EDITORIALS Pediatric High-Frequency Oscillation The End of the Road? High-frequency oscillation (HFO) is a ventilatory technique in which very small tidal volumes are delivered at high frequencies (3–15 Hz). It is believed to be ideal for lung protection in acute respiratory distress syndrome (ARDS) because high end-expiratory lung volume should minimize atelectrauma, and limiting endinspiratory lung stretch should concomitantly minimize volutrauma. Despite an early metaanalysis of patients with ARDS that suggested reduced mortality with HFO (1), two recent large randomized controlled trials (RCTs) in adults demonstrated that it was no better than a lung protective strategy delivered by conventional mechanical ventilation (2, 3). For the postneonatal pediatric ARDS population, only two RCTs enrolling 86 patients have investigated HFO (4, 5), likely because of the low incidence of this condition in children compared with adults and the consequent difficulty in recruiting enough patients. To address this shortcoming in the literature, in this issue of the Journal, Bateman and colleagues (pp. 495–503) (6) took advantage of a cluster RCT (7) of sedation strategies that enrolled 2,449 patients in 31 U.S. pediatric intensive care units to conduct a secondary analysis focused on 210 patients who received early HFO for moderate or severe ARDS. The investigators used propensity score adjustment to account for treatment indication bias, according to which severely hypoxemic patients are more likely to receive early HFO compared with the alternative strategy of initial conventional ventilation, with HFO added later in a small proportion of patients. The main finding was that HFO started within the first 2 days of intubation in patients with moderate to severe hypoxemia had no association with 90-day in-hospital mortality compared with patients who received only conventional ventilation or conventional ventilation followed by HFO. In a sensitivity analysis that derived an alternative propensity score model using all patients in the trial, regardless of severity of hypoxemia, HFO was associated with higher risk for mortality. As well, both models found that HFO was associated with greater use of neuromuscular blockade and opioids, and a higher risk of being discharged home with cognitive and functional impairment. Similarly, HFO was associated with longer ventilatory duration to day 28, although the absolute difference between groups is not directly interpretable because patients who died were assigned a value of 28 days. All outcomes were similar among centers, whether they used HFO in a high or low proportion of patients. Several theories have been postulated to explain the accumulating evidence of lack of benefit of HFO on clinical outcomes, including hemodynamic compromise at high mean airway pressures (8), suboptimal HFO strategies (9), and the effectiveness of nonHFO lung protection strategies (10–12). Examples of the latter point include RCTs showing that neuromuscular blockade with cisatracurium for the first 48 hours of ventilation (11), or ventilation in the prone position (12), decrease mortality for patients with moderate to severe ARDS, albeit not in children (13).
In this observational study design, the most common method of handling confounding resulting from unequal distribution of prognostically important variables between groups of patients treated (vs. not) with early HFO would have been multivariable regression. As reviewed previously (14), the propensity score allows for explicit assessment of the distribution of important confounders between groups of patients and identification of nonoverlap of important confounders, such as severity of hypoxemia in this case. The score is defined as the probability of being exposed to early HFO, conditional on covariates entered into a logistic regression model with HFO as the dependent variable. A strength of Bateman and colleagues’ analysis (6) was the inclusion of hypoxemia in the propensity model, as this factor is associated with both HFO use and outcome in pediatric ARDS (15). Once the score has been calculated for each patient, several methods are available to analyze the effect of HFO, including comparing outcomes between HFO-treated patients matched to untreated ones with the same score. Bateman and colleagues implemented another common method: they created five equally populated strata, using quintiles of the propensity score. This method is estimated to eliminate 90% of the bias resulting from measured confounders (16). Within strata, they compared outcomes of early HFO-treated patients with those of HFO-untreated patients, but because very few patients received HFO in the lower quintiles, they considered only the two quintiles with the highest scores. The success of the propensity score model can be judged by the similarity, within strata, of patients who received early HFO compared with those who did not. The degree of similarity is best judged by standardized differences, which, unlike P values, are independent of sample size (17). Of concern in this study is that the dramatically worse oxygenation index and organ dysfunction in patients receiving early HFO, expected clinically and evident in their Table 1 before generation of the propensity score, appeared to persist afterward. Subsequent results showed that within propensity score quintiles, early HFO patients were more severely hypoxemic or more likely to have cardiovascular failure, depending on the propensity model used. Additional techniques to adjust for this residual confounding, including multivariable regression or propensity score matching, would have been extremely helpful. Even with these supplementary analyses, however, readers may still be concerned that other unmeasured factors related to patients’ clinical status or trajectory before starting HFO, or related to physicians’ practice patterns, may have explained decisions to use HFO early. If so, then even with well-balanced groups created with a propensity score, patients receiving early HFO may simply have been initially sicker, which would explain their worse outcomes. What are the clinical implications of this study? First, given the paucity of RCTs of HFO in children and the results of the current study, as well as another multicenter cohort study (18) that found
Am J Respir Crit Care Med Vol 193, Iss 5, pp 471–485, Mar 1, 2016 Internet address: www.atsjournals.org
Editorials
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EDITORIALS harm from HFO, there is little evidence to support HFO as initial therapy in pediatric ARDS. Second, despite this conclusion, clinicians need not rush to abandon HFO; indeed, the control group in the study by Bateman and colleagues included patients who received HFO after day 1 (10% and 18% of control group patients in the highest two quintiles analyzed). This suggests the possibility of HFO as rescue therapy, similar to the control group protocol tested in a recent RCT in adults (2), in which 11% of control group patients received HFO for specific rescue indications. Future studies could investigate the use of HFO as a rescue therapy, or the potential for HFO to improve clinically important outcomes in subgroups. These could be defined by variables such as baseline hypoxemia, which appears to predict benefit in trials of high positive end-expiratory pressure (19), or immediate oxygenation response to HFO, an approach suggested for high positive end-expiratory pressure and recruitment maneuvers (20). Finally, clinicians who remain enthusiastic about HFO will rightly point out that no analysis of observational studies can account for unmeasured confounding, making the findings of Bateman and colleagues less compelling than those from an RCT. In summary, although not conclusive, the results of Bateman and colleagues suggest that routine early use of HFO in children with respiratory failure should be discouraged, other than in the context of RCTs. n
Author disclosures are available with the text of this article at www.atsjournals.org. Neill K. J. Adhikari, M.D., M.Sc. Department of Critical Care Medicine Sunnybrook Health Sciences Centre Toronto, Canada and Interdepartmental Division of Critical Care University of Toronto Toronto, Canada Arthur S. Slutsky, M.A.Sc., M.D. Keenan Research Centre for Biomedical Science Li Ka Shing Knowledge Institute of St. Michael’s Hospital Toronto, Canada and Interdepartmental Division of Critical Care University of Toronto Toronto, Canada
References 1. Sud S, Sud M, Friedrich JO, Meade MO, Ferguson ND, Wunsch H, Adhikari NK. High frequency oscillation in patients with acute lung injury and acute respiratory distress syndrome (ARDS): systematic review and meta-analysis. BMJ 2010;340:c2327. 2. Ferguson ND, Cook DJ, Guyatt GH, Mehta S, Hand L, Austin P, Zhou Q, Matte A, Walter SD, Lamontagne F, et al.; OSCILLATE Trial Investigators; Canadian Critical Care Trials Group. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med 2013;368:795–805. 3. Young D, Lamb SE, Shah S, MacKenzie I, Tunnicliffe W, Lall R, Rowan K, Cuthbertson BH; OSCAR Study Group. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med 2013;368: 806–813. 4. Samransamruajkit R, Prapphal N, Deelodegenavong J, Poovorawan Y. Plasma soluble intercellular adhesion molecule-1 (sICAM-1) in
472
pediatric ARDS during high frequency oscillatory ventilation: a predictor of mortality. Asian Pac J Allergy Immunol 2005;23:181–188. 5. Arnold JH, Hanson JH, Toro-Figuero LO, Gutierrez ´ J, Berens RJ, Anglin DL. Prospective, randomized comparison of high-frequency oscillatory ventilation and conventional mechanical ventilation in pediatric respiratory failure. Crit Care Med 1994;22:1530–1539. 6. Bateman ST, Borasino S, Asaro LA, Cheifetz IM, Diane S, Wypij D, Curley MA; RESTORE Study Investigators. Early high-frequency oscillatory ventilation in pediatric acute respiratory failure: a propensity score analysis. Am J Respir Crit Care Med 2016;193:495–503. 7. Curley MA, Wypij D, Watson RS, Grant MJ, Asaro LA, Cheifetz IM, Dodson BL, Franck LS, Gedeit RG, Angus DC, et al.; RESTORE Study Investigators and the Pediatric Acute Lung Injury and Sepsis Investigators Network. Protocolized sedation vs usual care in pediatric patients mechanically ventilated for acute respiratory failure: a randomized clinical trial. JAMA 2015;313:379–389. 8. Guervilly C, Forel JM, Hraiech S, Demory D, Allardet-Servent J, Adda M, Barreau-Baumstark K, Castanier M, Papazian L, Roch A. Right ventricular function during high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome. Crit Care Med 2012;40:1539–1545. 9. Kneyber MC, van Heerde M, Markhorst DG. Reflections on pediatric high-frequency oscillatory ventilation from a physiologic perspective. Respir Care 2012;57:1496–1504. 10. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301–1308. 11. Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, et al.; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:1107–1116. 12. Sud S, Friedrich JO, Adhikari NK, Taccone P, Mancebo J, Polli F, Latini R, Pesenti A, Curley MA, Fernandez R, et al. Effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: a systematic review and meta-analysis. CMAJ 2014;186:E381–E390. 13. Curley MA, Hibberd PL, Fineman LD, Wypij D, Shih MC, Thompson JE, Grant MJ, Barr FE, Cvijanovich NZ, Sorce L, et al. Effect of prone positioning on clinical outcomes in children with acute lung injury: a randomized controlled trial. JAMA 2005;294:229–237. 14. Chevret S. Propensity-matching analysis is not straightforward. Am J Respir Crit Care Med 2014;190:362–363. 15. Erickson S, Schibler A, Numa A, Nuthall G, Yung M, Pascoe E, Wilkins B; Paediatric Study Group; Australian and New Zealand Intensive Care Society. Acute lung injury in pediatric intensive care in Australia and New Zealand: a prospective, multicenter, observational study. Pediatr Crit Care Med 2007;8:317–323. 16. Rosenbaum PR, Rubin DB. Reducing bias in observational studies using subclassification on the propensity score. J Am Stat Assoc 1984;79:516–524. 17. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011;46:399–424. 18. Gupta P, Green JW, Tang X, Gall CM, Gossett JM, Rice TB, Kacmarek RM, Wetzel RC. Comparison of high-frequency oscillatory ventilation and conventional mechanical ventilation in pediatric respiratory failure. JAMA Pediatr 2014;168:243–249. 19. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, Slutsky AS, Pullenayegum E, Zhou Q, Cook D, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA 2010;303:865–873. 20. Goligher EC, Kavanagh BP, Rubenfeld GD, Adhikari NK, Pinto R, Fan E, Brochard LJ, Granton JT, Mercat A, Marie Richard JC, et al. Oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome: a secondary analysis of the LOVS and ExPress trials. Am J Respir Crit Care Med 2014;190:70–76.
Copyright © 2016 by the American Thoracic Society
American Journal of Respiratory and Critical Care Medicine Volume 193 Number 5 | March 1 2016
In this observational study design, the most common method of handling confounding resulting from unequal distribution of prognostically important variables between groups of patients treated (vs. not) with early HFO would have been multivariable regression. As reviewed previously (14), the propensity score allows for explicit assessment of the distribution of important confounders between groups of patients and identification of nonoverlap of important confounders, such as severity of hypoxemia in this case. The score is defined as the probability of being exposed to early HFO, conditional on covariates entered into a logistic regression model with HFO as the dependent variable. A strength of Bateman and colleagues’ analysis (6) was the inclusion of hypoxemia in the propensity model, as this factor is associated with both HFO use and outcome in pediatric ARDS (15). Once the score has been calculated for each patient, several methods are available to analyze the effect of HFO, including comparing outcomes between HFO-treated patients matched to untreated ones with the same score. Bateman and colleagues implemented another common method: they created five equally populated strata, using quintiles of the propensity score. This method is estimated to eliminate 90% of the bias resulting from measured confounders (16). Within strata, they compared outcomes of early HFO-treated patients with those of HFO-untreated patients, but because very few patients received HFO in the lower quintiles, they considered only the two quintiles with the highest scores. The success of the propensity score model can be judged by the similarity, within strata, of patients who received early HFO compared with those who did not. The degree of similarity is best judged by standardized differences, which, unlike P values, are independent of sample size (17). Of concern in this study is that the dramatically worse oxygenation index and organ dysfunction in patients receiving early HFO, expected clinically and evident in their Table 1 before generation of the propensity score, appeared to persist afterward. Subsequent results showed that within propensity score quintiles, early HFO patients were more severely hypoxemic or more likely to have cardiovascular failure, depending on the propensity model used. Additional techniques to adjust for this residual confounding, including multivariable regression or propensity score matching, would have been extremely helpful. Even with these supplementary analyses, however, readers may still be concerned that other unmeasured factors related to patients’ clinical status or trajectory before starting HFO, or related to physicians’ practice patterns, may have explained decisions to use HFO early. If so, then even with well-balanced groups created with a propensity score, patients receiving early HFO may simply have been initially sicker, which would explain their worse outcomes. What are the clinical implications of this study? First, given the paucity of RCTs of HFO in children and the results of the current study, as well as another multicenter cohort study (18) that found
Am J Respir Crit Care Med Vol 193, Iss 5, pp 471–485, Mar 1, 2016 Internet address: www.atsjournals.org
Editorials
471
EDITORIALS harm from HFO, there is little evidence to support HFO as initial therapy in pediatric ARDS. Second, despite this conclusion, clinicians need not rush to abandon HFO; indeed, the control group in the study by Bateman and colleagues included patients who received HFO after day 1 (10% and 18% of control group patients in the highest two quintiles analyzed). This suggests the possibility of HFO as rescue therapy, similar to the control group protocol tested in a recent RCT in adults (2), in which 11% of control group patients received HFO for specific rescue indications. Future studies could investigate the use of HFO as a rescue therapy, or the potential for HFO to improve clinically important outcomes in subgroups. These could be defined by variables such as baseline hypoxemia, which appears to predict benefit in trials of high positive end-expiratory pressure (19), or immediate oxygenation response to HFO, an approach suggested for high positive end-expiratory pressure and recruitment maneuvers (20). Finally, clinicians who remain enthusiastic about HFO will rightly point out that no analysis of observational studies can account for unmeasured confounding, making the findings of Bateman and colleagues less compelling than those from an RCT. In summary, although not conclusive, the results of Bateman and colleagues suggest that routine early use of HFO in children with respiratory failure should be discouraged, other than in the context of RCTs. n
Author disclosures are available with the text of this article at www.atsjournals.org. Neill K. J. Adhikari, M.D., M.Sc. Department of Critical Care Medicine Sunnybrook Health Sciences Centre Toronto, Canada and Interdepartmental Division of Critical Care University of Toronto Toronto, Canada Arthur S. Slutsky, M.A.Sc., M.D. Keenan Research Centre for Biomedical Science Li Ka Shing Knowledge Institute of St. Michael’s Hospital Toronto, Canada and Interdepartmental Division of Critical Care University of Toronto Toronto, Canada
References 1. Sud S, Sud M, Friedrich JO, Meade MO, Ferguson ND, Wunsch H, Adhikari NK. High frequency oscillation in patients with acute lung injury and acute respiratory distress syndrome (ARDS): systematic review and meta-analysis. BMJ 2010;340:c2327. 2. Ferguson ND, Cook DJ, Guyatt GH, Mehta S, Hand L, Austin P, Zhou Q, Matte A, Walter SD, Lamontagne F, et al.; OSCILLATE Trial Investigators; Canadian Critical Care Trials Group. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med 2013;368:795–805. 3. Young D, Lamb SE, Shah S, MacKenzie I, Tunnicliffe W, Lall R, Rowan K, Cuthbertson BH; OSCAR Study Group. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med 2013;368: 806–813. 4. Samransamruajkit R, Prapphal N, Deelodegenavong J, Poovorawan Y. Plasma soluble intercellular adhesion molecule-1 (sICAM-1) in
472
pediatric ARDS during high frequency oscillatory ventilation: a predictor of mortality. Asian Pac J Allergy Immunol 2005;23:181–188. 5. Arnold JH, Hanson JH, Toro-Figuero LO, Gutierrez ´ J, Berens RJ, Anglin DL. Prospective, randomized comparison of high-frequency oscillatory ventilation and conventional mechanical ventilation in pediatric respiratory failure. Crit Care Med 1994;22:1530–1539. 6. Bateman ST, Borasino S, Asaro LA, Cheifetz IM, Diane S, Wypij D, Curley MA; RESTORE Study Investigators. Early high-frequency oscillatory ventilation in pediatric acute respiratory failure: a propensity score analysis. Am J Respir Crit Care Med 2016;193:495–503. 7. Curley MA, Wypij D, Watson RS, Grant MJ, Asaro LA, Cheifetz IM, Dodson BL, Franck LS, Gedeit RG, Angus DC, et al.; RESTORE Study Investigators and the Pediatric Acute Lung Injury and Sepsis Investigators Network. Protocolized sedation vs usual care in pediatric patients mechanically ventilated for acute respiratory failure: a randomized clinical trial. JAMA 2015;313:379–389. 8. Guervilly C, Forel JM, Hraiech S, Demory D, Allardet-Servent J, Adda M, Barreau-Baumstark K, Castanier M, Papazian L, Roch A. Right ventricular function during high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome. Crit Care Med 2012;40:1539–1545. 9. Kneyber MC, van Heerde M, Markhorst DG. Reflections on pediatric high-frequency oscillatory ventilation from a physiologic perspective. Respir Care 2012;57:1496–1504. 10. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301–1308. 11. Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, et al.; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:1107–1116. 12. Sud S, Friedrich JO, Adhikari NK, Taccone P, Mancebo J, Polli F, Latini R, Pesenti A, Curley MA, Fernandez R, et al. Effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: a systematic review and meta-analysis. CMAJ 2014;186:E381–E390. 13. Curley MA, Hibberd PL, Fineman LD, Wypij D, Shih MC, Thompson JE, Grant MJ, Barr FE, Cvijanovich NZ, Sorce L, et al. Effect of prone positioning on clinical outcomes in children with acute lung injury: a randomized controlled trial. JAMA 2005;294:229–237. 14. Chevret S. Propensity-matching analysis is not straightforward. Am J Respir Crit Care Med 2014;190:362–363. 15. Erickson S, Schibler A, Numa A, Nuthall G, Yung M, Pascoe E, Wilkins B; Paediatric Study Group; Australian and New Zealand Intensive Care Society. Acute lung injury in pediatric intensive care in Australia and New Zealand: a prospective, multicenter, observational study. Pediatr Crit Care Med 2007;8:317–323. 16. Rosenbaum PR, Rubin DB. Reducing bias in observational studies using subclassification on the propensity score. J Am Stat Assoc 1984;79:516–524. 17. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011;46:399–424. 18. Gupta P, Green JW, Tang X, Gall CM, Gossett JM, Rice TB, Kacmarek RM, Wetzel RC. Comparison of high-frequency oscillatory ventilation and conventional mechanical ventilation in pediatric respiratory failure. JAMA Pediatr 2014;168:243–249. 19. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, Slutsky AS, Pullenayegum E, Zhou Q, Cook D, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA 2010;303:865–873. 20. Goligher EC, Kavanagh BP, Rubenfeld GD, Adhikari NK, Pinto R, Fan E, Brochard LJ, Granton JT, Mercat A, Marie Richard JC, et al. Oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome: a secondary analysis of the LOVS and ExPress trials. Am J Respir Crit Care Med 2014;190:70–76.
Copyright © 2016 by the American Thoracic Society
American Journal of Respiratory and Critical Care Medicine Volume 193 Number 5 | March 1 2016
