A nomogram to predict extubation failure in infants born before 32 gestational weeks: a single-center retrospective study

Introduction

In the past few decades, with progress made in perinatal medicine, the survival rate of preterm infants has increased year by year, and the incidence of neonatal respiratory distress syndrome (RDS) has increased (1). Despite the fact that the early use of pulmonary surfactants (PS) and non-invasive ventilation have been proven effective in the prevention and treatment of RDS, some preterm infants still require mechanical ventilation. However, prolonged mechanical ventilation may cause a series of complications. Studies have reported that mechanical ventilation may be associated with increased mortality, bronchopulmonary dysplasia (BPD), and neurodevelopment disorders (2-4). In addition, compared with non-invasive ventilation, mechanical ventilation exposes infants to a higher incidence of adverse events and neurotoxic sedatives (5,6). Given the adverse consequences associated with mechanical ventilation, neonatal teams need to attempt early extubation (7). Due to the lack of accurate tools, the appropriate time for extubation is often determined based on clinical experience, blood gas analysis, and chest X-ray examination. Some preterm infants experience extubation failure (EF) and subsequently require reintubation, which further gives rise to complications such as pneumothorax, pulmonary hemorrhage, intracranial hemorrhage, and hemodynamic instability (8). Several studies have reported that gestational age (GA), birth weight (BW), use of antenatal steroids, premature rupture of membranes (PROM), pH before extubation, anemia, and 5-minute Apgar score may be associated with EF among preterm infants (9-11). Identification of factors associated with EF may contribute to the reduction of the duration of mechanical ventilation, prevention of reintubation, and enhancement of clinical outcomes in preterm infants (8). This study aimed to analyze the risk factors for EF in preterm infants born before 32 weeks GA and establish a prediction model for EF by constructing a nomogram. We present this article in accordance with the TRIPOD reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-43/rc).

Methods

This retrospective study included preterm infants born at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine from January 2020 to December 2024. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Ethics Committee of Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University (No. 20251012) and individual consent for this retrospective analysis was waived.

Inclusion criteria were preterm birth at a GA of less than 32 weeks and invasive mechanical ventilation initiated within the first 24 hours of life.

Exclusion criteria were death occurring before the first extubation attempt, accidental extubation, or diagnosis of vital congenital malformations.

Of these, infants who were born between 2020 and 2023 served as the training set and who were born in 2024 served as the validation set. This study only analyzed the first extubation attempt after birth.

Data collection

Neonatal, maternal, and pre-extubation data were collected from the medical records. Neonatal characteristics were collected, including GA, BW, gender, small for gestational age (SGA), 1-min Apgar score, 5-min Apgar score, intubation in the delivery room, and PS administration. Maternal characteristics were collected, including cesarean section, advanced maternal age (AMA), chorioamnionitis, PROM (>18 hours) and use of antenatal steroids. Pre-extubation data were collected, including Postmenstrual age (PMA), body weight, Chronological age, pH, arterial partial pressure of carbon dioxide (PaCO₂), mean airway pressure (MAP), peak inspiratory pressure (PIP), positive end-expiratory pressure (PEEP), fraction of inspired oxygen (FiO₂), hemoglobin concentration (HB), respiratory severity score (RSS), number of intubation days and hemodynamically significant patent ductus arteriosus (hsPDA). The hematology examination (HB) was acquired 12 hours prior to extubation, and the blood gas examination (pH, PaCO₂, FiO₂) were obtained 0.5 hours before extubation, while FiO₂, MAP, PEEP, PIP and RSS were recorded or calculated at the time of extubation.

Definition and standards

EF was defined as the need for reintubation within 7 days after extubation. Extubation success (ES) was defined as survival for more than 7 days without reintubation.

The infants could be extubated if they met all of the following criteria: (I) Hemodynamic stability; (II) Active spontaneous breathing under synchronized intermittent mandatory ventilation (SIMV), PIP ≤18 cmH₂O, PEEP ≤6 cmH₂O, FiO₂ ≤40% and breathing rate 20–25 breaths/min with transdermal oxygen saturation ≥88% (infants using high-frequency ventilation should be transferred to SIMV before extubation); (III) PaCO₂ <65 mmHg, pH ≥7.2. The infants could be intubated and reintubated if they met any of the following criteria: (I) 3 or more apneas within 2 hours, medication or noninvasive ventilator intervention was ineffective; (II) desaturation (FiO₂ ≥50%, arterial partial pressure of oxygen <50 mmHg or transdermal oxygen saturation <85%); (III) PaCO₂ ≥65 mmHg, pH <7.20. All infants received continuous positive airway pressure (CPAP: Infant Flow SIPAP, CareFusion, USA) or non-invasive positive pressure ventilation (NIPPV: VentilatorSN, Mindray, China) after extubation.

SGA was defined by BW below the 10th percentile for GA and sex assessed by the Fenton growth curve (12). AMA is defined as maternal age ≥35 years at the time of delivery (13). Chorioamnionitis is defined as the presence of >5 neutrophils per high-power field in placental histopathological examination (14). Preterm Infants who were 3 or 4 days old and prior to extubation were evaluated by echocardiography. hsPDA was defined by continuous left-to-right flow across the patent ductus arteriosus (PDA), a ductus diameter ≥1.5 mm (or PDA:left pulmonary artery diameter ratio ≥0.5), plus one or more of the following criteria: (I) left atrium-to-aortic root ratio ≥1.5; (II) ductus flow velocity ≤2.5 m/s or mean pressure gradient across the ductus ≤8 mmHg; and/or (III) reversed diastolic flow in the descending aorta (15). All ultrasound studies were performed by pediatric cardiologists or neonatologists trained for neonatal echocardiography. For the infants who were diagnosed with hsPDA initially, conservative treatment (fluid restriction, appropriate respiratory support, etc.) was administered. Two or three days later, an echocardiogram was repeated. If hsPDA was still present, the infants would receive ibuprofen treatment. All infants diagnosed with hsPDA were treated with oral ibuprofen at high doses (with an initial dose of 20 mg/kg, followed by 10 mg/kg at 24 and 48 hours respectively). For infants who received ibuprofen treatment, a repeated echocardiogram was performed after the treatment. In our study, we diagnosed the infants with hsPDA based on the results of the last echocardiogram taken before extubation. If the PDA closed or became “not hemodynamically significant” after treatment, we would no longer classify it as hsPDA. Antenatal steroids were defined as dexamethasone 6 mg twice daily for 2 days. Steroids administration that was not completed 24 h before delivery was considered not to use antenatal steroids. The RSS was defined as MAP multiplied by FiO₂ (16). All infants were administered a loading dose of caffeine at 20 mg/kg prior to extubation and the subsequent doses were maintained at 5–10 mg/kg per day.

Statistical analysis

SPSS 27.0 and R 4.3.1 statistical software were used to analyze the data. Medians (25–75th percentile) or means (± standard deviation) were used to express quantitative variables, and percentages and frequencies represented categorical variables. Univariable analysis was used to determine the variables statistically associated with the presence of EF with a P value <0.05. Least absolute shrinkage and selection operator (lasso) regression was used for variable screening. Subsequently, multivariable logistic regression analysis was conducted. The nomogram was constructed based on the contribution of each independent risk factor to the outcome variable. The discriminatory efficiency of the model was evaluated using a receiver operating characteristic (ROC) curve. The calibration power was assessed using a nomogram calibration plot and the Hosmer-Lemeshow test. Decision curve analysis (DCA) was used to confirm clinical benefits. A P value less than 0.05 (two-sided) was regarded as statistically significant.

Results

A total of 131 and 47 preterm infants were, respectively, included in the training cohort and the validation cohort on Figure 1A. Among these 178 infants, they had a median GA of 28.0 weeks with an interquartile range (IQR) of 28.9–29.3 weeks, a median BW of 1,025 g with an IQR of 870–1,283 g. Ninty-four (52.8%, 94/178) infants were males, 146 (82.0%, 146/178) were cesarean section and 128 (71.9%, 128/178) received antenatal steroids.

Figure 1 Study population and outcomes of extubation in preterm infants. (A) Selection of patients included in study cohort. (B) The proportion of infants requiring reintubation after extubation within 168 hours. (C) The Proportion of extubation failure in infants with different gestational ages.

Among all preterm infants included, 21.3% (38/178) were reintubated within 3 days after extubation. Overall, 30.9% (55/178) failed extubation and were reintubated within 7 days of life, constituting the exposure group. The median reintubation time was 33 hours with an IQR of 10–90 hours (Figure 1B). The EF rate of infants born at 24, 25, 26, and 27 weeks of gestation age were 66.7% (4/6), 66.7% (10/15), 57.6% (15/26), and 40% (12/30), while the rate in infants born over 28 weeks of gestation age was 13.9% (14/101), respectively (Figure 1C). The respiratory reasons for EF included frequent apnea (67.3%, 37/55), desaturation (61.2%, 34/55), and CO₂ retention or acidosis (43.6%, 24/55). In addition, 2 (3.6%, 2/55) were reintubated due to late-onset sepsis, and 1 (1.8%, 1/55) due to abdominal problems.

The EF rates of the training cohort and the validation cohort were 31.2% (41/131) and 29.8% (14/47), respectively. PaCO₂ before extubation in the validation cohort was higher than that in the training cohort, and there were no significant differences in other baseline characteristics between two cohorts (Table 1).

Based on the clinical data in the training cohort, we identified 11 potential clinical indicators of EF after univariate analysis: GA, BW, PS use (>1 dose), and pre-extubation factors including PMA, body weight, pH, PaCO₂, HB, FiO₂, RSS, and hsPDA (Table 2).

Lasso regression was used to screen the 11 clinical indicators identified in the univariate analysis (Figure 2A,2B). Multivariate logistic regression analysis was performed on the screened variables. FiO₂ at extubation, PMA at extubation, and hsPDA before extubation were identified as independent risk factors of EF (Table 3). The corresponding nomogram was constructed to predict EF (Figure 3). Each risk predictor in the nomogram was converted to a 0–100 scale corresponding to the adjusted log odds. The scores for each predictor were summed to obtain the total score, which was then converted into predicted probabilities of EF.

Figure 2 Risk factors screened by least absolute shrinkage and selection operator regression analysis. (A) Cross validation diagram of penalty term. The vertical coordinate represents the AUC of the model, the lower horizontal coordinate represents log (λ), and the upper horizontal coordinate represents the number of variables corresponding to different values of log (λ). The two dotted lines in the figure represent two special values of λ: λ. min and λ.1se. λ. min is the corresponding λ value for maximum AUC, λ. 1se refers to the simplest λ value obtained by controlling AUC within a range of variance. In this study, λ.1se =0.1049 was selected, and the variables entered into the model were PMA at extubation, FiO₂ at extubation and hsPDA. (B) Plotting of least absolute shrinkage and selection operator regression coefficients for different values of penalty parameters, each curve represents the variation track of the coefficient of each candidate variable. The higher the λvalue, the greater the compression degree of the model, and the lower the number of candidate variables entering the model. AUC, area under the receiver operating characteristic curve; PMA, postmenstrual age; FiO₂, fraction of inspired oxygen; hsPDA, hemodynamically significant patent ductus arteriosus.

Figure 3 Nomogram for the prediction of extubation failure. This nomogram comprises a total of 6 axes, axes 2–4 represent the independent predictive factors for extubation failure in the predictive equation. Axes 5 and axes 6 are the risk value corresponding to the total score. EF, extubation failure; FiO₂, fraction of inspired oxygen; hsPDA, hemodynamically significant patent ductus arteriosus; PMA, postmenstrual age.

In the training cohort, ROC analysis of this nomogram was conducted and the area under the ROC curve (AUC) is 0.834 [95% confidence interval (CI): 0.759–0.909] (Figure 4), indicating that the model in this study has excellent discrimination. In the Hosmer-Lemeshow test, the P value was 0.95, demonstrating a nonsignificant difference between predicted values and observed values. The calibration plot evaluates the consistency between the model’s predicted probabilities and the actual observed probabilities. The close alignment between the ideal curve (dashed line) and the predicted curve (solid line) demonstrates the model’s high accuracy in risk quantification, validating the reliability of the nomogram (Figure 4). Additionally, DCA confirmed the clinical utility of the nomogram, showing a favorable net benefit across a range of threshold probabilities, suggesting its applicability in clinical practice (Figure 4).

Figure 4 Evaluation and validation of the nomogram model. (A) Nomogram ROC curves generated from the training cohort. (B) Nomogram ROC curves generated using the validation cohort. (C) Calibration plot for the training cohort. (D) Calibration plot for the validation cohort. (E) DCA for the training cohort. (F) DCA for the validation cohort. AUC, area under the ROC curve; DCA, decision curve analysis; ROC, receiver operating characteristic.

The results of the validation were displayed in Figure 4. The predictive accuracy of this nomogram in the validation cohort was slightly higher than that in the training cohort, with AUC =0.851 (95% CI: 0.710–0.961) (Figure 4). The Hosmer-Lemeshow test (P=0.19) and the calibration curve still showed good fitness and conformity (Figure 4). DCA showed that the model also provided good clinical benefits in the validation cohort (Figure 4).

Discussion

The EF rate of preterm infants in our hospital was 30.9%. EF rates in different regions and centers varied from 11.9% to 50% due to different inclusion criteria (17). Spaggiari et al. reported that the risk of EF decreased by 27% for each additional week of GA at birth (9). The results were similar in our study, but the EF rates at 24 weeks and 30 weeks of gestation age were not higher than those at 25 weeks and 31 weeks respectively, which is considered to be related to the relatively small sample size.

Most hospitals divide the observation window for EF into 48–72 hours or 7 days. Our study found that most infants who experienced EF were reintubated within 3 days, but 31.1% were still reintubated 72 to 144 hours after extubation, which was similarly reported in other neonatal intensive care unit (18). Shalish et al. conducted a longitudinal study of premature infants and found that an observation window of 7 days captured 77% of respiratory-related reintubations while only including 14% of non-respiratory cases (19). Wang et al. found that reintubation within 7 days post-extubation was due to frequent apnea, pulmonary hemorrhage, respiratory acidosis, pneumothorax, lung collapse, and increased breathing effort, while reintubation >7 days later was caused by infection-related events (20). In this study, we defined EF as needing reintubation within 7 days after extubation to include more infants with EF and to avoid new disease becoming the main cause of reintubation.

Our study found that PMA, FiO₂ at extubation, and hsPDA before extubation are independent factors to predict EF. Several studies have reported a significant correlation between PMA at extubation and EF (18,21-23). The lungs of preterm infants who are extubated prematurely are still immature. Therefore, some clinicians favor delaying extubation until minimal ventilatory settings have been sustained for a longer period or until the infant has gained more maturity (24). However, prolonged mechanical ventilation may increase the probability of ventilator-associated pneumonia and BPD (17). There is no good evidence to guide the optimal timing of extubation in preterm infants currently. In the randomized controlled trial of extremely preterm infants, there was no difference in EF or BPD rates between immediate and delayed extubation groups (25).

hsPDA is an important factor in EF (26,27). With reduction of MAP after extubation, the ductal shunt of hsPDA may be more severe than before, resulting in pulmonary edema, which affects the ventilation-perfusion ratio of the lungs and ultimately leads to EF. Considering that many symptomatic infants with hsPDA in our hospital are treated about one week after birth, infants who are extubated before ibuprofen treatment may be greatly affected by hsPDA.

Higher FiO₂ before extubation may indicate an increased probability of EF (21,23,28), which was also confirmed in our study. Preterm infants with high oxygen demand before extubation may experience a progressive increase in oxygen requirements as the level of respiratory support decreases after extubation and lack sufficient airway pressure support, which ultimately leads to EF. Fu et al. noted that ES depends on the adequacy of respiratory drive, the capacity of respiratory muscles, and the load imposed upon them, and thus EF is more likely to be predicted by comprehensive evaluation rather than univariate indicators (17). Several studies have reported a significant association between EF and RSS (22,29), which is calculated by multiplying MAP and FiO₂. Our study found that there was a significant difference in RSS in univariate analysis, but it was screened out after lasso regression, considering that it was related to collinearity with other variables.

Endotracheal reintubation poses significant clinical challenges, involving risks and potential negative impacts on the infants. Gupta et al. found that the respiratory status of premature infants deteriorated significantly after reintubation compared to that before extubation (30). Reintubation can lead to an increase in mortality rate, airway trauma, and hemodynamic instability (31-33). Therefore, in order to optimize the timing of extubation, reduce the risk of reintubation and visualize the relationship among the variables, a nomogram was designed, which increased the readability and practicality of the predictive model. Performance index assessments illustrated that the model was of good quality, and had excellent discrimination and calibration.

There are several limitations in this study. First, the prediction model was developed based on data from a single-center hospital in China, and the sample size is limited, whether the results of this study can be extended to other regions and countries requires further expansion of the sample size to verify. In the future, we plan to conduct a prospective multicentre cohort study to further validate the accuracy and stability of the model. Second, EF was defined as reintubation within 7 days after extubation, which, however, included some infants reintubated for non-respiratory reasons and potentially missed some data of respiratory-related reintubations occurring beyond the 7-day observation period. In future research, we will further expand the sample size, extend the observation time, and analyze the causes of EF in different time periods. Third, the time interval between the presence of hsPDA and extubation is unclear. Also, the impact of the duration of hsPDA after extubation on reintubation remains unknown. Prospective studies evaluating the duration of hsPDA and its effect on the reintubation will offer a deeper understanding of how hsPDA can be used to predict extubation readiness among preterm infants. Finally, different noninvasive ventilation modes after extubation had different reintubation rates. However, due to the limited study conditions, the non-invasive ventilation modes were not included in our analysis. Future studies can conduct randomized controlled trials to further explore the relationship between different non-invasive ventilation modes and EF.

Conclusions

This study found that FiO₂ at extubation, PMA at extubation, and hsPDA before extubation were independent risk factors to predict EF among preterm infants before 32 gestational weeks. The nomogram constructed based on independent factors can be used for the prediction of EF.

Acknowledgments

We acknowledged all the medical staffs who were involved in our study.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-43/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-43/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-43/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-43/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Ethics Committee of Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University (No. 20251012) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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