Pediatric Acute Respiratory Distress Syndrome Updates in the Light of the PALICC-2 Guidelines

Abstract

Acute respiratory distress syndrome (ARDS) was first described in adults. However, the risk factors for the development of ARDS, etiological causes, and the pathophysiology of the disease, as well as morbidity and mortality, are not the same in children and adults. Since adult definitions were used for many years and the definition of pediatric ARDS was not clear within these definitions, this situation caused the prevalence of pediatric ARDS to be underestimated. For the reasons stated above, the pediatric ARDS (PARDS) definition, which is made considering only children and is used today, was made by “The Pediatric Acute Lung Injury Consensus Conference (PALICC) Group” in 2015, and new updates were published in the PALICC-2 guideline in 2023. The aim of this review is to summarize the diagnostic and treatment approaches of PARDS according to the PALICC-2 guideline recommendations.

Definition

Acute respiratory distress syndrome (ARDS) was first described in adults in 1967.¹ The next definition for acute lung injury (ALI) and ARDS in adults was proposed by the “American-European Consensus Conference (AECC)” in 1994.² This definition was also used for the pediatric age group for a long time until it was revised again by the AECC in 2012.³ This new adult definition, also known as the “Berlin criteria,” did not include specific recommendations for children but introduced several significant changes. These changes are as follows:

• 1. The removal of the ALI definition, replaced by the categorization of ARDS severity as mild, moderate, and severe based on oxygenation impairment.

• 2. The requirement that positive end-expiratory pressure (PEEP) be at least 5 cmH₂O for the diagnosis of ARDS.

• 3. The replacement of pulmonary artery catheter placement, a highly invasive procedure used to rule out heart failure, with non-invasive and objective assessment tools such as echocardiography (ECHO).

Acute respiratory distress syndrome can result from pulmonary causes that directly lead to alveolar damage or extrapulmonary causes that indirectly cause alveolar injury. The etiological factors causing pediatric ARDS are summarized in Table 1. In children, non-invasive pulse oximetry (SpO₂) is more commonly used to assess and monitor oxygenation compared to the invasive measurement of arterial blood gases (ABG). The application of AECC and Berlin definitions, which are based on arterial partial oxygen pressure (PaO₂), to children presents substantial difficulties.⁴ Based on these definitions, many pediatric patients who actually have ARDS either fail to be diagnosed or are diagnosed late. Consequently, the prevalence of ARDS in the pediatric population was inaccurately calculated as lower than its actual rate.

Table 1.

Causes of Pediatric Acute Respiratory Distress Syndrome

Causes of Direct Alveolar Injury	Causes of Indirect Alveolar Injury
Pneumonia Aspiration pneumonia Inhalation injury Pulmonary contusion Drowning	Sepsis Trauma Acute pancreatitis Transfusion Burns Head trauma Disseminated intravascular coagulation Cardiopulmonary bypass

Another limitation of these adult definitions is the use of the PaO₂/inspiratory oxygen fraction (FiO₂) ratio in diagnosis and severity grading.^1,2 In addition to requiring ABG, FiO₂ is influenced by ventilator pressures, particularly PEEP; frequent adjustments of ventilator parameters in pediatric intensive care units (PICUs) compared to adults; and the greater variety of ventilator strategies and clinical approaches in children can lead to inaccurate results in diagnosing ARDS and determining disease severity in pediatric patients. For these reasons, Oxygenation Index (OI) [OI = (FiO₂ x MAP) x 100 / PaO₂, where MAP denotes Mean Airway Pressure] and Oxygen Saturation Index (OSI) [OSI = (FiO2 x MAP x 100) / SpO2] have been implemented to evaluate hypoxemia in the pediatric age group.^5,6

The anatomy and physiology of the respiratory systems in adults and children differ significantly (Table 2). Additionally, the risk factors and etiological causes for ARDS development, as well as the pathophysiology, morbidity, and mortality of the disease, are not the same in children and adults.⁷

Table 2.

Differences in Respiratory System Anatomy and Physiology Between Children and Adults

Feature	Children	Adults
Airway cartilage development	Incomplete	Complete
Airway resistance	Significantly increases with reduced airway radius	Increases less with reduced airway radius
Chest wall compliance	Higher due to incomplete ossification of the rib cage	Lower due to complete ossification of the rib cage
Alveolar development and effect on FRC	20-300 million alveoli (age-dependent); lower FRC	300 million mature alveoli; higher FRC
Respiratory muscle reserve	More diaphragm-dependent	Less diaphragm-dependent
Risk of vascular remodeling	Higher due to elevated pulmonary vascular resistance in the perinatal period	Lower
Metabolic demands	Higher	Lower

FRC, functional residual capacity.

For the aforementioned reasons, the pediatric ARDS (PARDS) definition, specifically designed with children in mind and currently in use, was developed by “The Pediatric Acute Lung Injury Consensus Conference (PALICC) Group” in 2015.⁷ Subsequently, in 2023, the PARDS definition was reassessed, and new revisions were published.⁸ (Table 3).

Table 3.

Pediatric Acute Respiratory Distress Syndrome Definition

Age	Patients with lung diseases related to the perinatal period are excluded.
Onset time	Develops within 7 days following a known clinical insult.
Source of edema	Respiratory failure that cannot be fully explained by heart failure or excessive fluid overload.
Imaging findings	New opacities (unilateral or bilateral) consistent with acute pulmonary parenchymal disease, not primarily due to atelectasis or pleural effusion. a
Oxygenationb	IMV: OI ≥ 4 or OSI ≥ 5 NIVc: Pao2/FiO2 ≤ 300 or SpO2/FiO2 ≤ 250 Classification of PARDS severity: Apply at least 4 hours after the initial PARDS diagnosis.
Special Populations d
Cyanotic heart disease	Presence of the above criteria with acute oxygenation impairment not explained by the heart disease.
Chronic lung disease	Presence of the above criteria with acute oxygenation impairment relative to baseline.
Left ventricular dysfunction	Diagnosis of PARDS is made if acute oxygenation impairment is unexplained by left ventricular dysfunction and new infiltrates on chest X-ray are present, along with compliance with the above criteria for age, onset time, and source of edema.

BiPAP, bi-level positive airway pressure; CPAP, continuous positive airway pressure; MV, mechanical ventilation; OI, oxygenation index ([FiO₂ x mean airway pressure (MAP) x 100] / PaO₂); OSI, oxygen saturation index ([FiO₂ X MAP X 100] / SpO₂); P/F, partial pressure of oxygen in arterial blood (PaO₂) / fraction of inspired oxygen (FiO₂); PARDS, pediatric acute respiratory distress syndrome;S/F, oxygen saturation measured by pulse oximetry (SpO₂) / FiO₂.

^aChildren who meet PARDS criteria but lack imaging capability in resource-limited settings are considered as having probable PARDS.

^bOxygenation should be measured in a stable state, not during transient desaturation episodes. When using SpO₂ for oxygenation assessment, ensure SpO₂ is ≤ 97%.

^cThe diagnosis of ARDS in noninvasive ventilation (NIV-ARDS) requires a full-face mask interface with continuous positive airway pressure (CPAP) or expiratory positive airway pressure (EPAP) ≥ 5 cm H₂O.

^dThe classification of PARDS severity does not apply to special populations.

Characteristics of the Pediatric Acute Respiratory Distress Syndrome Definition

Age

Due to the distinct and unique causes of acute hypoxemia in the perinatal period, patients with lung diseases associated with this period (e.g., prematurity-related lung disease, meconium aspiration syndrome, birth-acquired pneumonia, congenital diaphragmatic hernia, alveolocapillary dysplasia, etc.) were excluded from this new PARDS definition.¹⁰

Timing

Secondary hypoxemia and radiological lung findings resulting from a known clinical insult and/or disease must occur within 1 week.⁸

Origin of Edema

Respiratory failure must either occur without evidence of heart failure or fluid overload, or cannot be fully explained by heart failure and fluid overload.⁸

Lung Imaging Findings

The appearance of new unilateral or bilateral infiltrates on chest X-ray is consistent with acute parenchymal lung disease but not attributable to atelectasis or pleural effusion.⁸

Measurement of Oxygenation

In intubated patients on invasive mechanical ventilation (MV), the OI should be used if ABG measurements are available; otherwise, the OSI should be used. In patients on non-invasive ventilation, such as bi-level positive airway pressure (BiPAP) or continuous positive airway pressure (CPAP), followed with a full-face mask and a minimum pressure of 5 cmH₂O, the PaO₂/FiO₂ (P/F) ratio should be used if ABG is available; otherwise, the SpO₂/FiO₂ (S/F) ratio should be used. Oxygen therapy should be adjusted to maintain SpO2 levels between 88% and 97%.⁸

Diagnosis of Pediatric Acute Respiratory Distress Syndrome in Children with Cyanotic Heart Disease

The diagnosis is made in patients who develop sudden oxygenation impairment that cannot be explained by the underlying cardiac condition, provided that age, timing of onset, source of edema, and imaging findings meet the criteria mentioned above. The severity classification of PARDS, which will be discussed later and is calculated using OI and OSI, cannot be applied to this patient group.⁸

Diagnosis of Pediatric Acute Respiratory Distress Syndrome in Children with Chronic Lung Disease

Pediatric acute respiratory distress syndrome is diagnosed in patients who develop a sudden impairment in their baseline oxygenation levels, provided that age, timing of onset, and source of edema meet the criteria mentioned above, and new infiltrates are observed on chest X-ray. If these patients were already on invasive MV support before being diagnosed with PARDS, the severity classification calculated using OI and OSI cannot be applied.⁸

Diagnosis of Pediatric Acute Respiratory Distress Syndrome in Children with Left Ventricular Dysfunction

Pediatric acute respiratory distress syndrome is diagnosed in patients with acute oxygenation impairment that cannot be explained by left ventricular dysfunction, and with new infiltrates detected on chest X-ray, provided that age, timing of onset, and source of edema meet the criteria mentioned above.⁸

Pediatric Acute Respiratory Distress Syndrome Severity

According to the new PALICC report, PARDS can be diagnosed in patients on noninvasive ventilation (NIV) (using a full-face mask with BiPAP or CPAP ≥ 5 cmH₂O) based on the S/F or P/F ratio, and the new guidelines classify the severity of the disease. In patients with PARDS on invasive MV, the severity classification is made based on OI and OSI. Table 4 presents the classification of disease severity in patients on invasive and non-invasive MV. The guidelines recommend performing this severity classification 4 hours after the diagnosis of PARDS.^8,9

Table 4.

Pediatric Acute Respiratory Distress Syndrome Severity in Children on Non-Invasive and Invasive Mechanical Ventilation (apply at least 4 hours after initial diagnosis)

	Mild-Moderate	Severe
IMV	OI < 16 OSI < 12	OI ≥ 16 OSI ≥ 12
NIV	PaO₂/FiO₂ > 100 SpO₂/FiO₂ > 150	PaO₂/FiO₂ ≤ 100 SpO₂/FiO₂ ≤ 150

IMV, invasive mechanical ventilation; NIV, non-invasive mechanical ventilation.

OI = Oxygenation Index ([FiO₂ × Mean Airway Pressure (MAP) × 100] / PaO₂); OSI = Oxygen Saturation Index ([FiO₂ × MAP × 100] / SpO2).

Incidence

Studies conducted in the United States, Europe, Australia, and New Zealand have reported that the annual incidence of ARDS in the general population ranges from 17.9 to 81 per 100 000 based on the AECC definition. Similar studies from the same geographic regions have shown that the annual incidence in children is between 2 and 12.8 per 100 000. Acute respiratory distress syndrome can develop in 3.2% (1%-5%) of patients admitted to PICUs and in 6.1% of PICU patients requiring MV. Overall, PARDS patients constitute 1%-10% of all PICU admissions.¹⁰ Most adult and pediatric studies have reported that ARDS is more common in males than in females, while no significant difference in mortality between the sexes has been observed.^11-13

Pathophysiology

Adult ARDS is a condition that leads to severe hypoxemic respiratory failure by disrupting pulmonary gas exchange. Its pathogenesis involves lung epithelial and capillary damage, diffuse alveolar damage, inflammation, and surfactant deficiency. Non-cardiogenic alveolar/pulmonary edema occurs due to epithelial and endothelial injury (Figure 1).¹⁴ As a result of increased permeability in the alveolar epithelium-capillary endothelium, protein-rich fluid accumulates in the alveoli, adversely affecting alveolar gas exchange. Consequently, lung compliance decreases, and severe hypoxia develops, which may be accompanied by hypercapnia. Lung involvement is heterogeneous. Typically, pulmonary gas exchange disruption is also accompanied by microvascular circulatory insufficiency.¹⁵ Acute respiratory distress syndrome progresses through 3 phases:

Figure 1.

Drawing of normal alveolar structure and damaged alveoli. Depiction of pathways and multiple mediators involved in acute respiratory distress syndrome pathophysiology.¹⁴

Exudative Phase (0-6 Days)

During this phase, ALI and exudation (fluid leakage) result in an increased amount of fluid in the lungs. It is the period when hypoxemia is most severe. Endothelial and epithelial injuries are present. Some patients recover rapidly during this phase, while in others, the disease progresses, and they transition to the second phase within a week.¹⁶

Fibroproliferative Phase (7-10 Days)

This phase is characterized by the proliferation of soft tissue and other structural components in the lungs, along with an increase in fibroblasts due to lung damage. The term “stiff lung” is used to describe the lungs during this phase. Abnormally enlarged air sacs develop, and fibrotic tissue (scar) formation increases.¹⁶

Fibrotic Phase (>10-14 Days)

Inflammation subsides during this phase. Oxygenation improves, and extubation may become possible. Recovery of lung function may take 6-12 months, depending on the severity of the disease and the underlying cause. Pulmonary fibrosis of varying degrees may develop.¹⁶

In ARDS, mortality is initially due to hypoxemia and later to multiple organ failure. It is hypothesized that there are various differences in the progression and outcomes of ARDS observed in adults compared to PARDS. However, there is a lack of studies specifically addressing the pathophysiology of PARDS in the literature. The impact of postnatal lung maturation on PARDS pathophysiology, in particular, remains unknown.^15,16 Therefore, the PALICC consensus report emphasized that biomarker and genetic studies focusing on PARDS could provide guidance in uncovering the underlying pathophysiology. Additionally, it was suggested that studies investigating the pathophysiology of PARDS in animals of defined age groups should be conducted, considering the postnatal chronological development of the lungs and immune system. This approach could help reveal potential pathophysiological differences in PARDS across specific pediatric age groups.¹⁰

Etiology of Pediatric Acute Respiratory Distress Syndrome and Patients at Risk

The alveolar epithelial-capillary endothelial injury, which constitutes the main pathophysiology of PARDS, occurs either directly (e.g., pneumonia, inhalation injury) or indirectly (e.g., sepsis, burns) (Table 4). In indirect injury, systemic inflammation leads to endothelial damage, resulting in changes in permeability and microvascular thrombosis.^15,16

Patients with a history of chronic lung disease, immunodeficiency, immunosuppression (including cancer), prematurity, congenital heart disease, acquired heart disease, left ventricular dysfunction, or neuromuscular disorders, as well as those receiving home MV support, are at greater risk of developing PARDS compared to healthy children.¹⁰ Patients at risk of developing PARDS based on their oxygenation status are summarized in Table 5.

Table 5.

Probable Diagnosis of Pediatric Acute Respiratory Distress Syndrome and Patients at Risk for Pediatric Acute Respiratory Distress Syndrome

Age	Patients with lung diseases related to the perinatal period are excluded.
Timing	Develops within 7 days following a known clinical insult.
Source of edema	Respiratory failure that cannot be fully explained by heart failure or excessive fluid overload.
Imaging findings	New opacities (unilateral or bilateral) consistent with acute pulmonary parenchymal disease, not primarily due to atelectasis or pleural effusion.a
Oxygenation Threshold for Diagnosing Probable PARDS in Children Receiving Nasal Respiratory Support b,c
Nasal CPAP/BiPAP or HFNC (≥ 1.5 L/kg/min or ≥ 30 L/min): PaO2/FiO2 ≤ 300 or SpO2/FiO2 ≤ 250
Oxygenation Threshold for Diagnosing PARDS Risk b
Any interface:d Receiving oxygen supplementationd to maintain SpO2 ≥ 88%, but does not meet the criteria for PARDS or probable PARDS.
Special populations Cyanotic heart disease Chronic lung disease	Presence of the above criteria with acute oxygenation impairment not explained by heart disease. Presence of the above criteria with acute oxygenation impairment relative to baseline.

BiPAP, bilevel positive airway pressure; CPAP, continuous positive airway pressure; HFNC, high-flow nasal cannula; MV, mechanical ventilation; PARDS = pediatric acute respiratory distress syndrome; SpO₂ = oxygen saturation measured by pulse oximetry.

OI = Oxygenation Index ([FiO₂ × Mean Airway Pressure (MAP) × 100] / PaO₂); OSI = Oxygen Saturation Index ([FiO₂ × MAP × 100] / SpO2).

^aChildren in resource-limited environments where imaging is not available who otherwise meet possible PARDS criteria are considered to have possible PARDS.

^bOxygenation should be measured at a steady state and not during transient desaturation episodes. When SpO₂ is used, ensure that SpO₂ is ≤ 97%.

^CChildren on nasal noninvasive ventilation (NIV) or high-flow nasal cannula are not eligible for PARDS but are considered to have possible PARDS when this oxygenation threshold is met.

^dOxygen supplementation is defined as FiO₂ > 21% on invasive mechanical ventilation; or FiO₂ > 21% on NIV; or “oxygen flow” from a mask or cannula that exceeds these age-specific thresholds: ≥ 2 L/min (age < 1 yr), ≥ 4 L/min (age 1-5 yr), ≥ 6 L/min (age 6-10 yr), or ≥ 8 L/min (age > 10 yr). For children on a mask or cannula, oxygen flow is calculated as FiO₂ × flow rate (L/min) (e.g., 6 L/min flow at 0.35 FiO₂ = 2.1 L/min).

Treatment of Pediatric Acute Respiratory Distress Syndrome

There is no specific treatment for PARDS; instead, management focuses on treating the underlying condition, implementing lung-protective MV strategies, and providing other supportive therapies.^10,15 If the underlying cause is a lower respiratory tract infection and/or sepsis, appropriate antibiotic therapies should be initiated as promptly as possible, ideally in consultation with a pediatric infectious diseases specialist. If the cause is non-infectious, the patient should be closely monitored for the risk of secondary and ventilator-associated pneumonia (VAP). In the presence of any suspicion or evidence of infection, antibiotic therapy should be started promptly. The goal of lung-protective ventilation is to minimize additional morbidity and mortality by preventing further lung injury from barotrauma (pressure-induced damage), volutrauma (volume-induced damage), atelectotrauma (damage caused by alveoli collapsing and reopening during each breath cycle), and biotrauma (injury resulting from the release of mediators that activate the immune system at the cellular level, leading to damage in the lungs and other organs). For this purpose, strategies such as appropriately high PEEP, low tidal volume (TV), low FiO₂, permissive hypercapnia, and permissive hypoxemia are targeted.^8,15,17

Ventilatory Support

Non-Invasive Ventilation Support

Non-invasive ventilation is increasingly used in children with respiratory failure because it avoids complications associated with invasive ventilation, such as the need for and damage caused by an endotracheal tube (ETT), the requirement for sedation-analgesia-muscle relaxants, VAP, post-extubation upper airway narrowing, and similar issues. The humidified continuous high oxygen flow of high-flow nasal cannula oxygen therapy (HFNC), as well as CPAP and BiPAP methods, help keep the alveoli open through expiratory positive airway pressure (EPAP) applied during expiration. These methods reduce atelectasis, improve oxygenation, maintain airway patency without impairing airway clearance, and decrease the workload of respiratory muscles. Inspiratory positive airway pressure in BiPAP enhances TV, thereby increasing CO2 elimination, further improving oxygenation and reducing respiratory effort.^18,19

If NIV support is provided for the treatment of PARDS, the patient must be closely and dynamically monitored, and patients who do not respond to NIV should be intubated immediately. The application of NIV in the treatment of PARDS requires a team experienced in this approach.

It should be considered that oxygenation in PARDS patients receiving NIV support can deteriorate rapidly, and the severity of the disease may worsen. Therefore, all necessary equipment and an experienced team must be readily available for intubation and invasive MV support.^20,21 In patients with mild-to-moderate PARDS receiving NIV, if no improvement is observed within the first 6 hours, intubation should not be delayed. For NIV to be applied in the treatment of PARDS, a team experienced in this approach is essential. It should be considered that oxygenation in PARDS patients receiving NIV support can deteriorate rapidly, and the severity of the disease may worsen. Therefore, all necessary equipment and an experienced team must be readily available for intubation and invasive MV support.^20,21

In the treatment of PARDS, if NIV is to be used, an oronasal or full-face mask is recommended as the interface. These masks have been demonstrated to result in less air leakage and better patient-ventilator synchrony. Patients receiving NIV support should be closely monitored for side effects such as pressure injuries caused by the mask, gastric distension, barotrauma, and conjunctivitis. To prevent pressure sores and ulceration, a protective barrier should be used prophylactically whenever possible. Additionally, applying heating and humidification during NIV increases patient tolerance and prevents local inflammation caused by dry air, thereby reducing edema and airway resistance.²²

In NIV support, the most effective method is BiPAP with an oronasal or full-face mask. However, if the patient shows ventilator-patient asynchrony or if a nasal mask is used for this purpose, the CPAP method can also be preferred. Synchronization is critical for the success of NIV in PARDS, and sedative-analgesic agents can be used cautiously in uncooperative and non-compliant patients. However, the unnecessary or excessive use of sedative-analgesic agents may lead to the loss of spontaneous respiratory effort and airway protective reflexes, increasing the risk of early and unnecessary intubation.²³

Invasive Mechanical Ventilation Support

The primary goal of invasive MV support should be to ensure adequate oxygenation while protecting the lungs from ventilator-induced injury. In the treatment of PARDS, the most critical factor directly influencing prognosis is the MV strategy. Lung-protective ventilation strategies have been demonstrated to reduce both mortality and morbidity.¹⁶

Mode

No specific ventilation method has been established as superior for PARDS patients. In conventional MV, either pressure-targeted or volume-targeted ventilation methods can be used. It is recommended to utilize the method with which the medical team has the most experience.⁸

Tidal Volume/Plateau Pressure (P_plat) Limitations

In line with the goal of lung-protective ventilation, expiratory TV (VTe) should be targeted between 4 and 6 mL/kg in severe PARDS, where respiratory system compliance is significantly reduced, and 6-8 mL/kg in moderate and mild PARDS, where compliance is better. Plateau pressure is measured by briefly halting airflow during inspiration, and the patient’s breathing must be suppressed during this measurement. If the plateau pressure exceeds 30 cm H₂O, it is recommended to adjust VTe to below 6 mL/kg. When setting VTe, for pressure-targeted methods, the peak inspiratory pressure should remain below 28-30 cm H₂O. For volume-targeted methods, Pplat should be kept below 28 cm H₂O.⁸

Positive End-Expiratory Pressure

In line with the goal of lung-protective ventilation, high PEEP is applied to prevent alveolar collapse, especially during expiration, increase functional residual capacity, reduce atelectrauma, and achieve oxygenation at lower FiO₂ levels. In severe PARDS patients, moderate PEEP levels (10-15 cm H₂O), titrated based on oxygenation and hemodynamic response, are recommended. For severe PARDS patients, PEEP values exceeding 15 cm H₂O may be required, provided that plateau pressures are carefully monitored. While PEEP is increased gradually, indicators of oxygen delivery, respiratory system compliance, and hemodynamics should be closely monitored. It has been suggested that driving pressure (ΔP = plateau pressure − PEEP) may be a better predictor of prognosis and is correlated with mortality. It is generally recommended to maintain the driving pressure at or below 15.^8,24,25

High-Frequency Oscillatory Ventilation

In PARDS patients where chest wall compliance is not reduced and Pplat exceeds 28 cm H₂O, high-frequency oscillatory ventilation (HFOV) can be used as an alternative.⁷ During HFOV use, it is necessary to dynamically and gradually increase or decrease the MAP (Paw) to achieve the optimal lung volume and open alveoli. While reaching the ideal level, oxygenation, pCO2, chest X-ray findings, and hemodynamic parameters must be continuously monitored.²⁶ However, there is still insufficient scientific evidence and randomized controlled trials to recommend the routine use of HFOV in PARDS.²⁷ One study demonstrated that HFOV improved oxygenation in the short term during PARDS treatment but did not result in significant differences in morbidity or mortality. However, the number of patients in this study and in many others reporting benefits of HFOV in PARDS treatment was insufficient.²⁸ There are also studies indicating that the use of HFOV in PARDS treatment increases mortality, ICU stay, and duration of MV compared to other conventional MV treatments.²⁹ Especially in developing countries where ECMO is not available, HFOV can be used as a rescue therapy in severe PARDS.^27,30 The early initiation of HFOV treatment by experienced centers is thought to play a critical role in treatment success.^31,32 In conclusion, the routine use of HFOV in PARDS is not recommended. It may be considered for PARDS patients only when lung-protective MV strategies cannot be achieved with conventional MV.⁸

Endotracheal Tube Selection

For conventional MV, cuffed endotracheal tubes of appropriate size should be chosen to ensure adequate ventilation, and air leakage around the ETT should be avoided. However, cuff pressure should be intermittently checked and measured.³³ If the patient is under HFOV support, air leakage around the ETT may be allowed to enhance CO₂ elimination, as long as the targeted MAP (Paw) is maintained.

Gas Exchange

Initially, oxygenation and ventilation (pCO₂) targets should be determined for each patient based on their comorbidities and the severity of PARDS to prevent potential MV-related injury. For mild-to-moderate PARDS, the target SpO₂ is accepted as 92%-97%. In severe PARDS patients, lower SpO₂ values (88%-95%) are targeted. When SpO₂ drops below 92%, central venous oxygen saturation and oxygen delivery indicators should be monitored. To reduce ventilator-associated lung injury in moderate and severe PARDS patients, “permissive hypercapnia” should be applied. As described in lung-protective strategy guidelines, pH should be maintained between 7.20 and 7.30. There is insufficient evidence to recommend lower pH thresholds.³³

Contraindications for Permissive Hypercapnia

The contraindications are intracranial hypertension, severe pulmonary hypertension, certain types of congenital heart lesions, hemodynamic instability, and severe ventricular dysfunction.³³ Routine use of bicarbonate therapy is not recommended.³³

Other Adjunctive Therapies for the Lung

Inhaled Nitric Oxide

Although the routine use of inhaled nitric oxide (iNO) in PARDS treatment is not recommended, it may be used in cases of confirmed pulmonary hypertension and severe right ventricular dysfunction.⁸ A recent large-scale observational study demonstrated that iNO therapy in PARDS treatment has no benefits on mortality or ventilator weaning. In severe PARDS unresponsive to other supportive therapies, it can be considered as a rescue therapy or as a bridging therapy to extracorporeal membrane oxygenation (ECMO).³⁴ If iNO therapy is initiated, its effectiveness should be promptly evaluated, and if it proves ineffective, the treatment should be discontinued due to the risk of toxicity. Treatment usually begins with a dose of 5-10 ppm, with oxygenation improvement typically occurring within the first 12-24 hours. For doses of 10 ppm or higher, treatment should be tapered off gradually if continued for more than a few days. At the beginning of the treatment, hemodynamic instability (hypotension, tachycardia, hypoxemia) may occur, necessitating its discontinuation and patient reassessment. Methemoglobinemia (>5%) can develop during acute or prolonged treatment, and methemoglobin levels should be monitored daily. Sudden discontinuation of iNO may lead to rebound pulmonary hypertension.^34,35

Surfactant

Based on current evidence, the standard use of surfactant in PARDS treatment is not recommended. There is a need for randomized controlled trials, particularly in PARDS patients caused by specific conditions such as viral/bacterial pneumonia or drowning.⁸

Prone Position

In patients who remain in a continuous supine position, the basal regions of the lungs tend to collapse and progress to atelectasis due to various factors, such as the accumulation of intrapulmonary fluid in the basal alveoli and interstitial areas under the influence of gravity, and the pressure exerted on the basal regions by the heart, large vessels, and upper lung areas. As a result, alveoli in the upper lung regions are exposed to greater volume trauma due to MV pressures, while the basal alveoli remain collapsed, contributing further to ventilation/perfusion mismatch.

There is insufficient evidence to recommend the standard use of the prone position in PARDS treatment. However, in severe PARDS cases where oxygenation does not improve, the prone position should be applied, particularly in the early phase of MV support (first 3 days). Pads can be used to prevent erosion on the forehead, chest, iliac bones, and knees. It is recommended to maintain the prone position for at least 10-12 hours per day, ideally 16-20 hours.

A large-scale, multicenter, prospective, randomized controlled trial in adult ARDS patients found that in the group where the prone position was applied early and for at least 16 hours, ventilator-free days at days 28 and 90 were significantly higher, and mortality rates at days 28 and 90 were significantly lower compared to the supine position group.³⁶ The new 2023 guidelines do not recommend the routine use of the prone position.⁸ However, if adequate oxygenation cannot be achieved with conventional MV methods, the prone position may be considered. The optimal duration of application remains unclear.

Steroids

The results of studies investigating the effects of steroid therapy in ARDS treatment in adults are highly contradictory.³⁷ The variability in steroid dosages used in these studies (e.g., pulse doses, 1 mg/kg, 2 mg/kg) and the diverse underlying causes of ARDS have been suggested as reasons for these inconsistent results. There is insufficient information in the literature regarding steroid use in pediatric ARDS.

During the pandemic, particularly in adults with COVID-19-related ARDS, the use of high-dose methylprednisolone in refractory cases has been reported to improve expected survival rates and may be used as rescue therapy.³⁸ Although pediatric data are limited, a study examining COVID-19-related pediatric ARDS cases reported better clinical and radiological improvement in the group receiving high-dose methylprednisolone compared to the group receiving low-dose methylprednisolone.³⁹

Since PARDS is not a single disease but rather a result of highly heterogeneous conditions, it seems unlikely that definitive and meaningful conclusions can be drawn from potential future studies on this topic.⁴⁰ Consequently, the routine use of steroids in PARDS treatment is not recommended.⁸

Endotracheal Aspiration

Airway clearance is highly beneficial and important for PARDS treatment. However, unnecessary endotracheal aspiration may be harmful, as it can lead to the collapse of alveoli that were previously opened and kept open by high PEEP. Therefore, aspiration should be avoided unless necessary, especially in patients who have undergone lung recruitment maneuvers. According to current literature, neither open nor closed aspiration has a clear advantage over the other. Routine use of normal saline during aspiration is not recommended; it should only be used in the presence of thick and sticky secretions.⁸

Chest Physiotherapy

There is insufficient evidence to recommend it as a standard treatment and care option.⁸

Other Adjunctive Therapies

None of the following therapies have demonstrated proven benefits and should not be routinely used in PARDS patients: helium-oxygen mixture, inhaled/intravenous prostaglandins, plasminogen activator, fibrinolytics, anticoagulants, inhaled β2-adrenergic receptor agonists, inhaled ipratropium, intravenous antioxidants, or endotracheal N-acetylcysteine for secretion mobilization. Additionally, dornase alfa and cough assist devices have no established benefits outside of cystic fibrosis patients.⁸

Extrapulmonary Treatments

Sedation-Analgesia

Sedation-analgesia should be used at the “minimum but effective dose” to ensure patient compliance with MV, optimize oxygen delivery and consumption, and reduce respiratory workload. Studies, primarily in adult ARDS patients, have shown that patients receiving deep sedation have higher mortality, fewer ventilator-free days, greater extubation failure, higher tracheostomy requirements, and an increased incidence of delirium compared to those receiving light sedation.^41,42 The use of reliable and validated sedation-analgesia scales and protocols is recommended. A daily sedation-analgesia target should be established, sedation-analgesia breaks should be implemented as needed to predict dosage requirements, and doses should be dynamically titrated.⁸ Tolerance, dependence, and withdrawal symptoms should also be considered, and sedation-analgesia rotations and/or weaning schedules should be prepared as needed based on the extubation plan.^43,44 Intravenous midazolam from the benzodiazepine group is frequently preferred for sedation; however, in recent years, dexmedetomidine has been increasingly used due to its sedative, anxiolytic, and analgesic effects and its lower incidence of delirium compared to benzodiazepines.⁴⁵ Furthermore, dexmedetomidine use can reduce the doses and duration of benzodiazepines and opioids, which have significant addictive effects.⁴⁶ Ketamine can be used alone or in combination with other sedative drugs as a sedative-analgesic.⁴⁷ Among analgesics, morphine and fentanyl from the opioid group are the most commonly preferred agents.⁴⁸ Sedation and analgesia in PARDS facilitate synchronization and tolerance with MV.⁸

Muscle Relaxants

The use of muscle relaxants should be considered when patient-ventilator synchrony cannot be achieved with sedation-analgesia, effective MV is not possible, and particularly in patients receiving high PEEP (≥10 cm H₂O). To minimize side effects such as critical illness polyneuropathy and myopathy, the “lowest but effective dose” should be administered.

While using muscle relaxants, close monitoring of the patient is essential, and the treatment should be discontinued daily to assess sedation-analgesia and muscle relaxant dose titration. To prevent the development of polyneuropathy and/or myopathy, prolonged use should be avoided unless absolutely necessary, and, if possible, the treatment should be discontinued within 48 hours.⁴⁹ If muscle relaxants need to be used in patients at risk of seizures, electroencephalography monitoring should be performed.⁵⁰

Nutrition

Every PARDS patient should have an enteral nutrition plan, and if there are no contraindications, enteral feeding should be initiated early (within 72 hours), especially in mechanically ventilated patients, with the goal of achieving target calorie intake.⁵¹

Fluid Therapy

Fluid therapy should aim to ensure adequate intravascular volume, end-organ perfusion, and optimal oxygen delivery. However, non-cardiogenic pulmonary edema is one of the key features of PARDS. Excessive fluid administration can exacerbate pulmonary edema, negatively affecting gas exchange. If the patient is hemodynamically stable, maintaining a negative fluid balance can have a positive impact on lung function.⁵² For this purpose, diuretic therapies and preparing medications with limited fluid volumes, where possible, should be considered. In cases of renal failure unresponsive to diuretic therapy and/or more than 10% weight gain despite diuretics, continuous renal replacement therapy may be initiated.⁵³

Transfusion

In PARDS patients without cyanotic heart disease, active bleeding, or severe hypoxemia, who are clinically stable and have evidence of adequate oxygen delivery (e.g., normal central venous oxygen saturation, lactate levels), a lower hemoglobin threshold of 7 g/dL can be set for erythrocyte transfusion.⁸ For PARDS patients not meeting these criteria, there is no definitive recommendation regarding the lower hemoglobin threshold for transfusion.

Extracorporeal Life Support Systems

Extracorporeal Membrane Oxygenation Indications

Extracorporeal membrane oxygenation should be applied in patients with reversible lung disease or those eligible for lung transplantation who have inadequate gas exchange despite all lung-protective ventilation strategies.⁵⁴ Clinical condition and patient history should be carefully evaluated before making a decision. Although markers and criteria are not definitive, patients requiring high levels of MV support should be evaluated within the first 7 days.⁸

• Severe respiratory failure: Persistent PaO2/FiO₂ <60-80 or OI >40.

• Inadequate response to conventional MV ± other rescue therapies (e.g., HFOV, iNO, prone positioning).

• High ventilatory pressures (MAP >20-25 cm H₂O in conventional MV or >30 cm H₂O in HFOV, or evidence of iatrogenic barotrauma).

• Hypercapnic respiratory failure: Severe, persistent respiratory acidosis (pH <7.1) despite appropriate ventilator and patient management. In patients with accompanying hypoxemia or ventilation difficulties without contraindications, ECMO may be initiated earlier (in such cases, extracorporeal CO2 removal systems may fail).⁵⁵

Extracorporeal Membrane Oxygenation Implementation

An ECMO organization and application protocol should be in place. Venovenous ECMO (VV-ECMO) is preferred for respiratory support in patients without circulatory problems. Venoarterial ECMO (VA-ECMO) is selected for patients requiring both respiratory and circulatory support.⁵⁶

Mortality rates due to ARDS in children range from 10% to 40%, though these rates have been steadily declining in recent years.¹² Most patients succumb to the disease within the first 2 weeks. Children with PARDS frequently succumb to sepsis and multiple organ failure.⁵⁷

PARDS patients should be monitored for pulmonary function within the first 3 months after discharge. Eligible patients should undergo spirometry evaluations during this period. Non-pulmonary issues should also be closely monitored; within the first 3 months, assessments and follow-ups regarding quality of life, physical, neurocognitive, emotional, familial, and social functions are highly important.⁸

Funding Statement

This study received no funding.

Data Availability Statement:

The data that support the findings of this study are available on request from the corresponding author.