During the study period, a total of 668 premature infants were enrolled (Fig. 1). Among the entire cohort, HFOV was used as the rescue use in 307 (45.9%) patients, who had an initial OI ≥ 20. 211 (31.6%) patients were shifted from conventional ventilation because of poor response to conventional ventilation and/or clinical deterioration. The last 150 (22.5%) patients were enrolled because they experienced worsening respiratory failure during their early elective HFOV use with an initial OI < 20. The median (interquartile range [IQR]) gestational age and birth weight were 27.3 (25.3–31.0) weeks and 915.0 (710.0-1380.0) g, respectively. 61.1% of these patients were male, and most of them (70.4%) were delivered by cesarean section. The most common cause of refractory failure was RDS (62.4%, n = 417), followed by PPHN (22.3%, n = 149), severe sepsis (20.2%, n = 135), pulmonary hemorrhage (9.7%, n = 65), and pneumothorax (9.1%, n = 61). The demographic data of the study cohort are shown in Table 1.
Table 1
Baseline characteristics, clinical and biological features at the time of HFOV initiation according to final survival status
| | | | Final status at discharge post-HFOV use | | |
Characteristics | | All patients | | Non survivors | Survivors | | P value |
| | ( n = 668) | | ( n = 232) | ( n = 436) | | |
Gestational age (weeks), median (IQR) | | 27.3 (25.3–31.0) | | 26.5 (25.0–30.0) | 27.6 (25.6–31.2) | | < 0.001 |
Birth body weight (g), median (IQR) | | 915.0 (710.0-1380.0) | | 793.0 (640-1138.5) | 989.5 (760–1520) | | < 0.001 |
Gender, (male/female), n (%) | | 408 (61.1)/ 260(38.9) | | 132 (56.9)/100 (43.1) | 276 (63.3)/160 (36.7) | | 0.114 |
Apgar score at 5 min < 8, n (%) | | 384 (57.5) | | 158 (68.1) | 226 (51.8) | | 0.001 |
Outborn, n (%) | | 132 (19.8) | | 42 (18.1) | 90 (20.6) | | 0.262 |
Caesarean section, n (%) | | 470 (70.4) | | 167 (72.0) | 303 (69.5) | | 0.534 |
Premature rupture of membrane, n (%) | | 216 (32.3) | | 72 (31.0) | 144 (33.0) | | 0.664 |
Maternal fever/chorioamnionitis, n (%) | | 91 (13.6) | | 28 (12.1) | 63 (14.4) | | 0.41 |
Perinatal asphyxia, n (%) | | 68 (10.2) | | 33 (14.2) | 35 (8.0) | | 0.015 |
Major pulmonary diseases, n (%) | | | | | | | |
Respiratory distress syndrome | | 417 (62.4) | | 133 (57.3) | 284 (65.1) | | 0.054 |
Persistent hypertension of newborn | | 149 (22.3) | | 62 (26.7) | 87 (19.9) | | 0.051 |
Meconium aspiration syndrome | | 15 (2.2) | | 3 (1.3) | 12 (2.8) | | 0.226 |
Congenital diaphragmatic hernia | | 11 (1.6) | | 5 (2.2) | 6 (1.4) | | 0.451 |
Pneumothorax | | 61 (9.1) | | 24 (10.3) | 37 (8.5) | | 0.481 |
Pulmonary Interstitial emphysema | | 14 (2.1) | | 6 (2.6) | 8 (1.8) | | 0.574 |
Sepsis | | 135 (20.2) | | 68 (29.3) | 67 (15.4) | | < 0.001 |
Pneumonia | | 17 (10.5) | | 10 (4.3) | 7 (1.6) | | 0.610 |
Bronchopulmonary dysplasia | | 46 (6.9) | | 18 (7.8) | 28 (6.4) | | 0.524 |
Pulmonary hemorrhage | | 65 (9.7) | | 32 (13.8) | 33 (7.6) | | 0.013 |
Other cormorbidities, n (%) | | | | | | | |
Patent ductus arteriosus (PDA) | | 289 (43.3) | | 83 (35.8) | 206 (47.2) | | 0.005 |
PDA status post ligation | | 34 (5.1) | | 8 (3.4) | 26 (5.9) | | 0.196 |
Intraventricular hemorrhage* | | 63 (9.4) | | 26 (11.2) | 37 (8.5) | | 0.268 |
Congenital heart disease | | 21 (3.1) | | 14 (6.0) | 7 (1.6) | | 0.004 |
Gastrointestinal obstruction | | 23 (3.4) | | 10 (4.3) | 13 (3.0) | | 0.379 |
Others | | 19 (3.4) | | 9 (3.9) | 10 (2.3) | | 0.328 |
Results are presented as n (%) or median (25th, 75th percentiles) |
*Intraventricular hemorrhage > = grade III |
Among the 668 patients, 75.6% of all HFOV treatments were initiated within the first week of life, and 60.0% of the infants received HFOV starting on their first day of life. The median duration of HFOV use was 6.0 (3.0–20.0) days, and the median (IQR) duration of intubation with mechanical ventilation was 20.0 (13.0–49.0) days. Inhaled nitric oxide (iNO) and surfactant were used in 23.4% and 61.7% of cases, respectively. Cardiac inotropic agents were used in 70.5% of all events, and more than half (52.2%) of them required more than one cardiac inotropic agent.
Table 2 presents the initial ventilatory settings within the first 2 hours after initiation of HFOV. The MAP was increased from 7.8 ± 3.9 cm H2O on conventional ventilation (data immediately preceding HFOV) to 13.4 ± 8.5 cm H2O at initiation of HFOV (p < 0.001). The OI, FiO2, and AaDO2 at initiation of HFOV were also significantly higher than those on conventional ventilation (all p < 0.001, data not shown). Among the entire cohort, more than 80% of patients had an OI greater than 15 preceding initiation of HFOV. After initiation of HFOV, the therapeutic responses were examined at 2 hours, 6 hours and 12 hours after use of HFOV and the average daily OI, AaDO2, and blood gas analysis on the 2nd and 3rd day were also evaluated. Table 3 shows the therapeutic responses after the rescue use of HFOV. We found a significant improvement of oxygenation within the first 6 hours after initiation of HFOV, especially in patients on HFOV as rescue use. However, patients who experienced clinical deterioration during HFOV treatment (n = 150) had a significantly higher risk of mortality (p < 0.001) and progression to BPD (p = 0.032) due to ventilation-related complications or nosocomial infections (Table 3).
Table 2
HFOV management and HFOV-related complications during the first two days according to final survival status
| | Final status at discharge after use of HFOV | |
Parameter | All patients (n = 668) | Non survivors (n = 232) | Survivors (n = 436) | P value |
Ventilation settings, median (IQR) | | | | |
FiO2, % | 90.0 (60.0-100.0) | 100.0 (62.8–100.0) | 80.0 (60.0-100.0) | 0.001 |
Mean airway pressure, cm H2O | 12.0 (10.0–15.0) | 12.0 (10.0–15.0) | 12.0 (10.0–14.0) | 0.105 |
Delta P | 100.0 (33.0-100.0) | 90.0 (30.0-100.0) | 100.0 (35.0-100.0) | 0.001 |
Frequency, Hz | 12.0 (11.0–13.0) | 12.0 (11.0–13.0) | 12.0 (11.0–13.0) | 0.539 |
PH | 7.26 (7.14–7.36) | 7.23 (7.07–7.36) | 7.27 (7.17–7.36) | 0.011 |
PaCO2, mmHg | 51.6 (42.0-64.8) | 53.9 (42.6–72.0) | 50.5 (41.5–62.3) | 0.013 |
PaO2, mmHg | 48.0 (35.3–66.5) | 44.8 (32.2–61.8) | 50.0 (37.5–69.0) | 0.001 |
Oxygenation index | 12.0 (7.0–20.0) | 15.0 (8.0-31.8) | 11.0 (7.0–17.0) | < 0.001 |
AaDO2 | 434 (267–579) | 516.5 (280-590.8) | 396.5 (259–570) | 0.002 |
Adjuvant therapies, n (%) | | | | |
iNO use | 156 (23.4) | 66 (28.4) | 90 (20.6) | 0.027 |
Surfactant use | 412 (61.7) | 132 (56.9) | 280 (64.2) | 0.079 |
Dopamine | 471 (70.5) | 181 (78.0) | 290 (66.5) | 0.002 |
Dobutamine | 255 (38.2) | 122 (52.6) | 133 (30.5) | < 0.001 |
Epinephrine | 70 (10.5) | 48 (20.7) | 22 (5.0) | < 0.001 |
Milrinone | 61 (9.1) | 33 (14.2) | 28 (6.4) | 0.002 |
Corticosteroid | 5 (0.7) | 5 (2.2) | 0 (0) | 0.002 |
Results are presented as n (%) or median (25th, 75th percentiles) |
Table 3
Therapeutic responses and treatment outcomes of premature neonates (total n = 668) treated by high-frequency oscillatory ventilation (HFOV)
Therapeutic responses & Treatment outcomes | All patients (n = 668) | Rescue use of HFOV (total n = 518) | Early elective use of HFOV with clinical deterioration (n = 150) | P value |
OI at 2 hours after use of HFOV | 19.0 (15.0–34.0) | 24.0 (18.0–39.0) | 8.0 (6.0–12.0) | < 0.001 |
OI at 6 hours after use of HFOV | 12.0 (7.0–20.0) | 14.0 (8.0–23.0) | 8.0 (5.0-12.5) | < 0.001 |
OI at 12 hours after use of HFOV | 14.0 (8.0–23.0) | 17.0 (10.0-26.3) | 8.0 (5.0–13.0) | < 0.001 |
Average OI at 2nd day after use of HFOV | 15.0 (7.0–30.0) | 14.0 (6.0–30.0) | 21.0 (15.0–30.0) | < 0.001 |
Average OI at 3rd day after use of HFOV | 12.0 (5.0–27.0) | 10.0 (4.0–25.0) | 18.0 (8.0–29.0) | < 0.001 |
Highest OI during the HFOV course | 24.0 (18.0–42.0) | 22.0 (18.0–48.0) | 27.0 (19.0–56.0) | < 0.001 |
Therapeutic responses to HFOV | | | | |
Significant improvement of OI | 375 (56.1) | 303 (58.5) | 72 (48.0) | |
Non-significant improvement | 172 (25.7) | 110 (21.2) | 62 (41.3) | < 0.001 |
Condition downhill | 121 (18.1) | 105 (20.3) | 16 (10.7) | < 0.001 |
Progress to BPD* | 375 (56.1) | 279 (53.9) | 96 (64.0) | 0.032 |
Duration of HFOV (days) | 6.0 (3.0–20.0) | 6.0 (3.0–18.0) | 11.0 (4.0-34.5) | < 0.001 |
Duration of intubation (days) | 20.0 (3.0–49.0) | 20.0 (4.0-48.8) | 19.0 (3.0–49.0) | 0.349 |
Duration of mechanical ventilation (days) | 39.0 (10.0–74.0) | 35.0 (9.0–72.0) | 49.0 (10.5–85.0) | 0.078 |
Duration of hospital stay (days) | 75.0 (22.0-113.0) | 75.0 (24.0-113.0) | 77.0 (14.5-111.5) | 0.557 |
120-day mortality | 232 (34.7) | 149 (28.8) | 83 (55.3) | < 0.001 |
Results are presented as n (%) or median (25th, 75th percentiles) |
OI: oxygenation index; HFOV: high frequency oscillatory ventilation; BPD: bronchopulmonary dysplasia |
Patient outcomes and predictors of in-hospital mortality
Except for four patients whose family requested transfer to other hospital, all patients’ outcomes were obtained. 455 (68.1%) patients were successfully weaned off HFOV, 414 (62.0%) survived to NICU discharge and 436 (65.3%) were alive at 120 days. Among non-survivors, 100 (39.4%) died within the first week after use of HFOV, and 54 (21.3) died within the first 72 hours. 31.9% had use of HFOV for more than 14 days, and 29 (4.3%) had use of HFOV for more than 60 days. The median [IQR] duration of HFOV support, mechanical ventilation and hospital stay for 120-day survivors were 7 [4; 21], 49.5 [14; 74.8], and 95 [52.3; 123.3] days, respectively.
Final survivors had a significant lower rate of perinatal asphyxia, lower percentage to have low Apgar score at 5 minutes, and were not so extremely preterm and/or low birth body weight when compared with the non-survivors (Table 1). The underlying pulmonary diseases that caused severe respiratory failure were not significantly different between survivors and non-survivors, except sepsis was significantly more common in non-survivors. The mean airway pressure and frequency of HFOV settings at the first 48 hours were similar between 120-day survivors and non-survivors. However, non-survivors were administered significantly higher FiO2 and delta P, and exhibited higher severity of respiratory acidosis and hypoxemia (Table 2). Of note, most adjuvant therapies, including cardioinotropic agents, iNO, and blood transfusion, were more frequently used during the first two-days on HFOV in non-survivors than survivors.
Predictive factors of final in-hospital mortality were assessed using univariate analysis and a multivariate logistic model (Table 4). Lower birth weight, occurrence of sepsis, severe hypotension, numbers of organ dysfunction, low apgar score (≤ 7) at 5 minutes, perinatal asphyxia, initial severity of respiratory failure, and initial response to HFOV treatment were jointly selected as the variables to enrolled into the multivariate logistic regression model. No association was found between various pulmonary disease entities and survival in the multivariate analysis. After backward stepwise method, we found six variables, including lower birth weight, occurrence of sepsis, severity of hypotension, numbers of organ dysfunction, initial severity of respiratory failure and response to HFOV treatment were independently associated with final in-hospital mortality (Table 4). The nomogram based on these six independent variables was developed to predict the risk of mortality (Fig. 2), and the calibration curves for the probability were drawn (Supplementary Fig. 1). The sensitivity and specificity of this model were 70.6% and 72.8%, respectively. The area under the curve (AUC) for this model is 0.768 (Supplementary Fig. 2).
Table 4
Risk factors for final in-hospital mortality by multivariate analysis and multivariate stepwise analysis
Risk factors | Multivariate analysis | | Multivariate stepwise regression |
Adjusted OR (95% CI) | P value | | Adjusted OR (95% CI) | P value |
Gestational age (weeks) | | | | | |
< 28 weeks | 2.22 (1.27–3.87) | 0.005 | | 2.16 (1.24–3.75) | 0.007 |
28–31 weeks | 1.29 (0.69–2.40) | 0.421 | | 1.27 (0.69–2.34) | 0.450 |
≥ 32 weeks | 1 (reference) | | | 1 (reference) | |
Low apgar score at 5 minutes (≤ 7) | 1.02 (0.58–1.75) | 0.993 | | | |
Perinatal asphyxia | 1.04 (0.48–2.24) | 0.919 | | | |
Occurrence of sepsis | 1.74 (1.10–2.75) | 0.018 | | 1.82 (1.17–2.85) | 0.008 |
Highest OI during HFOV treatment | | | | | |
≤ 30 | 1 (reference) | | | | |
31–40 | 0.97 (0.52–1.64) | 0.746 | | | |
41–50 | 1.25 (0.62–2.55) | 0.533 | | | |
> 50 | 1.44 (0.83–2.49) | 0.190 | | | |
Initial OI at HFOV treatment※ | | | | | |
≤ 20 | 1 (reference) | | | 1 (reference) | |
21–30 | 0.72 (0.37–1.37) | 0.314 | | 0.73 (0.38–1.39) | 0.336 |
31–40 | 0.92 (0.33–2.53) | 0.862 | | 0.93 (0.34–2.55) | 0.880 |
> 40 | 3.05 (1.15–8.13) | 0.026 | | 3.31 (1.27–8.66) | 0.015 |
Response to HFOV within the first 3 days | | | | | |
Significant improvement of OI | 1 (reference) | | | 1 (reference) | |
Non-significant improvement | 1.25 (0.74–2.11) | 0.412 | | 1.29 (0.77–2.17) | 0.334 |
Condition downhill | 3.64 (1.82–7.27) | < 0.001 | | 4.05 (2.08–7.89) | < 0.001 |
Number of organ dysfunction* | | | | | |
No | 1 (reference) | | | 1 (reference) | |
1 | 1.73 (0.92–3.23) | 0.087 | | 1.77 (1.01–3.08) | 0.045 |
2 | 2.26 (0.86–5.94) | 0.098 | | 2.45 (1.34–4.47) | 0.004 |
≥ 3 | 2.91 (1.21–6.97) | 0.017 | | 3.05 (1.56–5.98) | 0.001 |
Severity of hypotension** | | | | | |
No | 1 (reference) | | | 1 (reference) | |
Mild hypotension | 0.98 (0.60–1.64) | 0.948 | | 1.02 (0.62–1.63) | 0.992 |
Moderate hypotension | 1.84 (1.13-3.00) | 0.015 | | 1.91 (1.17–3.09) | 0.009 |
Severe hypotension | 3.97 (1.94–8.13) | < 0.001 | | 4.37 (2.17–8.80) | < 0.001 |
Specific disease entities | | | | | |
PPHN | 1.44 (0.88–2.37) | 0.151 | | | |
Pulmonary hemorrhage | 1.58 (0.88–2.76) | 0.129 | | | |
Secondary pulmonary hypertension | 3.75 (0.73–19.32) | 0.115 | | | |
Patent ductus arteriosus | 0.83 (0.56–1.22) | 0.344 | | | |
OI: oxygenation index; RDS: respiratory distress syndrome; PPHN: persistent pulmonary hypertension of newborn; OR: odds ratio, 95% CI: 95% confidence interval |
※The average oxygenation index at 2 and 6 hours after initiation of HFOV was used |
*Number of organ dysfunction: including neurological, renal, hematological, and hepatic dysfunction |
**Mild hypotension was defined as patients who required only one cardioinotropic agents (usually dopamine < 10ug/kg/min) |
**Moderate hypotension was defined as patients who required both dopamine and dobutamine, with only one of them ≥ 10ug/kg/min to maintain adequate blood pressure |
**Severe hypotension was defined as patients who required epinephrine and/or more than two cardioinotropic agents (usually dopamine and dobutamine, both ≥ 10ug/kg/min) to maintain adequate blood pressure |