS is diagnosed has been reported. Specifically, the P/F ratio at the onset of ALI/ARDS has been shown to be an independent predictor of mortality and duration of mechanical ventilation. This finding was confirmed in a more recent pediatric cohort. Certainly, this finding is multifactorial and may be related to earlier diagnosis of the patient and institution of lung-protective management strategies rather than the measure itself being causative of the outcome.
The utility of measurements reflecting persistence of oxygenation defect after the onset (or diagnosis) of ALI/ARDS in predicting outcome has been well demonstrated. Children with persistently elevated P(A-a)O2 greater than 420 mm Hg from day 2 to day 5 after diagnosis demonstrate an increased risk of death with an OR of 26.7 (95% CI, 4.7–183) in a study of 60 patients with ARDS. P/F ratio after 24 hours of ARDS onset was able to predict mortality (p < 0.001) in a cohort of children stratified into four categories (severe ARDS, moderate ARDS, ALI, and acute respiratory failure) (Fig. 3). Increased mortality has been observed in children with lower P/F ratio after 24 hours of ALI/ARDS. In addition, both maximum oxygen index (OI) and minimum P/F ratio are good predictors of mortality; a minimum P/F ratio of less than 53 predicted risk of death greater than 70.5% with specificity of 92% and maximum OI greater than 53.5 predicted risk of death greater than 80% with specificity of 97%. Lower P/F ratio during hospital stay has also been observed to predict mortality.
(Enlarge Image)
Figure 3.
Reclassification of 146 children at 24 hr of acute respiratory distress syndrome (ARDS) onset after reassessment of oxygenation under standard ventilatory settings. AECC = American-European Consensus Conference, PEEP = positive end-expiratory pressure. Reprinted with permission from López-Fernández et al (7). Copyright 2014 Walter Kluwer Health.
Measurements of Ventilation Indices. Oxygenation reflects only a portion of the physiological deficits in PARDS. Recent pediatric studies have demonstrated the predictive value of CO2 exchange, and thereby lung perfusion, on outcomes just as has been seen in the adult population. Worse lung perfusion is thought to be due to dysregulated coagulation and vascular endothelial injury in the lungs of PARDS patients. Abnormal ventilation indices (VI = PaCO2 × peak airway pressure × respiratory rate/1,000) at the onset of disease in children with ARDS have been reported. Furthermore, significant discriminative ability of VI in predicting death was observed in those children whose VI did not improve by study day 3 (survivors exhibited VI between 30 and 35 throughout this time period, whereas nonsurvivors exhibited VI rising over 57 on day 3). The importance of the severity of VI on day 3 of lung injury was also demonstrated in a study of children with malignancy and ARDS. End-tidal alveolar dead space fraction (AVDSf) has also been shown to be independently predictive of mortality within the first day in children with acute hypoxemic respiratory failure even after controlling for severity of illness with Pediatric Risk of Mortality (PRISM) III (OR, 1.83; 95% CI, 1.23–2.7; p = 0.003).
Measurements of Simultaneous Oxygenation and Ventilation Indices. As our understanding of PARDS pathophysiology improves, it is important to recognize the incremental improvement in outcome prediction by measures that include both oxygenation and ventilation indices. The use of OSI or OI and AVDSf together can improve discrimination with area under the curve greater than 0.7, and the discriminative ability when using P/F or SaO2FIO2 and AVDSf is also quite acceptable (Fig. 4).
(Enlarge Image)
Figure 4.
The receiver operating characteristic plots for oxygen saturation index (OSI) and OSI + end-tidal alveolar dead space fraction (AVDSf). The area under the receiver operating characteristic plot (area under the curve [AUC]) increases when the AVDSf is added to OSI; however, this increase is not statistically significant (p = 0.1). Reprinted with permission from Ghuman et al (11). Copyright 2014 Walter Kluwer Health.
Going forward, however, PARDS investigators should examine and report findings at similar time periods through the course of PARDS using all of the above-mentioned indices. Specifically, we recommend studying indices at the onset of PARDS and at 24, 48, and 72 hours after onset of the disease as the utility of these measures in predicting outcome for clinical purposes as well as risk stratification for research studies is most salient at these time points. Furthermore, assessing patients after these time points likely eliminates the "extremes" of the patient populations, that is, those patients that survived and were discharged from the PICU or those that died.
Recommendations:
2.2.1 Of the measures available at the bedside, both oxygenation defect and ventilation defect have generally been found to be associated with outcome. There is great inconsistency in the literature, however, concerning the optimal timing of these measurements. We recommend evaluating respiratory indices and biomarkers at the onset of PARDS, within the first 24 hours of onset, as well as serial measures beyond that as indicated according to treatment and/or clinical studies. Strong agreement
2.2.2 For disease severity measures that can be made at the bedside, we recommend that future research studies evaluating both trajectory of illness and recovery should use standardized, minimal datasets with adequately explicit definitions. Strong agreement
2.2.3 Recent adult studies evaluating the effect of dead space ventilation, thereby reflecting lung perfusion, have been highly predictive of outcome. We recommend that future multicenter studies should examine the association of dead space and outcome of PARDS. Strong agreement
Measurements of Ventilator Parameters. Various ventilator parameters, including peak inspiratory pressures (PIP), positive end-expiratory pressures (PEEP), mean airway pressures (MAP), and tidal volume (TV) have been reported to have predictive value in children with ARDS. As these measures are decidedly clinician dependent and can be considered therapies rather than independent predictors, their utility in multivariate regression analyses is limited. An increased risk of death has been reported in those patients with increased PIP, PEEP, and MAP on univariate analysis and multivariate regression independent of severity of illness. Interestingly, Khemani et al studied 398 intubated patients with P/F ratio less than 300, of which 192 had bilateral infiltrates on chest radiograph. TV between 6 and 10 mL/kg was not associated with mortality on multivariate analysis, but higher TVs on day 1 were associated with greater ventilator-free days (OR, 0.88; 95% CI, 0.78–0.98); however, this did not reach statistical significance in the group with bilateral infiltrates (OR, 0.82; 95% CI, 0.70–0.96). Zhu et al also found no association between TVs less than 6 mL/kg to more than 10 mL/kg and mortality or ventilator-free days in a recent study of 345 children with acute hypoxemic respiratory failure. Although seemingly intuitive, most studies do not report associations of ventilation variables and barotrauma; one recent study reported an association between TV and increased risk of barotrauma.
Recommendation:
2.2.4 Studies examining the relationship between TV, peak airway pressures, PEEP, or MAPs with mortality or length of mechanical ventilation have resulted in conflicting results; some studies exhibit associations with outcomes while others do not. We recommend that future studies incorporating variables such as TV, peak and plateau airway pressures, PEEP, or MAP use explicit protocols and definitions such that these measures can be more robustly evaluated. Strong agreement
Measurements Requiring More In-depth Calculation
PRISM III and PIM-2. Other robust measures exist. However, these measures require a much greater collection of patient data and assessment of factors at ICU admission or over the first 12–24 hours of ICU and, therefore, these measures may not necessarily be relevant to the patient in whom PARDS develops 24 hours or more after admission. Specifically, PRISM III and PIM-2 are widely used and validated at predicting outcome, both in children who have ALI/ARDS and in the pediatric critical care population in general. The Pediatric Respiratory Failure Score was proposed to identify the highest risk children with ARDS who might benefit with treatment with extracorporeal membrane oxygenation. This score had a positive predictive value for mortality of 0.72 at onset and 0.7 between 0 and 132 hours. These measures essentially assess the extent of multiple organ system dysfunction. Unfortunately, these composite scores include respiratory variables and thereby instill confounding or colinearity in any multivariable analyses intended to dissect out the association of respiratory failure independent of other nonpulmonary organ system failures.
Multiple Organ System Dysfunction. Of the few studies large enough to allow for multivariate analyses, multiple organ system dysfunction has been the single most important independent clinical risk factor for mortality in children at the onset of ALI/ARDS. As expected, progressive increases in the number of failing nonpulmonary organ systems, often termed "new and progressive multiple organ dysfunction," in the days prior to the onset of ALI/ARDS all indicate progressively increased risk of mortality (Table 1). These findings have been cited to justify the use of noninvasive ventilatory support for ALI/ARDS in children as safest in those children with single organ system failure.
Various studies evaluate individual organ system failures. However, comparison is challenging given that there is no consensus to the exact definition of each individual organ system among these studies. For example, renal dysfunction is defined as an elevation in creatinine in some studies compared with the need for renal replacement therapy in other studies; renal dysfunction has been demonstrated to be a strong independent risk factor for mortality in the pediatric oncology population even on multivariable analysis. Given the variability in these definitions and the importance of evaluating their association with mortality, we believe there should be great effort in explicitly defining and validating these nonpulmonary organ failures in critically ill children, particularly, in future studies of PARDS.
Recommendation:
2.2.5 Among measures requiring more in-depth calculation, we recommend that the use of an estimate of multiple organ system failure should be included in any studies of clinical risk factors associated with outcome in PARDS patients. Strong agreement
2.2.6 While evaluating risk factors related to organ failure in research related to PARDS, caution should be exercised in the use of organ failure scoring systems that include indices of respiratory failure. We recommend the development of a validated, nonpulmonary organ failure definition for use in PARDS research. Strong agreement
Measurements of Biochemical Markers
Many biochemical markers have been measured in critically ill children, though to a lesser degree than those measured in adults, and few studies have focused on children with PARDS. Elevations of von Willebrand factor antigen and endothelin-1, reflecting endothelial injury; elevation of soluble intercellular adhesion molecule-1, reflecting macrophage activation and endothelial cell injury; and elevation in plasminogen activation inhibitor, reflecting dysregulated coagulation, resulting in alveolar fibrin deposition (Table 2), have all been associated with increased risk of mortality and prolonged need for mechanical ventilation in children. Elevations of beta natriuretic peptide have also been demonstrated to correlate with worse clinical outcome, but the magnitude of the elevation is to a far lesser degree than that seen in patients with myocardial dysfunction. Unlike studies in adult ARDS and pediatric sepsis, the use of various combinations of biomarkers in providing even stronger prediction of outcome has not been adequately examined in PARDS.
One of the potential values of the study of these biomarkers is in the development of diagnostic testing with greater sensitivity and specificity. If such testing were available as point of care testing, it could help in the risk stratification of patients since these markers are elevated at the onset of PARDS and may better predict outcomes. Elevations of these markers in the earliest days of lung injury also indicate that the pathophysiological process of PARDS is well underway often by the time that the clinician has recognized the extent of disease and certainly before these patients are approached for participation in clinical trials. This latter scenario is relevant given that most therapeutic trials are tested in animal studies within hours after the insult leading to the development of ARDS; by contrast, human subjects enrolling in clinical therapeutic trials are often consented and the investigational therapy is begun often days after the onset of the pathophysiological processes in PARDS. Insomuch as oxygenation defect, dead space ventilation and biomarker changes can be surrogates for the extent of lung tissue damage, the greater these measures deviate from "normal," the greater the extent of lung injury and, by extension, greater risk of mortality or prolonged mechanical ventilation.
Recommendation:
2.2.7 We recommend further research into the potential use of combinations of biomarker levels in providing a stronger prediction outcome. Strong agreement
Assessment of Early Response to Therapy
Early response to therapy has been demonstrated to predict outcome, although the definition of "early" has not been standardized in either clinical practice or research, therefore making comparison of studies difficult. An inability to rapidly reduce FIO2 is a simple, yet sensitive prognostic indicator of poor outcome. In addition, a significant association between response to inhaled nitric oxide treatment and outcome (r = 0.43; p < 0.02) has also been demonstrated; all children with a less than 15% improvement in OI did not survive in contrast to 61% of children with a more than 30% improvement in OI surviving.
Improvement in oxygenation indices within 24 hours of initiation of high-frequency oscillatory ventilation (HFOV) has also been associated with improved outcome. Conversely, failure of patients to improve after initiation of HFOV has been predictive of mortality. A combination of initial OI greater than 20 and failure to decrease this OI by greater than 20% within 6 hours of start of HFOV predicted death with 86% sensitivity and 83% specificity. P(A-a)O2 at 6 hours, oxygenation indices at 24 hours, and MAPs at 36 hours were significantly different in survivors compared with nonsurvivors after initiation of HFOV. Persistently high OI after 24 hours of HFOV is also predictive of increased mortality in children receiving HFOV.
Certainly, the early management of children with severe lung injury can directly influence their long-term outcome. There is general consensus that lung-protective mechanical ventilation and judicious management of both protein-rich blood product transfusions, especially plasma and platelets, and fluid therapy with the target of attaining euvolemia are associated with improved outcome. Importantly, disregard for these strategies has been associated with worse outcome with a clear association between TV and prevalence of barotrauma. These strategies are discussed in further detail later in this PARDS Consensus document (83).
Recommendation:
2.2.8 We recommend that early response to therapy should not be used as a primary outcome measure in phase III clinical research trials. Future research should explore the relationship of early response to therapy as an intermediate process variable linked to more clinically relevant, long-term outcomes (e.g., ventilator-free days and mortality). Strong agreement
Source...