Analysis of the effectiveness of pulmonary surfactant in the treatment of moderate and severe acute respiratory distress syndrome in infants and toddlers —a multicenter prospective study

doi:10.21203/rs.3.rs-1963064/v1

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Analysis of the effectiveness of pulmonary surfactant in the treatment of moderate and severe acute respiratory distress syndrome in infants and toddlers —a multicenter prospective study

https://doi.org/10.21203/rs.3.rs-1963064/v1

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Background

To determine the effectiveness of exogenous pulmonary surfactant (PS) on moderate or severe pediatric acute respiratory distress syndrome (PARDS) in infants and toddlers who need invasive mechanical ventilation support.

Methods

We conducted a multicenter prospective non-randomized control study in 14 tertiary pediatric intensive care units (PICUs) across China from 2016.12.1 to 2021.12.1. Infants and toddlers aged from 29 d to 3 years old with moderate or severe PARDS who needed invasive mechanical ventilation support were included and divided into experimental and controlled groups. In the experimental group, PS with a single dose of 140 mg was used after PARDS onset and it would be used once to thrice with an interval of 8 h according to the improvement of oxygenation index (OI). Patients in both groups received standard care.

Results

101 patients were enrolled, 34 in PS group, 67 in control group. Demographic and baseline clinical data have no statistic differences. Mortality in the PS group is significantly lower (5.9%, 2/34 vs. 31.3%, 21/67, P = 0.004). The OI decrease within 24 hours in patients who use PS thrice is significantly faster than that in the control group [5.9 (2.53,12.73) vs. 2.6 (-2.2, 6.2), P = 0.048]. Subgroup analysis shows that OI improvement within 24 h (0.32 ± 0.21 vs. 0.02 ± 0.45, t = 2.08, P = 0.046) and 72 h [0.37 (0.17, 0.56) vs. 0.03 (-0.31, 0.40), z=-1.885, P = 0.059]is greater in PS-3 group compared to dead patients in control group.

Conclusions

Exogenous PS delivery may improve the pulmonary oxygenation in the acute phase of moderate or severe PARDS among infants and toddlers, thereby further decrease mortality. PS is expensive and should be used properly. Further study is needed to verify the effectiveness of PS in treating PARDS and identify the reasonable administration time and dosage.

Trial registration:

The research was registered in Chinese Clinical Trial Registry website (Registration Number: ChiCTR-ONC-16009213, 17/09/2016).

pulmonary surfactant

pediatric acute respiratory distress syndrome

pediatric intensive care unit

oxygenation index

infants and toddlers

Pediatric acute respiratory distress syndrome (PARDS) is one of the major diseases in pediatric intensive care units (PICUs). Some studies have shown that the mortality rate of PARDS ranged from 24–40%^[1]. The type II alveolar epithelial cells and capillary endothelial cells are damaged during PARDS, which reduces the content of the pulmonary surfactant (PS) and inhibits its activity. Consequently, pulmonary oxygenation function rapidly deteriorates in a short time, this may lead to higher conditions of mechanical ventilation, extracorporeal membrane oxygenation use, and even death or severe disability in survival^[2]. One of the focuses of ARDS research is on the exogenous PS (porcine/bovine lung source or synthetic) and whether it can improve oxygenation and ameliorate the primary outcomes, such as mortality and mechanical ventilation duration.

Most studies support that exogenous PS can improve oxygenation without evident adverse effects, however, the relationship between PS and the primary outcomes remains unknown^[3–6]. The etiology of PARDS is more complicated than the neonatal RDS, and the outcomes are often influenced by underlying diseases and complications^[7]. The PS is expensive, meanwhile, the medication timing, dose, course of treatment, and improved oxygenation maintenance time are uncertain. Therefore, the 2015 Pediatric Acute Lung Injury Consensus Conference (PALICC) guidelines do not recommend PS as a routine treatment for PARDS. However, conduction of trials is recommended to identify the relationship between PS and the outcomes of PARDS ^[8]. Therefore, this multicentre prospective trial was conducted to investigate the effectiveness of exogenous PS on moderate and severe PARDS among infants and toddlers who needed invasive mechanical ventilation.

Study design and patients

This is a multicentre prospective non-randomised controlled trial conducted in 20 PICUs across China from 2016.12.1 to 2021.12.1. PARDS diagnosis and the severity grading are based on the 2015 PALICC guidelines. Patients’ inclusion criteria include: (1) infants and toddlers aged from 29 d to 3 years old of either gender with moderate or severe PARDS who need invasive mechanical ventilation and (2) whose length of PICU stay is ≥ 72 h. Patients’ exclusion criteria include: (1) patients with congenital or secondary heart diseases, or with chronic pulmonary diseases, (2) patients with tracheal lesions such as tracheal stenosis and malacia, (3) those with severe brain injuries, neuromuscular diseases, and some end-stage diseases, and (4) those with incomplete data uploaded.

Study drug

Surfactant (Calf Pulmonary Surfactant for injection, produced by Shuang He Inc., Beijing, China) is a modified natural lung surfactant. It is produced by extracting the phospholipids, cholesterol, triglycerides, free fatty acids, surfactant protein B, and surfactant protein C from the bovine lung surfactant of new-born calf lungs. It is approved by the China Food and Drug Administration to be used as PS for neonatal RDS. The study drug is commonly used in neonatal intensive care unit of each participating site, so we can easily get it by an application to Hospital Pharmacy Committee.

Group division and intervention

Patients were grouped according to the use of PS or not. It was not a randomised grouping given that PS use was decided together by doctors and the patients’ guardians. PS was used in patients in the experimental group under the doctors’ recommendation and agreement of their guardians. However, PS was not used for patients in the control group, either because it was not recommended by doctors or refused by guardians. The major factor to physicians’ recommendation is the severity of PARDS. The factors to parents’ decision mainly includes PS costs and the concern for long time living quality.

In the experimental group, PS with a single dose of 140 mg was used within 12 hours after PARDS onset. PS would be used once to thrice with an interval of 8 h according to the improvement of oxygenation index (OI). PS delivery: (1) after fully endotracheal aspiration, sedation/analgesic drugs and muscle relaxants are given to minimise spontaneous breathing and eliminate cough reflex, (2) PS is implanted into the trachea through an endotracheal tube using a small catheter in 4 equal aliquots, which would be fixed in four different positions (left, head up then down/right, head up then down), and (3) then extend tracheal suctioning is performed at least 2 h later.

Patients in both groups received standard care according to the hospital protocol. The basic patient care contained vital signs monitoring, fluid management, enteral feeds, pain management, and infection control if necessary. A lung-protective ventilation strategy was utilised to all patients in PICUs. Ventilator settings, such as PEEP, FiO₂, respiratory rate and tidal volume were adjusted to keep SpO₂ within 88%-97%. The tidal volume goal is mostly set to 6 to 8 ml/kg.

Data collection

Data was extracted from the hospital information system of each participating PICU and uploaded to a pre-designed case record form on the Chinese Clinical Trial Registry website (NO. ChiCTR-ONC-16009213，17/09/2016). Data extracted included patient demographics, blood gases, ventilator settings, complications, ventilator duration, PICU length of stay, and clinical outcomes. OI was derived from the data measured before and at 24 h, 48 h, and 72 h after the first dose of PS delivery (PARDS identified) in the experimental (control) group. The severity of illness was assessed when PARDS was identified by pediatric critical illness score (PCIs) ^[9]. PCIs is a widely used tool to assess disease severity in critically ill children in China. Listed items include cardiac/respiratory rate, systolic pressure, PaO₂, PH, Na+, K+, and serum creatinine/urea nitrogen, hemoglobin and gastrointestinal function. However, it is not a tool for assessment of children’s multi-organ function. The Pediatric Logistic Organ Dysfunction score was not collected in this study, however severe complications were listed in Table-1. The occurrence of pneumothorax, pulmonary haemorrhage, and mediastinal emphysema was also recorded.

Statistical Analysis

Quantitative data were presented as mean ± standard deviation (normal distribution) or median with interquartile range (non-normal distribution). Either the unpaired t-test or Mann-Whitney U test was used to compare data between the two groups. Counting data were presented as frequencies or percentages; Chi-square or Fisher’s exact test was used to compare data. Data were analysed by SPSS version 24.0. The P < 0.05 was considered statistically significant. The drawing tool is the GraphPad Prism 9.

Demographic and baseline clinical characteristics

A total of 101 patients were enrolled from 14 PICUs across China, 34 are in the PS group, meanwhile, 67 are in the control group. Six PICUs were excluded from this study because they didn’t report any relevant cases or their data uploaded was incomplete. Detailed demographic and baseline clinical information are listed in Table 1. There is no significant difference found in age, weight, gender, PCIs, baseline OI, and the etiology of PARDS. Patients with PARDS caused by pulmonary diseases are slightly more than by extrapulmonary diseases in both groups. In this study, the underlying diseases or complications associated with PARDS mainly include primary immunodeficiency, myelosuppression, septic shock, hematological tumour, and hemophagocytic syndrome, all have no significant differences between two groups.

Table 1

demographic and baseline clinical data
Variable	Standard care (n = 67)	PS treatment (n = 34)	Statistical value, P
Gender(M/F)	44/23	19/15	X² = 0.921, 0.337
Age(y)	1.06 ± 0.66	0.98 ± 0.65	T = 0.54, 0.59
Weight(kg)	9.4(7.0, 11.0)	8.9(7.0, 11.25)	Z=-0.06, 0.95
PCIS	76(70, 80)	71(70, 78)	Z=-1.46, 0.15
OI	14.5(10.1, 20.8)	16.35(11.68, 22.14)	Z=-1.03, 0.3
Etiology of PARDS
Pulmonary disease	34	18	X² = 0.044, 0.835
Extra-pulmonary disease	26	11	X² = 0.405, 0.525
uncertain	7	5	X² = 0.09, 0.764
Complications or underlying diseases	23	11	X² = 0.039, 0.843
Septic shock	6	2	X² = 0.023, 0.88
ID or MS	11	5	X² = 0.05, 0.824
Hematological tumor	4	0	X² = 0.835, 0.361
Hemophagocytic syndrome	6	0	X² = 1.833, 0.176
Others	9	7	X² = 0.866, 0.352
PCI: pediatric critical illness score; OI: oxygenation index; ID: immune deficiency; MS: myelosuppression

Outcomes

Mortality rate in the PS group is significantly lower than the control group (5.9%, 2/34 vs. 31.3%, 21/67, X² = 8.314, P = 0.004). There is no significant difference found in the length of PICU stay and length of hospital stay after PARDS are identified, mechanical ventilation mode and duration, OI at 0 h, 24 h, 48 h, and 72 h, and the average daily cumulative fluid volume within 72 h. Pneumothorax, mediastinal emphysema, and pulmonary haemorrhage are the reported complications of PS, all have no significant differences between two groups. Detailed information is shown in Table 2.

Table 2

treatments and outcomes
variable	Standard care n = 67	PS treatment n = 34	Statistical value, P
Length of PICU stay after PARDS identified	14(8, 24)	16(9, 25)	Z=-0.698, 0.485
Length of hospital stay after PARDS identified	20(12, 28)	19(14.75, 27.75)	Z=-0.654, 0.513
MV mode(C/H)	55/12	24/10	X² = 1.751, 0.186
MV time(h)	280(168, 446.5)	309(192, 540)	Z=-0.69, 0.49
daily liquid accumulation within 72 hours(ml/kg.d)	8.72 ± 13.61	10.74 ± 16.23	T=-0.659, 0.511
Local complications	10	5	X² = 0.001,0.977
pneumothorax	6	3	X² = 0.000, 1.0
Mediastinal emphysema	2	0	Fisher, 0.549
Pulmonary hemorrhage	2	2	X² = 0.027, 0.868
Mortality	31.3%	5.9%	X² = 8.314, 0.004
MV(C/H): mechanical ventilation (conventional/high frequency);

Figure 1 shows that the decrease of OI within 24 h in the PS group is faster than that in the control group, however, there was no significant difference found [3.08 (-1.05, 7.19) vs. 2.6 (-2.2,6.2), Z = -1.369, P = 0.171]. Therefore, further analysis was conducted according to the times of PS delivery. Figure 2 shows that the baseline of OI of patients who used PS thrice is higher than that in the control group, however, no significant difference was found. By contrast, the OI decrease within 24 h is significantly faster than that in the control group. Sub-group analysis was carried out between the patients with thrice PS delivery and children dead in the control group. There are no significant differences found in PCIs, baseline OI, age, body weight, underlying diseases, and complications. The detailed information is listed in Table 3. Figure 3 shows that the OI decreases within 24 h in the PS-3 group is faster than that in the sub-control group with a P-value of approximately 0.05. Improvement of OI within 24 h (OI decrease within 24 h/baseline OI) in PS-3 group is significantly greater than that in the sub-control group, and OI improvement within 72 h is also better. The mortality in the PS-3 group is 9% (1/11).

Table 3

comparison between patients with 3 times PS use and patients died in control group
Variable	PS treatment (n = 11)	Standard group (n = 21)	Statistical value, P
Gender(M/F)	6/5	12/9	Fisher, 1.0
Age(y)	1.15 ± 0.52	1.03 ± 0.75	T = 0.501, 0.62
Weight(kg)	9.94 ± 2.24	9.32 ± 3.28	T = 0.558, 0.581
PCIS	74.09 ± 5.15	73.14 ± 10.13	T = 0.29, 0.774
OI	22.05(11.3, 27.3)	18.6(11.6, 26.4)	Z=-0.099, 0.921
Complications	4	9	Fisher, 1.0
Daily liquid accumulation within 72 hours(ml/kg.d)	18.6 ± 21.74	5.08 ± 16.91	T = 1.946, 0.061
Local complications	3	7	Fisher, 1.0
Mortality	1/11	21/21	Fisher, 0.0

Pulmonary surfactant has been used in the PARDS treatment since many years ago^[10], it is not recommended as a routine drug in treating PARDS partly because its association with mortality, mechanical ventilation duration, and other direct prognostic indicators for PARDS is uncertain. Factors such as the inconclusive timing and dosage, the different components among different products, and the high cost also limit the routine use of PS^[11]. The dosage of PS is related to the area of the alveolar-capillary membrane; however, an accurate evaluation is difficult to achieve. Patients aged ≤ 3 years were chosen as the sample population to reduce the bias and cost in this study.

The early administration of a certain dose of the PS was found to accelerate the improvement of the OI among patients within 72 h, particularly within 24 h of the moderate or severe PARDS onset. A theoretical basis for exogenous PS in improving OI in ARDS is sufficient^[2]. Although there are numerous causes of PARDS, its common pathophysiological change is the decrease in the amount of endogenous PS and the inhibition of its activity caused by the damage of type II alveolar epithelial cells and capillary endothelial cells^[12]. Endogenous PS deficiency leads to alveolar collapse and intrapulmonary shunt, thus reducing the lung volume and lung compliance, thereby causing unimprovable hypoxemia, and pulmonary hypertension, and may be further followed by right heart failure, shock, multiple organ failure, and even death. Exogenous PS can play an alternative role in this stage. Most studies on the effectiveness of the PS on PARDS describe an improvement in pulmonary oxygenation^{[3, 4, 6, 12]}.

In our study, the mortality in the PS group is significantly lower than that of the control group. Based on the results of the subgroup analysis, we consider that the PS may reduce the mortality by accelerating OI improvement in acute phase of PARDS especially in children with "the most severe oxygenation deterioration"^[13]. Patients in the PS group were given PS once to thrice under their doctors’ recommendation according to the OI. Thus, patients in this group who used PS three times had the worst oxygenation level (as shown in Fig. 2). Some patients in the control group were not given PS because it was not recommended by their doctors as the oxygenation deterioration was relatively mild or could be improved rapidly after receiving common treatment with mechanical ventilation. Other patients in the control group had severe oxygenation deterioration and thus the use of PS was recommended, however, their guardians’ refusal of PS treatment causes this group of patients to have the highest mortality. In our study, children in the end-stage of diseases or with chronic cardiac/pulmonary diseases were excluded. Therefore, the dead patients in the control group were also considered to also have the worst oxygenation [baseline OI of the dead and surviving patients in the control group, 18.6 (11.6, 26.4) vs. 13.4 (9.95, 18.2), Z = 1.899, P = 0.058].

Although, most of the current studies confirm the effectiveness of the PS on improving oxygenation or decreasing the mechanical ventilation time, it is controversial whether PS can improve the mortality of PARDS^{[3, 5, 14–16]}. However, few studies suggest that PS can improve the mortality of PARDS^{[15, 16]}. We considered that is partly related to the different groups of patients included in different studies, and also the different timing and dosage of the PS used. The etiology of PARDS is very complicated, some patients with combined neuromuscular system diseases or have been in the end-stage of underlying diseases before the onset of PARDS. After the 2015 PALICC guidelines were published, some researchers also included children with chronic cardiac/pulmonary diseases. All the above-mentioned can contribute to the mortality and other primary outcomes of PARDS^[7]. Such kinds of patients were excluded from our study. It has been reported that the OI in the early stage of PARDS can predict its outcomes, which partly supports the results of this study^[17].

Oxygenation deterioration in some patients who have moderate/severe PARDS is less serious or can be well managed with common treatment such as mechanical ventilation. No evidence supports PS will be beneficial to these patients but rather increase medical expenses. Referring to the 25th percentile of baseline OI in subgroup analysis, the OI threshold of the PS treatment may be set to higher than 8 to avoid unnecessary waste of medical resources, except for some patients with rapid OI deterioration. Further studies are required to identify a new threshold. The reported duration of the endogenous PS damage is 4–8 days or longer, however, it is not supported with strong evidence therefore it is unclear^[18]. In our study, a dosage of 140 mg of PS, given to the patients up to thrice with an interval of 8 h during the acute phase of PARDS can significantly decrease the mortality, therefore, prolonged treatment till the endogenous PS recovery is not recommended. Pulmonary surfactant is delivered via a thin catheter combined with postural changes, this process may not ensure the equal distribution of PS. It is a sample and available method for drug administration and has been used in some research^{[3, 19]}.The effectiveness of this method is supported in our study. We did not find any pneumothorax, pulmonary hemorrhage, mediastinal emphysema, or other complications that are directly caused by exogenous PS delivery, the safety usage of the PS is similar to other studies^{[5, 15, 16]}.

Standard PS dose has not been established and remains exploration. In several published studies, the dose range is 20–175 mg/kg ^{[3, 15, 19]}. The subjects in our research are between 29d to 3ys old, and majority of them weigh between 4–13 kilograms. The PS product we use is 70 mg per servings and is relatively expensive. So, we used a fix dose of 140 mg per time, and prepared to repeat 1–3 times according to pulmonary oxygenation, which can ensure the total dose within the range of published studies and control the cost. Several studies evaluated the effectiveness of PS within 12–24 h after the initial dose, the extent of pulmonary oxygenation function improvement was individualized, while some patients suffered oxygenation deterioration after initial improvement ^{[3, 4, 15]}. We repeated blood gas analysis, calculated OI and reviewed the clinical status of patients at an interval of 8 h to assess the patients more carefully due to dose bias existed. We repeated doses of PS when pulmonary oxygenation or relative clinical status deteriorated or not improved. We described an association between PS administration and improvement of OI and mortality under our dosage regimen, although we must admit the dose bias does exist. Further studies should increase the sample size to explore the exact dose of PS through stratified analysis by weight or body length. we will also consider further study on elder children when the effectiveness and applicable dosage of PS is clearer.

The number of patients included in this study is relatively small. PS was administered via a thin catheter combined with postural changes, therefore, even distribution to all the lobes in both lungs is not ensured. Dose bias due to different lung volumes exists as we use the fixed dose in all patients. However, to our knowledge, there is no established dose recommendation for the use of PS in treating PARDS.

Exogenous PS delivery may improve the pulmonary oxygenation in the acute phase of moderate or severe PARDS among infants and toddlers, thereby further decrease mortality. PS is expensive and should be used properly. The OI threshold for PS medication needs further exploration. Further study is needed to verify the effectiveness of PS in treating PARDS and identify the reasonable administration time and dosage.

pediatric acute respiratory distress syndrome	PARDS
pediatric intensive care units	PICUs
pulmonary surfactant	PS
Pediatric Acute Lung Injury Consensus Conference	PALICC
oxygenation index	OI
pediatric critical illness score	PCIS

Ethics approval and consent to participate: This study was approved by the Ethics Committee of Beijing Children’s Hospital, Capital Medical University, No 2016-66. Informed consent to participate in the study have been obtained from participants’ guardians. We confirmed that all experiments were performed in accordance with relevant guidelines and regulations.

Consent for publication: No individual person’s data is included in this paper.

Availability of data and materials: The datasets generated during and/or analysed during the current study are not publicly available due to identify information included, but are available from the corresponding author on reasonable request. The research was registered in Chinese Clinical Trial Registry website (Registration Number: ChiCTR-ONC-16009213, 17/09/2016).

Competing interests: On behalf of all authors, the corresponding author states that there is no financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.

Funding: medical special fund from Wu Jieping Medical Association, NO. 320.6750.17192.

Authors’ contributions: Boliang Fang performed the data analyses and wrote the manuscript;

Suyun Qian and Jiansheng Zeng designed this research and revised the final paper;

Kechun Li and other authors performed the experiment and collected/uploaded the data, and helped perform the analysis with constructive discussions.

Acknowledgements: NO.

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No competing interests reported.

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Analysis of the effectiveness of pulmonary surfactant in the treatment of moderate and severe acute respiratory distress syndrome in infants and toddlers —a multicenter prospective study

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Version 1

Abstract

Background

Methods

Results

Conclusions

Trial registration:

Figures

Background

Methods

Results

Demographic and baseline clinical characteristics

Outcomes

Discussions

Limitations

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1