Acute respiratory distress syndrome in infants, children and young people

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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 experience^7,8. 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 outcomes^5,15, 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 ARDS^23,24. 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.

*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.