Acute respiratory distress syndrome (ARDS) is a severe clinical syndrome presents with dyspnea, tachypnea, refractory hypoxemia, decreased pulmonary compliance, and alveolar opacities on chest imaging. Historically, pediatric ARDS (PARDS) definitions were based on adult criteria, but the Pediatric Acute Lung Injury Consensus Conference (PALICC) later established criteria tailored to children [1–3]. PARDS presents as respiratory failure arising within one week of a known precipitating event, without complete explanation by heart failure or fluid overload, accompanied by chest radiography that reveals pulmonary infiltrates indicative of parenchymal illness [4].

A notable distinction from adult ARDS criteria is the incorporation of oxygenation index (OI) or oxygen saturation index (OSI) for severity classification. Mild PARDS is defined by an OI of 4 to less than 8, and an OSI of 5 to less than 7.5, moderate by an OI of 8 to less than 16 and OSI of 7.5 to less than 12, and severe by an OI of 16 or greater and an OSI of 12 or above [5].

The objectives of PARDS care are to address the underlying etiology, optimize oxygen delivery and air ventilation, with lung preservation from volutrauma, barotrauma, and atelectrauma. Non-depolarizing neuromuscular blocking agents (NMBAs) have been proposed as an adjunctive therapy for patients with intractable hypoxemia, ventilator dyssynchrony, and reduced pulmonary compliance [6,7]. NMBAs may improve oxygenation by decreasing oxygen consumption, promoting alveolar recruitment, and reducing respiratory muscle activity, thereby enhancing oxygen saturation (SpO2) and arterial oxygen partial pressure (PaO2) [8].

Cisatracurium, a 4 to 5 times more potent isomer of atracurium, offers a predictable organ-independent metabolism via Hofmann elimination, minimizing histamine release and laudanosine accumulation, making it safer and advantageous over other agents in critically ill pediatric patients requiring prolonged paralysis [9,10].

Evidence for NMBA use in ARDS remains conflicting. Some trials have reported that early cisatracurium infusion improves oxygenation, prolongs mechanical ventilator (MV) free days, and may improve survival [11–13], whereas others have shown no significant clinical benefit over standard care [14]. Given the limited evidence regarding the use of neuromuscular blockades in PARDS, we sought to compare the outcomes of continuous cisatracurium infusion versus intermittent bolus administration in children with PARDS.

A total of 142 patients were assessed for eligibility. After applying the inclusion and exclusion criteria, 32 patients were excluded. The remaining 110 eligible patients were randomized to receive either intermittent boluses of cisatracurium (group I, n=59) or continuous IV infusion (group II, n=51). During follow-up, 11 patients in group I and seven patients in group II discontinued the allocated intervention due to protocol deviations. However, they continued to be followed for outcome assessment. All randomized participants received the allocated intervention and were included in the ITT analysis (n=59 in group I; n=51 in group II) (Fig. 1).

Fig. 1.

CONSORT patient selection flowchart. Of the 142 screened patients, 110 were randomized (59 to intermittent boluses group, and 51 to the continuous infusion group). All randomized patients were included in the intention-to-treat analysis. NMBA: neuromuscular blocking agent.

There was no significant difference in demographic data, the etiology and severity of PARDS, PRISM III score, and GCS on admission between the studied groups. Regarding crude clinical outcomes, PICU mortality was significantly lower in group II compared to group I. Among survivors, patients receiving continuous cisatracurium infusion had a significantly shorter duration of MV and significantly shorter PICU LOS compared to those receiving intermittent boluses. Interleukin-8 showed no significant difference between the two studied groups at baseline and after 24h. However, interleukin-8 levels significantly decreased after 24h compared to day 1 in both groups as shown in Table 1.

As shown in Table S1, no statistically significant differences were detected between the groups regarding heart rate (HR), mean arterial blood pressure (MABP), hemoglobin, RBG, white blood cells (WBCs) count, hepatic aminases, serum albumin or renal function at any measured time points. However, several significant within-group changes occurred during the follow-up period. Both groups showed significant reduction in HR, RBG, and serum lactate from day 1 to day 3 and 7, indicating metabolic recovery. Creatinine clearance increased significantly within both groups during follow-up, while serum AST decreased significantly in group II by day 7. Inter-group differences in serum lactate emerged by days 3 and 7, with group II showing significantly lower values.

When the studied groups were stratified by PARDS severity in Table S3, mild cases demonstrated no significant inter-group differences in any of the assessed hemodynamic, hematologic, or organ function parameters during the follow-up period. In moderate-to-severe PARDS, inter-group differences became noticeable over time. By day 7, MABP was significantly higher, and serum lactate was significantly lower in group II. Group II also showed higher reductions in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Although albumin and creatinine clearance improved significantly with both groups, they demonstrated more rapid recovery in the continuous infusion group.

Table S2 shows that both groups exhibited significant improvements in pH, partial pressure of carbon dioxide (PaCO2), PaO2, bicarbonate (HCO3), FiO2, OI, and P/F ratio from day 1 to days 3 and 7. Intergroup differences in the study was limited; however, by day 7 group II showed significantly higher pH, lower MAP, and lower FiO2.

Stratified analysis in Table S4 showed no significant differences between groups in mild PARDS for any of the ventilation or oxygenation parameters. Both groups showed significant improvements in pH, PaCO2, FiO2, OI, and P/F ratio. In contrast, moderate-to-severe PARDS showed significant differences favoring continuous cisatracurium infusion. By day 7, group II exhibited significantly higher pH, lower FiO2, reduced PEEP, and lower MAP. OI improved significantly more in group II at days 3 and 7. Also, P/F ratio was significantly higher in group II in the same period. Collectively, these findings indicate that while both regimens improved gas exchange and oxygenation indices over time, continuous cisatracurium infusion was associated with superior improvements in ventilatory mechanics clinical outcomes in moderate-to-severe PARDS, supporting its potential role in optimizing management in this subgroup (Fig. 2).

Fig. 2.

Oxygenation index (OI) over time according to treatment group. (a) All randomized patients; (b) patients with mild pediatric acute respiratory distress syndrome (PARDS); (c) patients with moderate-to-severe PARDS. OI was assessed at baseline, day 3, and day 7.

Competing-risk regression using the fine-Gray hazard model was conducted to account for death as a competing event for both duration on MV and PICU discharge. Continuous cisatracurium infusion was significantly associated with higher hazard of successful liberation from MV in all participants (SHR 2.07; 95% CI 1.34–3.2; p=0.001). When stratified by PARDS severity, this effect was not significant among mild PARDS patients but remained strong and highly significant in those with moderate-to-severe PARDS (SHR 3.25; 95% CI 1.69–6.25; p<0.001), showing a more than threefold likelihood of extubation relative to intermittent boluses. When conducted for PICU LOS, it demonstrated similar patterns. Continuous cisatracurium infusion was associated with a significantly higher hazard of PICU discharge in the intention-to-treat population (SHR 2.09; 95% CI 1.34–3.26; p=0.001). While it did not also reach significance in mild PARDS, it remained strong and significant in moderate-to-severe cases (SHR 3.16; 95% CI 1.64–6.11; p=0.001) (Table 2) (Figs. 3 and 4). No cases of anaphylaxis or severe hypotension were observed. No clinically apparent ICU acquired weakness was documented; however, no neuromuscular assessment tool was used.

Fig. 3.

Cumulative incidence curves for extubation from mechanical ventilation. Fine-Gray competing-risk analysis accounting for death as a competing event. (a) All randomized patients; (b) patients with mild pediatric acute respiratory distress syndrome (PARDS); (c) patients with moderate-to-severe PARDS.

Fig. 4.

Cumulative incidence curves for pediatric intensive care unit (PICU) discharge. Fine-Gray competing-risk analysis accounting for death as a competing event. (a) All randomized patients; (b) patients with mild pediatric acute respiratory distress syndrome (PARDS); (c) patients with moderate-to-severe PARDS.

PARDS, defined by PALICC in 2015 and updated in 2023, remains a significant cause of PICU morbidity and mortality [4,21]. In adults, early neuromuscular blockade has shown mixed effects on oxygenation and survival, leaving its role uncertain [22,23]. Evidence in PARDS remains limited.

In the current study, in moderate-to-severe PARDS cases, the continuous infusion group had lower FiO2, OI, MAP, and PEEP on day 7 compared to the intermittent bolus group. A significant reduction in OI, MAP, and PEEP over time was observed only in the continuous infusion group. These findings align with Chandra et al. [24] who reported significantly lower OI after 48h of continuous vecuronium infusion compared with a control group that did not receive NMBA therapy. Similarly, Wilsterman et al. [25] observed immediate improvements in OI, PaO2/FiO2, and decreased MAP following rocuronium infusion in infants with moderate-to-severe PARDS. Supporting these results, a meta-analysis by Gao et al. [26] demonstrated that, in adults with ARDS, early NMBA use within 48h improved PaO2/FiO2 by 72–96h and reduced PEEP and plateau pressure, suggesting improved ventilation and gas exchange.

The observed benefits of continuous NMBA infusion in moderate-to-severe PARDS may be related to improved patient-ventilator synchrony with more controlled ventilation during the early phase of lung injury [27,28]. While prior studies suggested that spontaneous breathing during mechanical ventilation may contribute to regional ventilation inhomogeneity and pendelluft phenomena, these mechanisms were directly assessed in the present study. Therefore, any mechanistic interpretation should be considered hypothesis-generating rather than confirmatory [29,30].

The present study demonstrated a significant reduction in IL-8 levels 24h after admission in both groups, with no significant difference between them. This aligns with Grawe et al. [31] who reported that NMBAs exerted molecular benefits by reducing key biomarkers of tissue injury and systemic inflammation, including IL-8, which is a marker of endothelial damage. These findings suggest that NMBAs may attenuate the inflammatory cascade contributing to lung injury in ARDS. Similarly, Sottile et al. [32] observed that the use of NMBAs in ARDS patients with a PaO2/FiO2 ≤120 was associated with decreased markers of epithelial and endothelial injury. They also highlighted that unregulated spontaneous breathing may exacerbate lung damage in severe ARDS, further supporting the use of controlled NMBAs in moderate-to-severe ARDS patients.

In the present study, after adjusting death as a competing event, continuous cisatracurium infusion remained independently associated with earlier extubation and PICU discharge. This effect was concentrated almost exclusively among children with moderate-to-severe PARDS, while no significant advantage was observed in mild cases. These findings are consistent with Chandra et al. [24] who observed a reduction in mortality in PARDS patients treated with vecuronium. Lyu et al. [33] found that early 48h NMBA infusion in adults with moderate-to-severe ARDS significantly reduced ICU mortality and recommended short-term NMBA use during the early phase. Similarly, Torbic et al. [34] concluded that early NMBA administration improved oxygenation, lowered the incidence of ventilator-induced lung injury, and reduced mortality.

Shorter MV duration is clinically relevant given the acknowledged association between prolonged ventilation and adverse outcomes in critically ill children as increased mortality, extubation failure, ventilator-associated pneumonia, lung injury, nosocomial infections, and prolonged PICU/hospital stay [35–37].

In moderate-to-severe PARDS, NMBA use should follow the implementation of a lung-protective ventilation strategy with optimized PEEP and adequate sedation. Once MV and sedation are stabilized, NMBA use should be guided by objective physiological indicators such as persistent ventilator asynchrony, refractory hypoxemia, or unsafe ventilation parameters. Importantly, NMBAs should be discontinued promptly once gas exchange improves to facilitate spontaneous breathing and minimize potential complications [38].

This study had some limitations. The sample size was relatively small, especially after the stratification by PARDS severity. Subgroup analyses were exploratory and not powered for independent statistical significance, therefore it should be interpreted with caution. The unblinded nature of the study may have introduced bias; however, its impact was mitigated by using objective, predefined criteria for extubation and PICU discharge. ICU-acquired weakness and neurodevelopment of survivors were not assessed using a validated neuromuscular assessment tool. The study did not include direct assessment of respiratory effort, regional ventilation, or lung mechanics, limiting mechanistic inference regarding the clinical benefit. Although the trial was prospectively registered with a planned follow-up period of 10 days, harmonization to a 7-day protocol was done to ensure consistent data capture across centers. This modification did not alter endpoint definitions or conclusions.

In conclusion, continuous cisatracurium infusion was associated with improved clinical outcomes in moderate-to-severe PARDS compared to intermittent boluses, including enhanced oxygenation, higher incidence of extubation from MV, and PICU discharge, while outcomes in mild PARDS were comparable between groups.

MKT: Conceptualization, Methodology, Formal analysis, Investigation, Resources, Writing – Original Draft, Visualization. HMI: Conceptualization, Methodology, Validation, Writing – Review & Editing, Supervision. HAB: Investigation, Validation, Writing – Review & Editing. OMI: Conceptualization, Methodology, Validation, Writing – Review & Editing, Supervision, Project administration.

None of the material has been partially or totally produced with the help of any artificial intelligence software or tool.

The authors did not receive any funding or sponsorship support.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.