Literature review
Additional file
3 reports the basic data of clinical trials included in the review. Trials were very heterogeneous for patients’ age, type of ARDS, entry criteria and case mix, surfactant type, dose and administration technique, injected volume and ventilatory policy. These are main points that may have prevented to have solid results. In particular, patients’ age was especially variable in pediatric trials, with one expanding enrolment beyond pediatric age (including patients with malignances up to 25 years old) [
25]. Ventilatory strategy is also variable and, notably, often not protocolized and left to the decision of attending physicians in neonatal trials. Table
1 summarizes the characteristics of surfactant preparations trialed for ARDS in children and neonates as bolus administration or broncho-alveolar lavage. Six natural and one synthetic surfactant have been used. Animal-derived surfactants were either bovine or porcine and produced with various techniques. Surfactant preparations have extremely variable phospholipid profile and protein concentrations [
26]. The synthetic surfactant (lucinactant) contains a synthetic peptide (KL
4 or sinapultide) designed to mimic the sequence pattern of amphipathic helix of SP-B. Sinapultide is a 21-amino-acid hydrophobic synthetic peptide consisting of four leucine (L) and a lysine (K) repeating units. Moreover, it has a simple phospholipid profile, consisting of only dipalmitoylphosphatidylcholine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol and palmitic acid.
Table 1
Characteristics of surfactants trialed for ARDS, in children and neonates as bolus and/or broncho-alveolar lavage
Beractant | Abbvie | USA | Bovine | Minced lung | 25 | Yes | Yes |
Bovactant | Boehringer Ingelheim Pharma | Germany | Bovine | Lung lavage | 45 | Yes | No |
Calfactant | ONY/Pneuma Pharmaceuticals | USA | Bovine (calf) | Lung lavage | 35 | Yes | No |
Kelisu (Calf Surfactant for injection) | CR Double Crane | China | Bovine (calf) | Lung lavage | 30 | No | Yes |
Lucinactant | Discovery Lab | USA | Chemical | Synthetic | 30 | Yes | No |
Poractant-α | Chiesi Farmaceutici | Italy | Porcine | Modified minced lung | 80 | Yes | Yes |
Surface | CENSA | Cuba | Porcine | Lung lavage | 25 | Yes | No |
Tables
2 and
3 summarize the review results: eight and ten trials investigated the use of surfactant for ARDS in children [
25,
27‐
33] and neonates [
34‐
43], respectively. Notably, one manuscript was not considered because it was a subgroup
post hoc analysis of another trial [
44].
Table 2
Synthesis of results: surfactant therapy in children
Table 3
Synthesis of results: surfactant therapies in neonates
None of the pediatric trials used the PALICC definition specific to PARDS [
2]. Surfactant improved oxygenation in almost all these trials [
25,
27‐
33], and mortality was lowered in 3 out of 8 trials [
28‐
30]; other respiratory outcomes were also often ameliorated. Biochemical and biophysical parameters were not studied.
The Montreux definition of NARDS was released in 2017 and only one trial used it [
43]. All the other neonatal trials enrolled patients with respiratory disorders appearing as NARDS but defined with variable criteria. Only one trial provided mortality data and showed improvement [
41], and only one provided some biological or biophysical results [
34]. Surfactant improved oxygenation in the 7 out of 10 trials [
35,
37‐
40,
40‐
43]. Other outcomes were ameliorated in 6 trials [
34‐
36,
38,
41,
42].
Expert consensus
The following statements were approved:
1.
There are sufficient preclinical and clinical data to support targeted research on surfactant therapies for PARDS and NARDS. Studies should be performed according to the currently available PARDS and NARDS definitions and considering the more recent knowledge on ARDS pathobiology (strong agreement).
Nowadays, the availability of appropriate clinical definitions for PARDS and NARDS [
1,
2] (Additional file
1) represents an important step forward to improve ARDS care and recognizes that differences exist between patients of various ages and severity. Few trials have used these definitions, and their implementation is urgently warranted. Although both the PALICC and the Berlin [
45] definitions could be used for adolescents or young adults [
3], it is advisable to prefer the pediatric definition to allow further comparison and data aggregation [
3]. Some neonatal respiratory disorders that may appear as NARDS have been variously defined before the release of the Montreux definition of NARDS [
1]. Nonetheless, pathophysiology and biology are shared between these disorders and the use of an unique definition can speed up research and development of surfactant therapies for a wider number of patients [
1]. Knowledge of ARDS and surfactant pathobiology has significantly advanced during recent years, and new concepts have been introduced, such as the role of secretory phospholipase A2 enzymes in the surfactant catabolism [
11,
46], the vicious cycle connecting surfactant catabolism and inflammation [
17], the deficiency and injury of surfactant proteins [
23,
47], the variable cellular injury in direct (primary) and indirect (secondary) ARDS [
14,
16] and the lower susceptibility of infant and juvenile compared to adult lung tissue [
9]. These concepts should be taken into account in future trial design.
2.
PARDS and NARDS should be considered as syndromes and should be preclinically studied according to key characteristics, such as direct (primary) or indirect (secondary) nature, clinical severity, infectious or non-infectious origin or patients’ age (strong agreement).
Several NARDS and PARDS experimental models are available to mimic these characteristics [
48‐
51], but results of preclinical investigations cannot have the same value for all patients, since subtypes of PARDS and NARDS show relevant differences in pathobiology and pathophysiology. Several factors should be considered in pre-clinical models: trigger, animal size and the degree of lung development (i.e., patients’ age), presence of immunodeficiency or comorbidities, as well as the initial severity and the ventilatory strategy [
1,
8,
52]. Unfortunately, the need of different preclinical model to mimic different clinical situations has often gone unnoticed and may have negatively influenced the perception of research results. Accumulating data show that these factors significantly influence the clinical course and outcomes: thus it is important to consider them before starting a clinical trial [
14,
16,
17,
53‐
55]. Lung size and the volume available for aeration are also important as they will influence surfactant volume of distribution, the actual alveolar delivery and consequently the optimal dose and administration method [
56]. The type of surfactant preparation and its concentration must also be considered since the administered volume may significantly influence the amount of phospholipids actually reaching the alveoli [
56]. For these reasons, there is a clear need of translational studies focused on at least some of these factors [
57]. In this context, studies aiming to clarify the optimal surfactant concentration and dose to be administered are urgently needed.
2.
Explanatory should be preferred over pragmatic design for future clinical trials on PARDS and NARDS (strong agreement).
This is the direct clinical counterpart of the previous point. ARDS is a very heterogeneous syndrome with various origins, presentations, severity, comorbidities and co-interventions. Trials enrolling broad groups of patients mixing all these factors are called pragmatic and seek a ‘real-world’ answer regarding an established intervention or refinement of current care [
58]. This is not the case of surfactant and ARDS, since surfactant therapies are not yet standard of care for NARDS and PARDS and may represent a major improvement, rather than a minor refinement. Furthermore, although surfactant has a strong preclinical background suggesting its usefulness in ARDS, several concomitant clinical factors could influence response to treatment and outcomes [
14,
16,
17,
53‐
55]. Patients’ age, type of ARDS, comorbidities, timing of the intervention, type and dose of surfactant, ventilatory policy and cointerventions are examples of the factors potentially important to stratify for. Trials with a highly specific selection or stratification are called explanatory and are more suitable and likely to provide significant results, although they are more complex and long-lasting [
58]. There are at least 10 items to be considered in order to evaluate the pragmatism of a trial design [
59]. Thus, future clinical trials should be as more explanatory as possible and focus on homogeneous groups of patients, according to the recently accumulated knowledge. In the UK, such trials are termed ‘efficacy and mechanism evaluation studies’ as they allow experimental mechanism evaluation that is unhindered by predefined trial outcome measures [
60]. The choice of an explanatory design reflects the complexity of PARDS and NARDS, the need to consider them as multifaceted syndromes and to learn from correspondent preclinical models. When it comes to PARDS, patients’ age should also be restricted as much as possible, as it may significantly influence surfactant pharmacology and susceptibility to lung injury [
9]. It is interesting to note that ventilation is the main co-intervention in these trials and was extremely variable and even non-protocolized in neonatal trials. This significantly reduces the trial quality and may have hindered the possibility to detect any effect of surfactant therapy.
A next step for a correct trial design would be a formal post hoc analysis of available data trying to identify which type of patients and ARDS should be the more likely to benefit from surfactant or which surfactant preparation should be preferred. According to a similar
post hoc analysis of clinical trials conducted in adults [
61] and to the recent knowledge on ARDS pathobiology and pharmacology [
62], direct (primary) ARDS is more likely to benefit from surfactant treatments. In the future, we can imagine an even more individualized therapy by using genomic approaches or biomarkers of ARDS severity and type: the surfactant adsorption test [
63‐
65] and the surfactant protein-D assay [
66,
67] are two of the most advanced tools in this field. These, and other that may eventually come, can open the way for a precision medicine approach to ARDS surfactant therapy, as it is proposed in similar fields [
68]. From a pharmacological point of view, preferably, an enhanced surfactant more resistant to phospholipase and inactivation has higher chances to be beneficial. A more concentrated surfactant seems also preferable, but the ideal dose and administration technique as well as the best strategy to spread it and increase alveolar delivery are still unknown and require specific studies.
4.
Different clinical outcomes need to be chosen for PARDS and NARDS, according to the trial phase and design, type of trigger, severity class and/or surfactant treatment policy (strong agreement).
In general, trials must be conducted taking into consideration the most recent epidemiological data and a combination of clinically meaningful short- and long-term outcomes. For instance, it would be illogical to have mortality as a short-term outcome for mild PARDS or NARDS, as these are already subjected to relatively low mortality, while oxygenation, physiology parameters and burden of care measures are more suitable. As long-term outcomes, respiratory function measures may be preferred over pediatric quality of life measures which may be influenced by several other confounders [
69].
Pathophysiological and biological plausibility is extremely important. Researchers should give priority to outcomes with a known direct pathophysiological link with the syndrome (such as short-term mortality, ventilator-free days and indices of gas exchange or oxygenation) [
70‐
72]. Conversely, clinical endpoints that do not have a direct and clear connection with PARDS or NARDS should not be considered as primary outcomes. For instance, preterm neonates affected by NARDS may have negative long-term outcomes related to prematurity rather than to NARDS itself. Similarly, PARDS patients with malignancies may have a number of complications and negative outcomes because of their underlying disease rather than PARDS itself. Need for extracorporeal life support should only be considered if homogeneously available and defined in each recruiting center.
Finally, not only endpoints, but also the trajectory of disease should be considered in trial design. There are multiple benefits in doing so. For instance, oxygenation or ventilation metrics as well as lung mechanics parameters are repeated measures that lend themselves to multilevel (mixed effects) modeling. This will increase statistical power, which may be very important when studying particular populations in explanatory trials. This is also consistent with a personalized medicine approach as described above. Last but not least, multilevel modeling/trajectory analysis may adjust for the presence of other influencing factors such the availability of extra-corporeal life support or other co-interventions.