Acute respiratory distress syndrome in infants, children and young people

GGC Paediatric Guidelines
NHS GGC

Objectives

To provide clear, evidence-based recommendations on the diagnosis and management of paediatric ARDS within PICU.

Scope

This guideline is intended for all healthcare professionals caring for children with ARDS in the Paediatric Intensive Care Unit at the Royal Hospital for Children, Glasgow.

Audience

All medical and nursing staff caring for patients with ARDS should be familiar with the protocol.

Quick Reference Flow Chart

Summary

Acute respiratory distress syndrome is an acute, inflammatory lung injury leading to increased pulmonary vascular permeability, increased lung weight and loss of aerated lung tissue characterized by bilateral lung infiltrates on chest X-ray, and hypoxaemia. The global standard definition is the 2012 Berlin definition1 – this has been adapted for use in Paediatric practice. ARDS occurs within 7 days of the known insult and can be graded in severity using the Oxygenation index (Mild 4-8, Moderate 8-16 and Severe >16) or Oxygen saturation index (OSI) 2,3. It cannot be otherwise explained by cyanotic heart disease, chronic lung disease and/ or left ventricular dysfunction. The mortality associated with ARDS is high in children (10-12% in mild to moderate ARDS and 33% in severe cases)4. ARDS in children is most often caused by pneumonia, sepsis and aspiration. ARDS is associated with significant morbidity related to secondary infection, prolonged hospital admission, critical illness neuropathy and a reduction in health related QOL.

The majority of evidence regarding management of paediatric ARDS has been translated from research involving adult patients. The PALICC consensus recommendations (2015) were developed by a group of 27 experts who reviewed evidence and generated definitions and guidelines for management of ARDS in children. In order to ensure inclusion of up to date, relevant evidence supporting management strategies for ARDS in children, a series of literature searches were conducted by the NHS GGC Library service in March 2021. The following sections highlight the results of these searches and include synthesis of the PALICC review. The resulting protocol reflects the recommendations within the PALICC statement.

1. Do the following ‘lung protective’ strategies work in ventilation of paediatric patients with ARDS?
     a. Low tidal volumes and limited peak inspiratory pressures

Unlike the adult population5, a randomized controlled trial of tidal volume does not exist for ARDS. Recommendations have therefore been extrapolated from adults and, as a general rule most units will aim for 6ml/kg targeted tidal volumes based on the results from the ARDSnet ARMA trial. This randomized 861 adult patients to receive either 12ml/Kg (maximum peak inspiratory pressure of 50) or 6ml/Kg (maximum peak inspiratory pressure of 30was stopped early due to findings that lower tidal volumes were associated with reduced mortality and more ventilator-free days5. It should be noted that subsequent commentary discussed the fact that 12ml/Kg was a relatively extreme upper limit of tidal volume and potential harm from volutrauma may have contributed to observed benefit. In addition, higher PEEP in the lower tidal volume group may have improved outcomes. Wong et al 6 conducted an observational study that found that a lung protective mechanical ventilation strategy (including low tidal volumes) reduced mortality. However a number of observational studies performed that show an inverse relationship between tidal volume and mortality in children that contradicts the adult experience7,8. In considering these studies further it may be that they were confounded by several factors e.g. more sick patients selected for lower tidal volumes and more likely to die as a result of underlying lung pathology, and the fact that most patients were managed on pressure limited ventilation. As a result, in 2015, PALICC (Paediatric acute lung injury consensus conference) agreed to advise use of lower tidal volumes and limited peak pressures as a ‘weak’ recommendation3.

b. High peak end expiratory pressure

The position that higher peak end expiratory pressures (PEEP) would be beneficial was based on the prevention of collapsing alveoli in each breath cycle, thereby limited atelectasis9. Two meta-analyses of adult data have found that higher PEEP is associated with lower mortality 10,11 and a clinical trial in children concluded similar findings i.e. PEEP settings lower than ARDSnet model were associated with increased mortality12. PALICC therefore recommends strongly, the use of PEEP up to 15cmH2O to support children with severe ARDS, although care should be taken in patients who have decreased preload i.e. dehydrated, distributive shock.

Recruitment manoevures (RM’s, transient increase in transpulmonary pressures with the aim of opening alveoli) are common practice in adult intensive care and were shown to improve oxygenation and restore lung volume in patients with ARDS 13. However, the ART trial, 2017 14, found that lung recruitment manouevres and titrated PEEP were associated with increased mortality. Some mechanical ventilators have dynamic software that can perform RM’s. RM’s can also be performed manually through sequential increases in PEEP until optimal TV’s are met. Paediatric evidence evaluating RM’s is limited, and the available evidence is inconclusive. RM’s appear to be most useful after circuit disconnection and post suctioning. This is reflected in PALICC advice to use ‘careful recruitment manoeuvres in the attempt improve severe oxygenation failure’.

c. Actively target Permissive hypoxaemia and permissive hypercapnea

A number of adult and paediatric studies have shown that improved oxygenation does not improve outcomes5,15, therefor PALICC ‘strongly’ recommends Oxygen saturation targets of 92-97% in children with mild ARDS and 88-92% in children with severe ARDS. Therefore, any child who is being ventilated for ARDS should be saturating within the range of 88-92%. The clinical question of Oxygen saturation targets in PICU has never been answered in an RCT. OxyPICU16 is currently recruiting with the aim of answering this question. The inclusion criteria is not focussed on pARDS, but results may help to support (or negate) specific targets.

PALICC also ‘strongly’ recommends the use of permissive hypercapnea when ventilating patients with severe ARDS in order to limit baro- and volutrauma. Levels should be targeted accordingly to maintain pH within the range of 7.15-7.3(H+ 50-70)3. This approach should be avoided in a subset of children who have contraindications such as intracranial hypertension and pulmonary hypertension. Care should also be taken in the child with cardiovascular instability i.e. hypotensive or on multiple inotropes and consideration of cardiopulmonary interactions in targeted ARDS management.

2. Does proning work for children with ARDS?

Proning has been shown to improve mortality in adult patients with ARDS, in particular those with severe ARDS who are also managed with lung protective ventilation strategies as seen in the results of the PROSEVA trial 17,18. However, a multi-centre randomized controlled trial conducted in the USA enrolled 102 paediatric patients and randomized them to receive either 20hrs of proning per day for 7 days or to remain supine. Results showed no difference in ventilator free days (primary outcome) or in mortality or recovery time (secondary outcomes).  Another RCT is being conducted and will report in 2024 (estimated) on the outcomes in children with severe ARDS who are 19. Until then PALICC advise considering proning in patients with severe ARDS but not as a routine strategy.

3. Should we be fluid restricting paediatric patients with ARDS?

There are no paediatric randomized controlled trials evaluating the use of fluids in ARDS. Again, management is extrapolated from adult data and supported by a number of paediatric observational studies. The FACTT trial 20randomized 1000 adults with acute lung injury to receive one of two strategies: either liberal fluid to optimize cardiac output and organ function (other than lungs) or fluid restriction to limit pulmonary oedema. There was no significant difference in mortality at 60days, but the conservative strategy led to improved lung function and reduced duration of mechanical ventilation and duration of intensive care admission. Two observational studies support these findings and showed that a positive fluid balance led to increased mortality and prolonged ventilation 21,22. As a result, PALICC recommends ‘goal-directed therapy’ by which intravascular volume is maintained at the same time as limiting fluid overload3.  This may include a strategy in which fluid resuscitation is given initially to stabilize a critically unwell child, followed by fluid restriction guided by balance and end organ function.

4. Are steroids useful in ARDS?

Steroids have been considered for use in patients with ARDS as a mechanism of reducing the inflammatory process and are used in up to 35% of paediatric patients with ARDS23,24. Meduri et al conducted a meta-analysis of 9 RCT’s investigating the use of low-moderate dose prolonged glucocorticoid treatment in 816 adult patients with ARDS25. The analysis showed that steroid use was associated with reduced duration of ventilation, mortality, ICU admission and length of stay. However, findings have not been convincing in paediatrics. Drago et al 26conducted a small RCT (35 patients) and found no difference in mortality, duration of ventilation and ICU length of stay, but suggested that a larger RCT would be beneficial. An observational study was conducted evaluating effects of systemic steroids in children with ARDS and found that steroids were associated with fewer ventilator free days27. Another observational study found that there was an improvement in Oxygen saturation index (OSI) in 60% of patients treated with low dose methylprednisolone and that a 20% improvement in OSI was independently associated with survival. As a result of this conflicting evidence there is wide variation in practice between centres with some incorporating steroids as a ‘rescue therapy’ on days 10-14. PALICC recommends against the use of steroids in children with ARDS28.

5. Does neuromuscular blockade improve Oxygenation in paediatric patients?

Neuromuscular blockade has been used widely in adult intensive care as a strategy for improving oxygenation in patients with early severe ARDS29. The Acurasys trial, 2010, 30randomised patients with severe ARDS to 48hours cisatracurium or no neuromuscular blockade and found that early neuromuscular blockade improved 28 and 90 day mortality. It should be noted that in adults, atracurium and cisatracurium are more often used than aminosteroids (vecuronium and rocuronium) and the use of aminosteroids has been linked to adverse effects such as myopathy and need to be further evaluated31. There are no randomised controlled trials in paediatric patients. PALICC recommends consideration of neuromuscular blockade where sedation is not proving adequate for maintenance of oxygenation32. This may be more relevant in the child in which there is patient/ ventilator asynchrony and high ventilator settings risking barotrauma. If using neuromuscular blockade, clinicians must consider methods of adequate assessment of pain, distress and level of sedation33.

6. What role does high frequency oscillation ventilation (HFOV) have in management of ARDS?

HFOV is rarely used in adult intensive care due to a lack of supporting evidence. The OSCAR (2013)34 and OSCILLATE (2013 - )35 randomised controlled trials found either no significant difference or increased mortality with use of HFOV in adult patients with ARDS. Both trials included patients with moderate/ severe ARDS and randomised to HFOV or conventional mechanical ventilation relatively early on in management i.e. not used as a rescue therapy. Notably less than half of patients screened were randomised. There are several observational studies in paediatric patients with mixed results – Wong et al 6 and Gupta et al 36 found that the use of HFOV in children was associated with an increase in 28 day mortality, and El-Nawawy et al 37and Pinzon et al 38 found that HFOV improved oxygenation but not outcomes. As with many observational studies, confounding factors must be included in any interpretation of these results.

In paediatrics, HFOV is used as a ‘rescue therapy’ for hypoxaemia refractory on conventional mechanical ventilation. HFOV facilitates gas exchange by delivering very small tidal volumes at frequencies of 3 to 15Hz (most often 8-12Hz). Smaller tidal volumes, avoidance of alveolar over-distension and better recruitment due to higher mean airway pressures are thought to be lung-protective.

Decisions regarding escalation to HFOV are usually based on oxygenation and pressures on conventional ventilation. PALICC recommends that HFOV is considered when plateau pressures of 28 are reached in patients with moderate-severe.

7. When should we consider ECMO in paediatric ARDS?

ECMO is used to support respiratory failure and is a recognized treatment option for patients with severe ARDS. It has been suggested that ECMO could reduce barotrauma related lung injury, multi-organ failure and mortality in patients with ARDS. Two large multi-centre RCT’s have investigated the use of ECMO in the management of ECMO adult patients with ARDS. The CESAR trial 39 found a reduction in relative risk of death and disability with treatment in a specialist ECMO centre (N.B. not all patients in treatment arm received ECMO) and the EOLIA trial 40 found no significant difference in mortality between those receiving ECMO and those who did not. No RCT’s investigating the role of ECMO in ARDS have been conducted in paediatrics and available retrospective cohort studies have provided limited evidence to support use of ECMO 41,42.

PALICC guidelines recommend consideration of ECMO in any child failing to respond to all the above measures, where the child is thought to have a reversible cause of ARDS or likely consideration for lung transplant. This should be done on a case-by-case basis, taking into account risks and benefits of , and should be considered early (i.e. less than 7 days) in patients failing to improve on standard therapy. * this is due to poorer outcomes in children initiated on ECMO after X days as per ELSO data- see table below.

 

Total Runs

Avg Run Time

Longest Run Time

Survived

% Survived

ARDS, post op/ trauma

20

248

711

14

70%

ARDS, not postop/trauma

388

377

4379

269

69%

Total Paediatric Respiratory Runs

3435

338

3011

2308

67%

*Paediatric respiratory runs from 2016 to 2020 – ELSO International report April 2021

8. Any additional adjunctive therapies?

A systematic review of the use of inhaled nitric oxide found no benefit in the outcomes of patients with ARDS 43. Likewise, there is no evidence of mortality benefit in the use of surfactant in management of adult patients with ARDS44. However, there are indicators that surfactant may be of use in management of paediatric ARDS.

Conclusion

Consensus guidelines for management of paediatric ARDS are largely based on experience in adults. To date, there are no long term follow up studies in children. However, more recently trials are being conducted in the paediatric population that will further inform these recommendations31. There are varying approaches regarding outcome assessment in pARDS trials – ventilator free days, length of stay, post recovery pulmonary function tests. To date, there is no consensus as to the best.

First and foremost, it is essential to treat the underlying cause and minimise ongoing inflammation e.g. early antibiotics/ inflammatory source control. At present, the use of lung protective strategies (low tidal volumes, limited peak pressures, high PEEP and permissive hypoxaemia and hypercapnea) and goal-directed fluid therapy are supported by evidence for all children with severe ARDS. Proning and neuromuscular blockade are options available for children with severe ARDS who are not achieving adequate oxygenation despite lung protective ventilation. Steroid therapy is advised against in all children with . Rescue therapies include HFOV and ECMO and must be considered on a case-by-case basis.

DIAGNOSIS (PALICC Guidelines)

DIAGNOSIS (PALICC Guidelines) table

AETIOLOGY AND INVESTIGATIONS

ARDS in children is most commonly caused by pneumonia, sepsis and aspiration. There are many other underlying conditions that can cause ARDS including trauma, burns, pancreatitis, inhalational injury, transfusion and cardiopulmonary bypass.

Baseline Investigations:

Bloods

FBC, CRP, Procalcitonin, biochemistry, coagulation, G&S, Blood Cx

Respiratory

Throat swab, NPA, BAL (Bacteriology and virology)

Imaging

CXR, ECHO, Chest USS

Consider

PJP screen if significant hypoxaemia.
Bronchoscopy, CT Chest

MANAGEMENT

Ventilation strategy:

Targets:

  • SpO2: 92-97% (mild), 88-92% (moderate/ severe)
  • H+: 50-70 (regardless of pCO2 unless ECHO evidence of severe pulmonary hypertension OR consideration made for concurrent neuroprotection).

Modes:

  • Conventional ventilation - V
  • HFOV – reserved for cases where plateau pressures >28

Pressures:

  • Limit to max PIP 32
  • PEEP 10-15 (care where children have decreased preload)
  • Increase Ti to 1-1.2s depending on set – monitor I:E ratio and expiratory flow trace to avoid ‘breath stacking’
  • Recruitment manoeuvres may be of benefit when circuit has been disconnected or following ETT suctioning.
  • iNO if documented pulmonary hypertension or RV Dysfunction – assess response with ECHO

Adjunctive therapy

  • Proning – 16-20hrs in children with severe ARDS
  • Fluids – ‘Goal-directed therapy’ i.e. conservative but avoiding compromising intravascular volume. May need resuscitation and then restriction - consider fluid balance and end-organ function.
  • Neuromuscular blockade – consider in severe ARDS
  • Steroids – no evidence for steroids in children with ARDS. In severe ARDS where all other options have been exhausted there may be a window for considering this i.e. from day 7 to 14.

ECMO

  • Discuss if hypoxaemia persists despite optimization using above
  • Also consider if concomitant refractory shock, ventricular failure or air leak syndrome
  • Trial of iNO and HFOV before ECMO
  • Counsel parents re; risks of ECMO

Day 7 review:

All patients, if failing to improve, should have a respiratory review.

Consider involving other specialties on a case by case basis i.e. I.D, rheumatology and cardiology.

Consider MDT discussion regarding prognostic CT i.e. PICU, respiratory +/- others involved in care.

FLOW CHART

Flowchart

Editorial Information

Last reviewed: 05/01/2023

Next review date: 05/01/2025

Author(s): Dr Kirsty Houston, PICM Grid Trainee; Dr Cheryl Gillis, Consultant in PICM; Dr Colin Begg, Consultant in PICM & Guidelines Lead.

Version: 1

Approved By: Paediatric Therapeutic & Risk Committee

References
  1. The ARDS Definition Task Force*. Acute Respiratory Distress Syndrome: The Berlin Definition. JAMA. 2012;307(23):2526-2533. doi:10.1001/jama.2012.5669
  2. Orloff KE, Turner DA, Rehder KJ. The Current State of Pediatric Acute Respiratory Distress Syndrome. Pediatr Allergy Immunol Pulmonol. 2019;32(2):35-44. doi:10.1089/ped.2019.0999
  3. Jouvet P, Thomas NJ, Willson DF, et al. Pediatric Acute Respiratory Distress Syndrome: Consensus Recommendations from the Pediatric Acute Lung Injury Consensus Conference. In: Pediatric Critical Care Medicine. ; 2015. doi:10.1097/PCC.0000000000000350
  4. Khemani RG, Smith L, Lopez-Fernandez YM, et al. Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology (PARDIE): an international observational study. Lancet Respir Med. 2019;7(2):115-128. doi:10.1016/S2213-2600(18)30344-8
  5. Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. New England Journal of Medicine. Published online 2000. doi:10.1056/NEJM200005043421801
  6. Wong JJM, Lee SW, Tan HL, et al. Lung-Protective Mechanical Ventilation Strategies in Pediatric Acute Respiratory Distress Syndrome. Pediatric Critical Care Medicine. 2020;21(8):720-728. doi:10.1097/PCC.0000000000002324
  7. Erickson S, Schibler A, Numa A, et al. Acute lung injury in pediatric intensive care in Australia and New Zealand - A prospective, multicenter, observational study. Pediatric Critical Care Medicine. Published online 2007. doi:10.1097/01.PCC.0000269408.64179.FF
  8. Khemani RG, Conti D, Alonzo TA, Bart RD, Newth CJL. Effect of tidal volume in children with acute hypoxemic respiratory failure. Intensive Care Medicine. Published online 2009. doi:10.1007/s00134-009-1527-z
  9. Rimensberger PC, Cheifetz IM. Ventilatory Support in Children With Pediatric Acute Respiratory Distress Syndrome. Pediatric Critical Care Medicine. Published online 2015. doi:10.1097/pcc.0000000000000433
  10. Phoenix SI, Paravastu S, Columb M, Vincent JL, Nirmalan M. Does a higher positive end expiratory pressure decrease mortality in acute respiratory distress syndrome?: A systematic review and meta-analysis. Anesthesiology. Published online 2009. doi:10.1097/ALN.0b013e31819fae06
  11. Briel M, Meade M, Mercat A, 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 - Journal of the American Medical Association. Published online 2010. doi:10.1001/jama.2010.218
  12. Khemani RG, Parvathaneni K, Yehya N, Bhalla AK, Thomas NJ, Newth CJL. Positive end-expiratory pressure lower than the ards network protocol is associated with higher pediatric acute respiratory distress syndrome mortality. American Journal of Respiratory and Critical Care Medicine. Published online 2018. doi:10.1164/rccm.201707-1404OC
  13. Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med. 2006;354(17):1775-1786. doi:10.1056/NEJMoa052052
  14. Cavalcanti AB, Suzumura ÉA, Laranjeira LN, et al. Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome. JAMA. 2017;318(14):1335-1345. doi:10.1001/jama.2017.14171
  15. Curley MAQ, Hibberd PL, Fineman LD, et al. Effect of prone positioning on clinical outcomes in children with acute lung injury: A randomized controlled trial. Journal of the American Medical Association. Published online 2005. doi:10.1001/jama.294.2.229
  16. Wiley D, Peters M. A randomised multiple centre trial of conservative versus liberal oxygenation targets in critically ill children (Oxy-PICU). doi:10.1186/ISRCTN92103439
  17. Guérin C, Reignier J, Richard J-C, et al. Prone Positioning in Severe Acute Respiratory Distress Syndrome. New England Journal of Medicine. 2013;368(23):2159-2168. doi:10.1056/NEJMoa1214103
  18. Sud S, Friedrich JO, Adhikari NKJ, 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. Published online 2014. doi:10.1503/cmaj.140081
  19. RN MAQC PhD. PROSpect: Prone and Oscillation Pediatric Clinical Trial. clinicaltrials.gov; 2021. Accessed September 12, 2021. https://clinicaltrials.gov/ct2/show/NCT03896763
  20. Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. New England Journal of Medicine. Published online 2006. doi:10.1056/NEJMoa062200
  21. Díaz F, Nuñez MJ, Pino P, Erranz B, Cruces P. Implementation of preemptive fluid strategy as a bundle to prevent fluid overload in children with acute respiratory distress syndrome and sepsis. BMC Pediatr. 2018;18(1):207. doi:10.1186/s12887-018-1188-6
  22. Willson DF, Thomas NJ, Tamburro R, et al. The relationship of fluid administration to outcome in the pediatric calfactant in acute respiratory distress syndrome trial. Pediatr Crit Care Med. 2013;14(7):666-672. doi:10.1097/PCC.0b013e3182917cb5
  23. Peter JV, John P, Graham PL, Moran JL, George IA, Bersten A. Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: Meta-analysis. BMJ. Published online 2008. doi:10.1136/bmj.39537.939039.BE
  24. Santschi M, Jouvet P, Leclerc F, et al. Acute lung injury in children: Therapeutic practice and feasibility of international clinical trials. Pediatric Critical Care Medicine. Published online 2010. doi:10.1097/PCC.0b013e3181d904c0
  25. Meduri GU, Siemieniuk RAC, Ness RA, Seyler SJ. Prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ARDS. Journal of Intensive Care. Published online 2018. doi:10.1186/s40560-018-0321-9
  26. Drago BB, Kimura D, Rovnaghi CR, et al. Double-Blind, Placebo-Controlled Pilot Randomized Trial of Methylprednisolone Infusion in Pediatric Acute Respiratory Distress Syndrome. Pediatric Critical Care Medicine. Published online 2015. doi:10.1097/PCC.0000000000000349
  27. Yehya N, Servaes S, Thomas NJ, Nadkarni VM, Srinivasan V. Corticosteroid exposure in pediatric acute respiratory distress syndrome. Intensive Care Medicine. Published online 2015. doi:10.1007/s00134-015-3953-4
  28. Tamburro RF, Kneyber MCJ. Pulmonary Specific Ancillary Treatment for Pediatric Acute Respiratory Distress Syndrome. Pediatric Critical Care Medicine. Published online 2015. doi:10.1097/pcc.0000000000000434
  29. Gainnier M, Roch A, Forel JM, et al. Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Critical Care Medicine. Published online 2004. doi:10.1097/01.CCM.0000104114.72614.BC
  30. Papazian L, Forel J-M, Gacouin A, et al. Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome. New England Journal of Medicine. 2010;363(12):1107-1116. doi:10.1056/NEJMoa1005372
  31. Allareddy V, Cheifetz IM. Clinical trials and future directions in pediatric acute respiratory distress syndrome. Annals of Translational Medicine. Published online 2019. doi:10.21037/atm.2019.09.14
  32. Valentine SL, Nadkarni VM, Curley MAQ. Nonpulmonary treatments for pediatric acute respiratory distress syndrome: Proceedings from the Pediatric Acute Lung Injury Consensus Conference. Pediatric Critical Care Medicine. Published online 2015. doi:10.1097/PCC.0000000000000435
  33. Harris J, Ramelet A-S, van Dijk M, et al. Clinical recommendations for pain, sedation, withdrawal and delirium assessment in critically ill infants and children: an ESPNIC position statement for healthcare professionals. Intensive Care Med. 2016;42(6):972-986. doi:10.1007/s00134-016-4344-1
  34. Young D, Lamb SE, Shah S, et al. High-Frequency Oscillation for Acute Respiratory Distress Syndrome. New England Journal of Medicine. 2013;368(9):806-813. doi:10.1056/NEJMoa1215716
  35. Ferguson ND, Cook DJ, Guyatt GH, et al. High-Frequency Oscillation in Early Acute Respiratory Distress Syndrome. New England Journal of Medicine. 2013;368(9):795-805. doi:10.1056/NEJMoa1215554
  36. Gupta P, Green JW, Tang X, et al. Comparison of High-Frequency Oscillatory Ventilation and Conventional Mechanical Ventilation in Pediatric Respiratory Failure. JAMA Pediatr. 2014;168(3):243. doi:10.1001/jamapediatrics.2013.4463
  37. El-Nawawy A, Moustafa A, Heshmat H, Abouahmed A. High frequency oscillatory ventilation versus conventional mechanical ventilation in pediatric acute respiratory distress syndrome: A randomized controlled study. Turk J Pediatr. 2017;59(2):130-143. doi:10.24953/turkjped.2017.02.004
  38. Pinzon AD, da Rocha TS, Ricachinevsky C, Piva JP, Friedman G. High-frequency oscillatory ventilation in children with acute respiratory distress syndrome: experience of a pediatric intensive care unit. Revista da Associação Médica Brasileira (English Edition). 2013;59(4):368-374. doi:10.1016/S2255-4823(13)70489-2
  39. Peek GJ, Clemens F, Elbourne D, et al. CESAR: conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory failure. BMC Health Serv Res. 2006;6:163. doi:10.1186/1472-6963-6-163
  40. Combes A, Hajage D, Capellier G, et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. New England Journal of Medicine. 2018;378(21):1965-1975. doi:10.1056/NEJMoa1800385
  41. Barbaro RP, Xu Y, Borasino S, et al. Does Extracorporeal Membrane Oxygenation Improve Survival in Pediatric Acute Respiratory Failure? Am J Respir Crit Care Med. 2018;197(9):1177-1186. doi:10.1164/rccm.201709-1893OC
  42. Peng C-C, Wu S-J, Chen M-R, Chiu N-C, Chi H. Clinical experience of extracorporeal membrane oxygenation for acute respiratory distress syndrome associated with pneumonia in children. Journal of the Formosan Medical Association. 2012;111(3):147-152. doi:10.1016/j.jfma.2011.01.006
  43. Karam O, Gebistorf F, Wetterslev J, Afshari A. The effect of inhaled nitric oxide in acute respiratory distress syndrome in children and adults: a Cochrane Systematic Review with trial sequential analysis. Anaesthesia. 2017;72(1):106-117. doi:https://doi.org/10.1111/anae.13628
  44. Meng S-S, Chang W, Lu Z-H, et al. Effect of surfactant administration on outcomes of adult patients in acute respiratory distress syndrome: a meta-analysis of randomized controlled trials. BMC Pulmonary Medicine. 2019;19(1):9. doi:10.1186/s12890-018-0761-y