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Pulmonary Specific Ancillary Treatment for Pediatric Acute Respiratory Distress Syndrome: Proceedings From the Pediatric Acute Lung Injury Consensus Conference

Tamburro, Robert F. MD1; Kneyber, Martin C. J. MD, PhD, FCCM2,3

Pediatric Critical Care Medicine: June 2015 - Volume 16 - Issue 5_suppl - p S61–S72
doi: 10.1097/PCC.0000000000000434
PARDS Supplement
Free

Objective: To provide an overview of the current literature on pulmonary-specific therapeutic approaches to pediatric acute respiratory distress syndrome to determine recommendations for clinical practice and/or future research.

Data Sources: PubMed, EMBASE, CINAHL, SCOPUS, and the Cochrane Library were searched from inception until January 2013 using the following keywords in various combinations: ARDS, treatment, nitric oxide, heliox, steroids, surfactant, etanercept, prostaglandin therapy, inhaled beta adrenergic receptor agonists, N-acetylcysteine, ipratroprium bromide, dornase, plasminogen activators, fibrinolytics or other anticoagulants, and children. No language restrictions were applied. References from identified articles were searched for additional publications.

Study Selection: All clinical studies pertaining to pulmonary-specific therapeutic approaches to pediatric acute respiratory distress syndrome were reviewed. If clinical pediatric data were sparse or unavailable, the findings from studies of adult acute respiratory distress syndrome and animal models that might be relevant to pediatric acute respiratory distress syndrome were examined.

Data Extraction: All relevant studies were reviewed and pertinent data abstracted.

Data Synthesis: Over the course of three international meetings, the pertinent findings of the literature review were discussed by a panel of 24 experts in the field representing 21 academic institutions and 8 countries. Recommendations developed and the supporting literature were distributed to all panel members without a conflict of interest and were scored by using the Research ANd Development/University of California, Los Angeles Appropriateness method. The modified Delphi approach was used as the methodology to achieve consensus among the panel.

Conclusions: Overall, the routine use of surfactant, inhaled nitric oxide, glucocorticoids, prone positioning, endotracheal suctioning, and chest physiotherapy cannot be recommended. Inhaled nitric oxide should only be used for patients with documented pulmonary hypertension and/or right ventricular failure. Prone positioning may be considered in patients with severe pediatric acute respiratory distress syndrome. Future studies are definitely warranted to establish the role, if any, of these ancillary treatment modalities in pediatric acute respiratory distress syndrome.

1Department of Pediatrics and Public Health Sciences, Division of Critical Care Medicine, Pennsylvania State University College of Medicine, Penn State Hershey Children’s Hospital, Hershey, PA.

2Department of Paediatrics, Division of Paediatric Intensive Care, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

3Critical care, Anaesthesiology, Perioperative Medicine & Emergency Medicine (CAPE), University of Groningen, Groningen, The Netherlands.

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.

For information regarding this article, E-mail: rtamburro@psu.edu

Acute respiratory distress syndrome (ARDS) is a devastating disease primarily characterized by a disruption of the alveolar-capillary membrane resulting in pulmonary edema, influx of immune cells (e.g., polymorphonuclear neutrophils) and protein-rich fluid, massive inflammation, activation of coagulation pathways, and dysfunction of surfactant (1). Clinically, ARDS is characterized by hypoxemia, ventilation-perfusion mismatch, intrapulmonary shunting, increased dead-space, and decreased lung compliance. These pathophysiologic and clinical features have triggered many investigators to study numerous pharmacological approaches for the prevention and treatment of ARDS in critically ill adults (2). However, few of these approaches have been extensively explored in critically ill children secondary to a variety of reasons including the lower incidence and mortality rate in children compared with adults (3). Furthermore, pediatric ARDS (PARDS) covers a heterogeneity of underlying diseases that vary substantially between young infants and older children (4). This variability may affect clinical features and response to therapy, which must be considered when evaluating the efficacy of pharmacological interventions. Consequently, much of the routine treatment for PARDS is based on data from adults or anecdotal experiences from pediatric critical care physicians. The applicability of adult data to PARDS has been questioned (5). Many pulmonary-specific therapies including inhaled nitric oxide (iNO), surfactant, or steroids are implemented despite the lack of established scientific evidence in children (6, 7). This section provides an overview of the current literature on pulmonary-specific therapeutic approaches to PARDS to determine recommendations for clinical practice and/or future research. If clinical pediatric data are sparse or unavailable, the findings from studies of adult ARDS and animal models that might potentially be relevant to PARDS are examined.

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METHODS

PubMed, EMBASE, CINAHL, SCOPUS, and the Cochrane Library were searched from inception until January 2013 using the following keywords in various combinations: ARDS, treatment, nitric oxide, heliox, steroids, surfactant, etanercept, prostaglandin therapy, inhaled beta adrenergic receptor agonists, N-acetylcysteine, ipratroprium bromide, dornase, plasminogen activators, fibrinolytics or other anticoagulants, and children. No language restrictions were applied. References from identified articles were searched for additional publications.

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Nitric Oxide

Nitric oxide (NO) is synthesized in the vascular endothelium by NO synthase. Its main effect is relaxation of the smooth muscle by increasing the intracellular cyclic guanosine monophosphate. Theoretically, iNO is an ideal pulmonary vasodilator because of its short and local action. Vasodilation mainly occurs in areas that are adequately ventilated causing blood to shunt away from poorly ventilated areas (8). Ventilation/perfusion mismatch is one of the hallmarks of ARDS (9). iNO may therefore be considered for use in ARDS to reduce ventilation/perfusion mismatch by reducing dead-space ventilation and, thereby, improve oxygenation. The clinical response to iNO has been reported in various (individual) case series, demonstrating a rapid improvement in oxygenation even with a concentration as low as 1 part per million (ppm) (10–13). Over the past 2 decades, three randomized controlled trials (RCTs) have been performed in children with ARDS (14–16). The first RCT was performed by Day et al (14), comparing the effects of 10 ppm iNO in 10 pediatric patients with acute bilateral lung disease requiring a positive end-expiratory pressure (PEEP) greater than 6 cm H2O and an FIO2 greater than 0.5 for more than 12 hours with 12 control patients. The main finding of this study was an immediate but unsustained improvement in pulmonary vascular resistance and systemic oxygenation defined by the oxygen index (OI). No beneficial effect on mortality was observed although their study was not designed to assess mortality. Following this study, Dobyns et al (15) performed a prospective multicenter placebo-controlled RCT of 108 children more than 1 month old with severe acute hypoxemic respiratory failure (i.e., OI > 15) randomized to iNO 10 ppm (n = 53 children) or control (n = 55). Patients with a congenital heart defect or after cardiac surgery were not included in this study. Patients were stratified into five groups, including pneumonia with or without concomitant chronic lung disease, sepsis, immunodeficiency, and miscellaneous (e.g., trauma or pulmonary hemorrhage). Notably, nearly half of the patients suffered from underlying diseases (i.e., chronic lung disease or immunodeficiency). Although the RCT confirmed the positive effect of iNO on oxygenation, nearly half of the patients managed with iNO were identified as failures because there was no improvement in the OI. Furthermore, mortality was comparable between the two groups although the trial was also not designed to assess this issue. Subgroup analysis revealed a possible beneficial effect of iNO in immunocompromised patients and those with severe hypoxemia (i.e., OI > 25) although the small sample size in these analyses precludes the robustness of these findings. The third RCT was performed by Ibrahim and El-Mohamady (16) who randomized 32 children 2 months to 10 years old with severe ARDS (PaO2/FIO2 ≤ 200 mm Hg, positive inspiratory pressure ≥ 30 cm H2O, and an FIO2 ≥ 0.5) to one of three groups: 1) 24 hours of iNO at 5 ppm in the prone position, 2) 24 hours of iNO at 5 ppm in the supine position, or 3) no iNO in the prone position. In line with the two other studies, these investigators observed a significant improvement in oxygenation but not in mortality. Based on these three trials, data suggest that although iNO improves oxygenation in PARDS, it does not positively affect patient outcomes. This conclusion is strengthened by the outcome of a recent Cochrane analysis of 604 children and adults with ARDS (17). Oxygenation was improved in the iNO group evidenced by a significantly higher PaO2/FIO2 ratio (mean difference, 15.91 mm Hg; 95% CI, 8.25–23.56). However, there was no documented improvement in mortality (odds ratio [OR], 1.06; 95% CI, 0.93–1.22), duration of mechanical ventilation, ventilator-free days, or length of ICU or hospital stay in the iNO cohort (17). Additionally, there appeared to be an increased incidence of renal impairment in patients managed with iNO (OR, 1.59; 95% CI, 1.17–2.16). Based on these data, the routine use of iNO for PARDS cannot be recommended. In concurrence with a previous European Society for Pediatric and Neonatal Intensive Care consensus statement, its use should only be considered in patients with documented pulmonary hypertension or severe right ventricular dysfunction (18). In patients with intractable hypoxemia (e.g., severe PARDS according to the Berlin definition) (19, 20), iNO may be considered as rescue therapy from, or as a bridge to, extracorporeal life support. When used, assessment of benefit must be undertaken promptly and serially to minimize toxicity and limit serious adverse events. In addition, its use should be appropriately weaned and discontinued as soon as possible if a beneficial effect in these patients cannot be achieved. Given the paucity in data, future studies should be undertaken to identify the role of iNO, if any, in severe PARDS (Table 1).

TABLE 1

TABLE 1

Recommendation:

4.1.1 iNO is not recommended for routine use in PARDS. However, its use may be considered in patients with documented pulmonary hypertension or severe right ventricular dysfunction. In addition, it may be considered in severe cases of PARDS as a rescue from or bridge to extracorporeal life support. When used, assessment of benefit must be undertaken promptly and serially to minimize toxicity and to eliminate continued use without established effect. Finally, future study is needed to better define its role, if any, in the treatment of PARDS. Strong agreement

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Exogenous Surfactant

Given the pathophysiologic similarities with infantile respiratory distress syndrome, and fueled by the success of surfactant replacement in that population, much interest has been generated in using surfactant replacement therapy in the non-neonatal PARDS population (21–31). Additionally, a host of animal studies, uncontrolled case reports, and case series have suggested a potential benefit to exogenous surfactant replacement therapy in PARDS. Despite these encouraging findings, clinical trials of exogenous surfactant outside of the neonatal population have provided mixed results at best.

In 1996, Willson et al (32) conducted an open-label uncontrolled observational trial of calf lung surfactant extract (calfactant) in acute hypoxemic respiratory failure in 29 children from six PICUs. In that trial, acute hypoxemic respiratory failure was defined as the need for ventilatory support, radiographic evidence of bilateral infiltrates, and an OI greater than or equal to 7. Surfactant therapy resulted in an immediate improvement in oxygenation that afforded weaning of ventilatory support in 24 of the 29 patients (83%). Although three patients developed air leaks associated with surfactant use, overall mortality was only 14% for the cohort which compared quite favorably with survival estimates for this patient population at that time.

Subsequently, Luchetti et al (33, 34) conducted two small trials of porcine surfactant (curosurf) in infants with severe bronchiolitis. In the first trial, 20 children requiring positive pressure ventilation were randomized to receive mechanical ventilation with or without porcine surfactant (10 in each arm) (33). Although there were no deaths in the trial, surfactant use was associated with improved oxygenation, decreased inspiratory pressures, and shorter ventilation courses and PICU stays. The second trial, which was multicenter, included 40 patients (20 in each arm) with respiratory failure secondary to a respiratory syncytial virus (RSV) infection (34). In that trial, intratracheal porcine surfactant therapy was again associated with improved oxygenation, increased compliance, shorter duration of ventilation, and decreased PICU length of stay. In addition, earlier treatment (within 24 hr of admission) appeared to be associated with a more robust effect. The surfactant appeared to be well tolerated, and there were no deaths in either arm of the trial.

During the time of these trials, Willson et al (35) conducted a prospective randomized controlled unmasked trial of intratracheal calfactant instillation in pediatric acute hypoxemic respiratory failure. Using the same treatment protocol as in their uncontrolled trial, surfactant use was again associated with improved oxygenation as well as decreased length of ventilation time and shorter PICU stays. There was no difference in mortality between the two treatment groups; however, overall mortality was only 12%. A subsequent multicenter randomized open-label German study compared bovine-based, intratracheally instilled surfactant with a standardized treatment in 35 children (20 surfactant vs 15 controls) with severe ARDS (PaO2/FIO2 < 100 mm Hg) (36). Surfactant use was associated with improved oxygenation 2 hours after therapy; however, the difference in oxygenation was only maintained at 48 hours for the group that started with a PaO2/FIO2 ratio greater than 65 mm Hg and those without pneumonia. There was a trend toward lower mortality (44% vs 60%) and a lesser need for rescue therapies in the surfactant group, but neither of these differences attained statistical significance.

The findings of these multiple smaller studies provided the rationale for a multicenter randomized placebo-controlled masked trial of calf surfactant (calfactant) in 153 infants, children, and adolescents with respiratory failure from acute lung injury (37). Among the patients treated with surfactant, oxygenation improved significantly more than among controls as had been demonstrated in the previous pediatric surfactant trials. Despite this improved oxygenation, there was no difference in the ventilator-free days between the two groups, the primary outcome of the study. However, in this trial, which is the largest non-neonatal pediatric surfactant trial to date, mortality was significantly reduced in the surfactant cohort (placebo 27 of 75 [36%] vs surfactant 15 of 77 [19%]; OR for survival, 2.32; 95% CI, 1.15–4.85). Unfortunately, there was an unequal distribution of immunocompromised patients, and controlling for an immunocompromised state in multifactorial analysis rendered no difference in mortality between the two treatment groups (OR for survival, 2.11; 95% CI, 0.93–4.79).

Although the results of this trial were confounded by the unequal distribution of the immunocompromised patients, the findings provided support for further study, the Calfactant in Acute Respiratory Distress Syndrome trial. This large international multicenter placebo-controlled trial of calfactant was conducted with both an adult and pediatric arm. The trial used a novel form of calfactant, pneumosurf, which was twice as concentrated as traditional calfactant. Also, the trial was limited to direct lung injury defined as injury originating on the alveolar side of the alveolar-capillary membrane (e.g., pneumonia and aspiration). Unfortunately, both arms of the trial were closed prematurely during interim analysis secondary to futility. The results of the pediatric trial were recently published (38). In addition to having no effect on mortality, calfactant therapy was found to have no effect on oxygenation. The lack of improvement in oxygenation was most unexpected as calfactant had consistently improved oxygenation in the previous trials, and this trial was limited to those presumably most likely to benefit from this therapy. The investigators offered alterations in the treatment protocol including the use of a more concentrated form of surfactant, the lack of a recruitment maneuver, and the use of two rather than four installation positions as potential explanations for the lack of effect on oxygenation.

Most recently, a third multinational prospective blinded randomized controlled phase II trial of intratracheal instillation used a synthetic formulation of surfactant (lucinactant) among infants less than 2 years old (39). In that trial, the use of lucinactant appeared to improve oxygenation but no other markers of outcome including mortality, length of ventilation, or length of stay.

Thus, given the mixed results of exogenous surfactant administration over many years of well-conducted studies, this therapy cannot be recommended as routine therapy for the treatment of PARDS (Table 1). However, given its record of improved oxygenation across most studies, and its impact on more long-standing clinical outcomes in some, further study appears warranted. That study must be focused on identifying the subset of patients who are most likely to benefit from this therapy. In addition, study should be concentrated on identifying the optimal preparation and mode of delivery of exogenous surfactant. It is hoped that with such study, the true role of surfactant therapy in treating PARDS, if any, can be established.

Recommendation:

4.2.1 At this time, surfactant therapy cannot be recommended as routine therapy in PARDS. Further study should focus on specific patient populations that may be likely to benefit and specific dosing and delivery regimens. Strong agreement

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Prone Positioning

Prone positioning has been offered as a mode to improve oxygenation and outcomes from acute hypoxemic respiratory failure for over 35 years (40, 41). Several mechanisms for its beneficial effect have been offered. However, the data to support its benefit have not been consistent, and thus, its routine use in PARDS cannot be recommended.

Nearly 2 decades ago, the potential benefit of proning in PARDS was described in a small case series of seven children (42). In that report, placing the children in the prone position for 30 minutes was associated with improved oxygenation and oxygen delivery, but not with any significant effect on heart rate, mean arterial blood pressure, or cardiac output. Shortly thereafter, Curley (43) reviewed the prone positioning literature (adult and pediatric) and identified 20 clinical studies assessing nearly 300 patients. That review suggested that improved oxygenation was common, being reported in 69% of the cases, and that serious adverse events were rare with this therapy. Consequently, further study among children appeared warranted.

In 2000, Curley et al (44) assessed the physiologic changes and safety of placing children with acute lung injury requiring mechanical ventilation in the prone position for 20 hours. In this single-center prospective study, 25 consecutive patients with bilateral lung disease and a PaO2/FIO2 ratio less than or equal to 300 mm Hg underwent 214 positioning cycles without any critical incident or persistent decrease in oxygenation. Furthermore, 84% of patients experienced improved oxygenation with prone positioning. Similar results were obtained in a single-center prospective randomized controlled crossover trial (45). In that trial, 10 children with severe acute hypoxemic respiratory failure (mean PaO2/FIO2 ratio of 97 mm Hg) were randomized to receive either prone positioning for 12 hours followed by 12 hours of supine placement or supine positioning for 12 hours followed by prone positioning for 12 hours. Prone positioning was associated with a significant improvement in oxygenation within 2 hours of placement into that position in 9 of the 10 cases. No serious adverse effects were attributed to the prone positioning. That same year, Bruno and a group (46) from Brazil published the results of a single-center nonrandomized prospective trial of prone positioning in mechanically ventilated children with significant lung injury characterized by a need for a peak inspiratory pressure greater than or equal to 30 cm H2O, an FIO2 greater than or equal to 0.5, and a PaO2/FIO2 ratio less than or equal to 200 mm Hg. Each patient served as their own control. Eighteen children with a mean age of 11.5 months and an initial mean PaO2/FIO2 ratio of 96 mm Hg were studied. Approximately a quarter of these children (27.7%) improved their PaO2/FIO2 ratio by 20 mm Hg after 1 hour of proning. In 2002, Casado-Flores et al (47) reported a prospective single-center study in which they rotated 23 PARDS patients from the supine to the prone position or vice versa every 8 hours. In their report, and quite similar to that reported in the study by Curley, 18 of the 23 patients (78%) improved their PaO2/FIO2 ratio by 15% or more when placed in the prone position. Although not statistically significant in that small trial, only 39% of these responders died compared with 80% of the children who had no benefit with prone positioning. In 2003, Relvas et al (48) retrospectively reviewed 40 pediatric patients with ARDS who were placed in the prone position for management of their lung disease. They demonstrated an overall improvement in oxygenation with prone positioning that was more pronounced when pronation was used for longer periods (18–24 hr vs 6–10 hr). The mean OI decreased from a baseline value of 24.8 to a mean of 16.7 after a brief period of prone positioning (6–10 hr) and to 11.4 after a prolonged period of prone positioning (18–24 hr). Concurrently, the group from Spain reported on the use of prone positioning in 18 children with acute hypoxemic respiratory failure unresponsive to conventional therapy (49). In their report, prone positioning was associated with a 33% increase in the mean PaO2/FIO2 ratio and a 24% decrease in the mean OI. Overall, 61% of the children demonstrated a 20% or greater increase in their PaO2/FIO2 ratio in that study.

With improved oxygenation being a consistent finding across multiple relatively small studies, and a highly favorable safety profile, Curley et al (50) conducted a relatively large multicenter RCT of 102 intubated and mechanically ventilated pediatric patients assessing the impact of prone positioning within 48 hours of satisfying the criteria for acute lung injury (PaO2/FIO2 ratio ≤ 300 mm Hg). Patients were randomized to either supine or prone positioning. Patients randomized to the prone positioning arm were placed prone within 4 hours of randomization and remained so for 20 hours each day. Ninety percent of the patients randomized to the prone arm were considered responders (defined a priori as a ≥ 20 mm Hg increase in the PaO2/FIO2 ratio or a ≥ 10% decrease in the OI after a supine to prone turn). However, the study was halted at the planned interim analysis on the basis of futility. Although the process of proning again appeared to be safe (51), no differences could be detected between the two treatment arms in terms of ventilator-free days (the primary outcome), all-cause mortality, the time to recovery from lung injury, the number of organ-failure-free days, cognitive function, or overall health. In light of the findings of this very well-designed and conducted trial (52), the routine use of prone positioning cannot be recommended for the treatment of PARDS.

However, that trial focused on acute lung injury and not specifically on ARDS which reflects a more significant impairment of oxygenation (PaO2/FIO2 ≤ 200 mm Hg). Furthermore, since the publication of that report, data have surfaced that suggest prone positioning might be helpful for the most severely hypoxic patients (53, 54). In 2008, Sud et al (53) published a meta-analysis on the impact of prone positioning among patients requiring mechanical ventilation for acute hypoxemic respiratory failure. Thirteen studies were assessed (1,559 patients; adult and pediatric) including 10 studies that assessed mortality as an outcome. Although prone positioning was again found to improve oxygenation, and perhaps decrease the incidence of ventilator-associated pneumonia, there was no demonstrable effect on mortality (risk ratio, 0.96; 95% CI, 0.84–1.09; p = 0.52). However, given its sustained improvement on oxygenation, the authors suggested that it should be considered in those patients with very severe hypoxemia. Following up on that work, this same group published a meta-analysis of 10 trials consisting of 1,867 participants (adults and children) to assess the impact of prone positioning on mortality among patients with severe acute hypoxemic respiratory failure defined as a PaO2/FIO2 less than 100 mm Hg (54). They reported that prone positioning was associated with decreased mortality in patients with a PaO2/FIO2 less than 100 mm Hg (risk ratio, 0.84; 95% CI, 0.74–0.96; p = 0.01; seven trials, n = 555) but not in patients with a PaO2/FIO2 ratio greater than or equal to 100 mm Hg (risk ratio, 1.07; 95% CI, 0.93–1.22; p = 0.36; seven trials, n = 1,169). They concluded that prone positioning should not be performed routinely in all patients with acute hypoxemic respiratory failure but that it should be considered for patients with severe hypoxemia.

In light of the two meta-analyses suggesting a benefit to prone positioning among the most severely hypoxemic patients, a well-conceived RCT of prone positioning in adults with severe ARDS was recently conducted by the Proning Severe ARDS Patients study group (55). They randomized 466 adults with severe ARDS defined as a PaO2/FIO2 ratio less than 150 mm Hg, an FIO2 greater than or equal to 0.60, a PEEP greater than or equal to 5 cm H2O, and a tidal volume that approximated 6 mL/kg to either supine or prone positioning. Patients randomized to the prone arm remained prone for at least 16 hours a day, and this treatment approach was used for up to 28 days. Patients randomized to the prone arm of the trial (n = 237) experienced a 50% reduction in all-cause mortality at 28 days (the primary outcome of the trial) compared with those who remained in the supine position (16.0% vs 32.8%; hazard ratio, 0.39; 95% CI, 0.25–0.63; p < 0.001). Although this trial focused exclusively on adults, and despite recognized differences between adults and children in respiratory mechanics, the magnitude of the difference in mortality in this well-designed and conducted trial suggests that consideration should be given to the use of this therapy in children with severe hypoxemia. At a minimum, it is a call for further study among children with severe hypoxemic respiratory failure.

In sum, the use of prone positioning has been consistently associated with improved oxygenation in multiple studies among children with acute hypoxemic respiratory failure (Table 1). Additionally, although one report suggests that prone positioning may be associated with a cephalad movement of the endotracheal tube (56), this therapy has an established record of safety with serious adverse events rarely being reported. However, despite these encouraging findings, the implementation of this therapy has not been found to be associated with other clinical outcomes including mortality in studies of children with acute lung injury. The one well-designed RCT of prone positioning in children with acute lung injury was terminated secondary to futility. Consequently, the routine use of prone positioning as treatment for PARDS cannot be recommended. However, supported by the recent RCT of its use in adults with severe hypoxemia, prone positioning should be considered in children with PARDS characterized by severe hypoxemia. Further study is clearly indicated, and study of children with severe hypoxemia would appear to be a reasonable initial focus.

Recommendation:

4.3.1 Prone positioning cannot be recommended as routine therapy in PARDS. However, it should be considered an option in cases of severe PARDS. Further pediatric study is warranted, particular study stratifying on the basis of severity of lung injury. Weak agreement

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Endotracheal Suctioning

Clearly, maintaining a patent airway is essential to the safe care of any mechanically ventilated patient. Therefore, endotracheal suctioning is probably one of the most performed interventions in the ICU despite the fact that it is not based on sound scientific evidence (57). There is no reported RCT demonstrating a positive contribution of endotracheal suctioning to patient outcome. On the contrary, one group reported right upper lobe lung collapse in 24% of pediatric cardiac ICU patients who were managed with routine deep endotracheal suctioning using uncontrolled negative pressures (58). The incidence of lung collapse decreased to 7% when graduated suction catheters and suction vacuums less than 165 cm H2O were introduced. Consequently, the value of routine endotracheal suctioning in PARDS merits further study such that practice is evidence informed and not based solely on local belief and long-standing opinion (59, 60). In addition, the technique used to perform endotracheal suctioning also requires further study focusing on a comparison of open versus closed suctioning. Although no RCT evaluating the effect of closed versus open suctioning on patient outcome could be identified in any patient population (including PARDS patients), two observational studies have found that open endotracheal suctioning causes an immediate drop in dynamic compliance and expired tidal volume indicative of a loss of lung volume in a heterogeneous group of mechanically ventilated children (61, 62). Performing a recruitment maneuver after open endotracheal suctioning did not provide any benefit in these patients (63). This finding may be of particular interest and concern for PARDS patients, in whom there is an increased tendency for alveolar collapse. Furthermore, such repeated derecruitment and subsequent recruitment (when the patient is connected back to the ventilator) may exacerbate ventilator-induced lung injury (64, 65). One open randomized crossover trial of open versus closed suctioning of 14 patients found that disconnection from the ventilator resulted in the greatest loss of lung volume (66). Consequently, the authors suggested that closed in-line suctioning may be preferable avoiding this disconnection and the resultant alveolar derecruitment.

Given this paucity in data, the only recommendation that can be offered is adherence to the American Association of Respiratory Care clinical guidelines for endotracheal suctioning, of which some recommendations may especially apply to the PARDS patient. These guidelines recommend only to perform suctioning if secretions are present and to use shallow suctioning without disconnecting the patient from the ventilator. The routine instillation of isotonic saline prior to endotracheal suctioning is not recommended, given the absence of evidence of effect and possible harm (67). Nonetheless, it may be acknowledged that instillation of isotonic saline prior to endotracheal suctioning may be indicated at times for lavage to remove thick tenacious secretions. Future studies regarding the value of routine endotracheal suctioning in PARDS as well as the optimal technique are warranted.

Recommendations:

4.4.1 We recommend that maintaining a clear airway is essential to the PARDS patient. However, endotracheal suctioning must be performed with caution to minimize the risk of derecruitment. Strong agreement

4.4.2 There are insufficient data to support a recommendation on the use of either an open or closed suctioning system. However, in severe PARDS, consideration should be given to the technique of suctioning with careful attention to minimize the potential for derecruitment. Strong agreement

4.4.3 The routine instillation of isotonic saline prior to endotracheal suctioning is not recommended. However, the instillation of isotonic saline prior to endotracheal suctioning may be indicated at times for lavage to remove thick tenacious secretions. Strong agreement

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Chest Physiotherapy

The use of chest physiotherapy for airway clearance and sputum evacuation in mechanically ventilated children is highly controversial and cannot be considered standard of care (68). Furthermore, the efficacy of chest physiotherapy for PARDS has not been tested in a single RCT to date. In addition, there are no published case series or observational data to suggest a possible benefit in the PARDS patient. Therefore, while awaiting future studies, there are insufficient data to recommend chest physiotherapy as a standard of care in the PARDS patient. Similarly, there are no data to support the use of a cough assist device in this patient population.

Recommendation:

4.5.1 There are insufficient data to recommend chest physiotherapy as a standard of care in the PARDS patient. Strong agreement

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Corticosteroids

ARDS is characterized by an overwhelming inflammatory process (69). This has prompted interest in anti-inflammatory treatment, including the use of glucocorticoids. In a piglet model of one-lung ventilation, the use of prophylactic methylprednisolone prior to collapse of the lung was associated with reduced levels of inflammatory mediators in both the collapsed and ventilated lungs (70). This suggests that there may be an indication for glucocorticoids. However, the available pediatric data are limited to case series, including the use of methylprednisolone (initial loading dose 5 mg/kg, and subsequent maintenance therapy for 2 wk of 2 mg/kg every 6 hr) in a 12-month-old infant with late ARDS, and a case series of six children treated with high-dose steroids (71–74). To date, no RCTs have been performed investigating the efficacy of glucocorticoids in PARDS. Van Woensel and coworkers (75) studied the effects of dexamethasone in young children with moderate-to-severe RSV bronchiolitis, some of whom would certainly have met the criteria for PARDS. The primary endpoint for that study was the length of mechanical ventilation. After the third interim analysis, the RCT was stopped prematurely secondary to futility.

Given the lack of pediatric data, it can be safely concluded that the efficacy of glucocorticoids has been neither ascertained nor refuted. Consequently, the use of glucocorticoids as routine therapy for PARDS cannot be recommended. Unfortunately, studies performed in adults with ARDS also fail to provide a clear answer. In fact, two systematic reviews of published adult data reported conflicting results. In one analysis of nine randomized trials, no definitive benefit from corticosteroids could be established. In contrast, a subsequent analysis of five cohort studies and four RCTs suggested a beneficial effect of steroids on mortality and/or reduced ventilator dependency using prolonged low-dose steroid therapy (76, 77).

Nonetheless, glucocorticoid therapy is often used in daily pediatric critical care medicine (6, 7). This signifies that future studies are definitely needed to identify specific PARDS patient populations that might benefit from glucocorticoid therapy as well as the specific dosing and delivery regimens that need to be used. Additionally, study will need to identify potential complications (e.g., increased nosocomial infections) associated with this intervention.

Recommendation:

4.6.1 At this time, corticosteroids cannot be recommended as routine therapy in PARDS. Further study should focus on specific patient populations that are likely to benefit from corticosteroid therapy and specific dosing and delivery regimens. Strong agreement

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Other Ancillary Therapies

Inhaled prostaglandin I2, a natural pulmonary vasodilator known as epoprostenol or iloprost, may be considered as a therapeutic approach in a similar manner as iNO (78). Few pediatric data assessing prostaglandin I2 are available consisting only of a single-center observational study and one small RCT in children with acute lung injury (79, 80). Dahlem et al (80) observed a significant median improvement of 26% in the OI following nebulization of 30 ng/kg/min epoprostenol. To date, the effect of epoprostenol nebulization on patient outcome has not been explored any further. Additionally, inhaled β-adrenergic receptor agonists have not been studied in children; however, the current adult evidence discourages the use of β2-agonist among ARDS patients (81). Heliox is another potential therapy for PARDS as it has been found to attenuate the inflammatory effects of mechanical ventilation in an experimental setting (82, 83). However, it has not been studied in PARDS. N-Acetylcysteine is a potent antioxidant agent and may therefore be considered as a therapeutic option for PARDS. However, little pediatric data exist, and no significant positive effect could be demonstrated with its use in adult ARDS (84). Therefore, no recommendation for the use of IV or inhaled prostaglandin therapy, inhaled β-adrenergic receptor agonists, heliox, or N-acetylcysteine IV for antioxidant effects can be supported. Additionally, there also are no data to support the intratracheal use of N-acetylcysteine for mobilizing secretions. Similarly, there are no sufficient data to support a recommendation for the use of ipratroprium bromide, dornase alpha outside the cystic fibrosis population, plasminogen activators, fibrinolytics, or other anticoagulants. None of these ancillary therapies have been tested in RCTs.

The use of etanercept (Enbrel), a soluble tumor necrosis factor (TNF)-α-binding protein, is one pharmacologic therapy that merits consideration for the treatment of PARDS secondary to a unique condition that occurs in a selected population; that is, the idiopathic pneumonia syndrome following allogeneic hematopoietic stem cell transplant (HSCT). The finding of elevated TNF-α levels both in plasma and bronchoalveolar fluids of HSCT patients with the idiopathic pneumonia syndrome has stimulated interest in treating this condition with TNF-α inhibition. Multiple uncontrolled clinical case series, in both children and adults, have supported the use of etanercept for this purpose (85–88). Additionally, a retrospective analysis of the addition of etanercept to corticosteroid treatment for idiopathic pneumonia syndrome suggested improved outcomes including increased overall survival with the addition of etanercept (89). However, in that report, the two groups were treated in different time eras with the corticosteroid and etanercept group being treated in the more recent era. Consequently, the improved outcomes may have simply represented overall improvements in care over time and not the effect of etanercept. Most recently, a multicenter prospective phase II single-arm open-label trial assessed the value of etanercept in 28 children with idiopathic pneumonia syndrome following stem cell transplant (90). In that trial, the combination of etanercept and corticosteroids was associated with unexpectedly high overall survival (89% at day 28 and 63% at 1 yr) when compared with survival rates in published studies. Response rates were highest if therapy was implemented prior to mechanical ventilation. Concurrently, a multicenter phase III double-blinded placebo-controlled trial of etanercept for the treatment of idiopathic pneumonia syndrome in adults was closed prematurely secondary to futility after only 34 of a proposed 120 patients were enrolled (91). Although no statistically significant improvement in survival was appreciated in this small sample size, the etanercept arm was associated with a 17% absolute increase in overall survival (50% vs 33%) and a nearly three-fold longer median survival (171 d [95% CI, 11–362] vs 64 d [95% CI, 26–209]). Clearly, further study of etanercept appears warranted for this specific etiology of PARDS in this high-risk patient population.

Recommendations:

4.7.1 No recommendation for the use of the following ancillary treatment is supported: helium-oxygen mixture, inhaled or IV prostaglandins therapy, plasminogen activators, fibrinolytics, or other anticoagulants, inhaled β-adrenergic receptor agonists or ipratropium, IV N-acetylcysteine for antioxidant effects or intratracheal N-acetylcysteine for mobilizing secretions, dornase alpha outside of the cystic fibrosis population, and a cough assist device. Strong agreement

4.7.2 No recommendation for the use of stem cell therapy can be supported. It must be considered experimental therapy at this point. Strong agreement

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CONCLUSIONS

Pharmacological treatment of PARDS remains challenging because the quantity of scientific evidence is disappointingly low. Although the possible beneficial effects of exogenous surfactant and iNO have been studied to a certain degree, there is no significant data on glucocorticoids or other ancillary treatment modalities. Unfortunately, with the exception of prone positioning, proposed nonpharmacological therapies are equally unfounded with little vigorous testing to support their use. Overall, the routine use of surfactant, iNO, glucocorticoids, prone positioning, endotracheal suctioning, and chest physiotherapy cannot be recommended. iNO should only be used for patients with documented pulmonary hypertension and/or right ventricular failure. Prone positioning may be considered in patients with severe PARDS. Future studies are definitely warranted to establish the role, if any, of these ancillary treatment modalities in PARDS.

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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, 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; acute respiratory distress syndrome; pulmonary therapies

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