Duration of mechanical ventilation and clinical outcomes in very low birth weight infants: A single center 10-years cohort study

Abstract

BACKGROUND:

Despite the important role of MV in reducing mortality in very preterm infants, its use is often associated with complications. The study was aimed to determine the duration of mechanical ventilation (MV), which significantly increased the risk of adverse outcomes in very low birth weight (VLBW) infants.

METHODS:

Data obtained from a prospectively created computer database were used in a retrospective cohort study. The database included information about 1980 VLBW infants <32 weeks of gestation who were cared for at the tertiary care center between January 2010 and December 2020.

RESULTS:

Out of 1980 VLBW infants, 1086 (55%) were ventilated sometime during the hospital stay. 678 (62.43%) of ventilated babies survived until discharge. With ROC analysis, it was identified that MV duration of 60.5 hours had 79.3% sensitivity and 64.6% specificity for the prediction of BPD with the AUC of 0.784 (95% CI 0.733–0.827; p < 0.0001). The duration of MV above 60.5 hours was a significant risk factor for bronchopulmonary dysplasia (aOR 6.005, 95% CI 3.626–9.946), death (aOR 3.610, 95% CI 2.470–5.276), bronchopulmonary dysplasia/death (aOR 4.561, 95% CI 3.328–6.252), sepsis (aOR 1.634, 95% CI 1.168–2.286), necrotizing enterocolitis (aOR 2.606, 95% CI 1.364–4.980), and periventricular leukomalacia (aOR 2.191, 95% CI 1.241–3.867).

CONCLUSIONS:

Duration of MV longer than 60.5 hours is an independent risk factor for adverse outcomes in VLBW infants. It is essential to increase and optimize efforts to avoid MV or extubate very preterm infants as soon as possible, before reaching the established threshold duration of invasive respiratory support.

Keywords

Clinical outcomes mechanical ventilation very-low-birth-weight infants

1 Introduction

Respiratory failure is a common clinical problem in very low birth weight (VLBW) infants which leads to potentially serious complications. Its treatment usually requires use of respiratory support [1, 2]. Despite the widespread application of non-invasive methods of such support during the last decades, endotracheal mechanical ventilation (MV) is still an important intervention, especially in very tiny babies [3, 4]. At the same time, its use is often associated with complications especially when applied for a prolonged period [5]. Duration of MV determines outcomes in VLBW infants. Immature lungs are more vulnerable to damage and MV increases the risk of secondary lung injury, which is a significant factor for bronchopulmonary dysplasia (BPD) development [3 , 7]. About one half of extremely preterm infants fail their first attempt at extubation and require reintubation and resumption of MV [8]. Exposure to a greater number of MV courses is associated with the progressive increase in the risk of BPD and the need for oxygen supplementation at discharge compared with a single course of ventilation [9]. It was found that the particular method of respiratory support from the seventh day of life affected the development of BPD. Using of MV compared with non-invasive respiratory support, or no support at each postnatal day increased the proportion of infants with severe BPD [10]. Continuous MV during the first 48 h of life is predictive of BPD development in VLBW infants [11]. MV for 15–28 days increased the risk of mortality, the incidence of BPD, pulmonary hypertension, retinopathy of prematurity requiring surgical correction, periventricular leukomalacia (PVL), poor physical growth as well as prolonged length of stay and parenteral nutrition in VLBW neonates.⁵ Neonates who were ventilated ≥125 days had lower respiratory support weaning rate, more severe neurological impairment, and delay in exclusive oral feeding at 18 months of corrected age (CA) [13]. Duration of MV also influences the severity of the BPD. Thus, it was shown that the duration of MV longer than 36 days was a significant predictor for moderate to severe BPD in extremely preterm infants [12].

It is important to find out what specific duration of MV becomes a significant risk factor for the development of BPD and other complications to identify best practice interventions to accelerate extubation.

The study was aimed to determine the duration of MV, which significantly increased the risk of adverse outcomes in VLBW infants with GA <32 weeks.

2 Materials and methods

2.1 Patients and study design

Data obtained from a prospectively created ten-year computer hospital database were used in a retrospective cohort study. The infants with a birth weight of <1500 grams and gestational age of <32 weeks who needed MV anytime during the hospital stay were included in the study. VLBW infants who were not cared for with MV were excluded.

The duration of MV of each baby and their BPD morbidity were used to generate the receiver operating characteristic (ROC) curve first. Then all included infants were retrospectively divided into two groups based on the threshold duration of MV that was predictive for BPD development according to the results of ROC analysis. The main perinatal characteristics, morbidities, and clinical outcomes were compared between the groups to confirm the clinical significance of the established MV threshold.

2.2 Study outcomes

The primary study outcome was the duration of MV, which significantly increased the risk of BPD development in VLBW infants with GA <32 weeks. The secondary study outcomes included the incidence of BPD, death, BPD or death, PVL, sepsis, and necrotizing enterocolitis (NEC), depending on the established threshold duration of MV.

2.3 Clinical definitions

RDS was diagnosed based on a requirement for supplemental oxygen to maintain a pulse oximeter saturation over 90% within the first 24 hours of life and X-ray data consistent with RDS. BPD was diagnosed at 36 weeks of postmenstrual age (PMA) according to the clinical definition after an oxygen reduction test [14, 15]. Intraventricular hemorrhage (IVH) and PVL were assessed by head ultrasound and on autopsy when applicable. The severity of IVH was classified according to Papile [16]. The presence of patent ductus arteriosus (PDA) was confirmed by Doppler-Echocardiography [17]. NEC was diagnosed according to modified Bell’s criteria [18]. Neonatal sepsis was diagnosed based on the criteria of the European Medicines Agency [19].

2.4 Procedures and monitoring

All newborns with clinical signs of respiratory distress breathing spontaneously were routinely managed on nasal continuous positive airway pressure (CPAP). Criteria for intubation and MV were: 1) FiO₂ ≥60% or PaCO₂ ≥55 mm Hg, or pH <7.2 while on CPAP with a maximum pressure of 8 cm H₂O; 2) considerable and progressive clinical respiratory deterioration with tachypnea or dyspnea; 3) pathologic apnea episodes. Synchronized intermittent pressure-controlled mandatory ventilation combined with pressure-support ventilation was routinely used for endotracheal respiratory support.

The need for MV after birth and FiO₂ ≥30% in infants ≤26 weeks or FiO₂ ≥40% in infants >26 weeks on CPAP of at least 6 cm H₂O were an indication for surfactant administration. During the study period, our respiratory management changed from endotracheal intubation, starting MV, and surfactant administration in case of CPAP failure (a need for FiO₂ ≥60% with CPAP of 6–8 cm H₂O) to the early rescue surfactant administration (FiO₂ ≥30–40% with CPAP of 6–8 cm H₂O) to avoid MV. INSURE or LISA technique was used in newborns treated with CPAP.

2.5 Statistical analysis

Data were analyzed using descriptive and comparative statistics. The ROC curve was used to assess the ability of the specific MV duration to predict BPD development, determining the area under it and calculating the corresponding sensitivity and specificity. To control for potentially confounding variables, the ROC curves for subgroups of infants with GA of 28–31 weeks and 22–27 weeks were generated separately, and logistic regression analysis (LRA) was used to make sure that the defined threshold was an independent and reliable predictor of BPD development. Nominal data are presented as numbers (%). Nonparametric continuous data are presented as a median (interquartile ranges). They were compared using the Mann–Whitney U test. All values were considered significant if p < 0.05.

3 Results

The database included information about 1980 VLBW infants <32 weeks of gestation who were cared for at the tertiary care center between January 2010 and December 2020. One thousand eighty-six (55%) out of 1980 VLBW infants with GA of <32 weeks required MV during their hospital stay. Six hundred seventy-eight (62.43%) of ventilated babies survived until discharge. The proportions of babies with the gestational age of 30–32 weeks, 28–30 weeks, and below 28 weeks have not changed significantly during the study period (p = 0.392).

With ROC analysis, it was established that in the population of VLBW infants with GA of 22–31 weeks MV duration of at least 60.5 hours had 79.3% sensitivity and 64.6% specificity for the prediction of BPD development with an AUC of 0.780 (95% CI 0.733–0.827, p < 0.0001) (Fig. 1). At the same time, ROC analysis in the subgroups of infants with GA of 28–31 weeks and 22–27 weeks has not revealed a significant deviation from this value (at least 66.5 hours in neonates with GA of 28–31 weeks and at least 71.5 hours in neonates with GA of 22–27 weeks, p < 0.05).

Fig. 1

Receiver operating characteristic curve for duration of MV as a predictive factor for BPD development. The best MV duration cut-off value is indicated on the graph.

The groups formed using the threshold of 60.5 hours were not different in terms of the frequency of selected maternal risk factors, intrauterine growth, mode of delivery, and proportions of infants delivered from multiple pregnancies, the need for extended resuscitation, low Apgar scores at 5 minutes of life or treatment with surfactant. At the same time, newborns who needed a more prolonged period of MV were significantly less in weight, more immature, and more often intubated at birth (Table 1). Infants from this group had more than five times higher incidence of BPD, significantly higher mortality, and differed from the comparison group in composite outcome BPD/death. The more prolonged period of MV was also reliably associated with severe brain injury, sepsis, and NEC (Table 2). Infants who required more than 60.5 hours of MV also spent more days on antibiotic therapy and in the neonatal intensive care unit (Table 2).

Table 1

Demographic and perinatal comparison of the groups

Characteristics	MV < 60.5 h	MV≥60.5 h	P
	(n = 642)	(n = 444)
Preeclampsia	107 (16.67)	80 (18.02)	0.561
Placenta abruption	106 (16.51)	79 (17.79)	0.580
Clinical chorioamnionitis	21 (3.27)	20 (4.50)	0.294
Antenatal steroids	517 (80.52)	343 (77.25)	0.192
Cesarean section	271 (42.21)	193 (43.47)	0.680
Multiple pregnancy	169 (26.32)	108 (24.32)	0.457
Birth weight, grams	1020 (840–1270)	940 (750–1200)	0.000076
Gestational age, weeks	28 (26–30)	28 (26–29)	0.00071
Small for gestational age	35 (5.45)	21 (4.73)	0.596
Males	348 (54.21)	248 (55.86)	0.591
Apgar <4 at 5 min	57 (8.88)	47 (10.59)	0.347
Intubation at birth	352 (54.83)	280 (63.06)	0.0068
Chest compressions at birth	36 (5.61)	22 (4.95)	0.638

Notes. Data are presented as number of cases (%) or median (interquartile range). MV –mechanical ventilation.

Table 2

Comparative morbidity and mortality, and features of some therapeutic interventions in the groups

Diseases	MV < 60.5 h	MV≥60.5 h	p
	(n = 642)	(n = 444)
Bronchopulmonary dysplasia	28 (4.36)	107 (24.10)	0.00001
Intraventricular hemorrhage	185 (28.82)	227 (51.13)	0.000001
Severe intraventricular hemorrhage (grade 3-4)	63 (9.81)	116 (26.13)	0.000001
Hemodynamically significant PDA	101 (15.73)	75 (16.89)	0.610
Periventricular leukomalacia	21 (3.27)	39 (8.78)	0.00009
Neonatal sepsis	80 (12.46)	85 (19.14)	0.003
Necrotizing enterocolitis	16 (2.49)	25 (5.63)	0.008
Death	196 (30.53)	212 (47.75)	0.000001
Bronchopulmonary dysplasia or death	223 (34.74)	292 (65.77)	0.00001
Surfactant therapy	566 (88.16)	403 (90.76)	0.175
Duration of MV, hours	14 (5–34)	127 (86.0–216.0)	0.0000001
Duration of MV in survivors, hours	11 (4–24)	127 (86.5–216.0)	0.0000001
Duration of CPAP, hours	97 (49–169)	97 (49–241)	0.404
Antibiotic therapy duration, days	11 (3–36)	17 (6.5–47)	0.0000001
Antibiotic therapy duration in survivors, days	25.5 (10–43)	38.5 (16.0–60.5)	0.0000001
Length of NICU stay, days	12 (3–49)	19 (7–61)	0.0000001
Length of NICU stay in survivors, days	33.5 (10–57)	53 (19–78)	0.0000001

Notes. Data are presented as number of cases (%) or median (interquartile range). MV–mechanical ventilation, PDA –patent ductus arteriosus.

The MV duration ≥60.5 hours threshold was used in the LRA in which adverse outcomes and specific morbidities served as dependent variables. In addition to the duration of MV ≥60.5 hours, the logistic regression models included maternal chorioamnionitis, preeclampsia, cesarean section, gestational age, being small for gestational age, the need for intubation and chest compressions at birth, Apgar score less than 4 at the 5 minutes of life, surfactant administration, development of sepsis, hsPDA, pneumothorax, severe IVH, and duration of antibacterial treatment.

The following independent variables significantly influenced the risk of BPD: duration of MV longer than 60.5 hours, hsPDA, sepsis, antibiotic therapy duration, and GA. Among them, the duration of MV longer than 60.5 hours had the greatest impact (OR 6.005, 95 % CI 3.626–9.946) (Table 3). Duration of MV above 60.5 hours was also a significant risk factor for death, BPD/death, sepsis, PVL, and NEC (Table 4).

Table 3

Adjusted odds ratio for BPD significant risk factors

Risk factors	aOR	95 % CI	p
Duration of MV longer than 60.5 hours	6.005	3.626–9.946	0.0001
Hemodynamically significant patent ductus arteriosus	3.094	1.799–5.321	0.0001
Sepsis	1.836	1.059–3.182	0.03
Antibiotic therapy duration	1.063	1.052–1.073	0.0001
Gestational age	0.839	0.749–0.941	0.003

Notes. aOR –adjusted odds ratio. CI –confidence interval, BPD –bronchopulmonary dysplasia, MV –mechanical ventilation.

Table 4

Significance of MV longer than 60.5 hours as an independent factor affecting morbidity and mortality

Morbidity and mortality	aOR	95 % CI	p
Death	3.610	2.470–5.276	0.0001
BPD/death	4.561	3.328–6.252	0.0001
Sepsis	1.634	1.168–2.286	0.004
Necrotizing enterocolitis	2.606	1.364–4.980	0.004
Periventricular leukomalacia	2.191	1.241–3.867	0.008

Notes. aOR –adjusted odds ratio. CI –confidence interval, BPD –bronchopulmonary dysplasia, MV–mechanical ventilation.

4 Discussion

Even though MV remains a life-saving intervention, especially for extremely preterm neonates [20], exposure to MV is a significant risk factor for BPD development and other complications in this vulnerable population [21].

In this retrospective cohort study, we described short-term clinical outcomes in a cohort of 1086 very preterm VLBW infants with RDS who were cared for with MV for 11 years. We found that in VLBW infants the duration of MV longer than 60.5 hours reliably predicted BPD development, and newborns, who were on MV longer than 60.5 hours, had a significantly higher incidence of BPD, BPD/death, sepsis, PVL, NEC, and death. Based on the results of LRA, the prolonged MV was a significant and independent predictor of these adverse clinical outcomes, which can determine long-term consequences, such as poor physical growth and neurological development, as well as long-term respiratory morbidity and the need for re-hospitalizations [22 –24].

Ventilation longer than 60.5 hours in our patients increased the probability of adverse clinical outcomes typically associated with preterm birth. Not surprisingly, infants who needed MV longer than 60.5 hours had a significantly lower GA and were smaller compared to infants who were on ventilation of a shorter duration. That is why we used LRA to confirm the independent and significant impact of the established MV duration threshold on BPD development and other clinically important outcomes. The analysis showed that both the threshold duration of MV and GA independently and significantly predicted the adverse clinical outcomes in our VLBW population, with the strongest effect associated with prolonged ventilation. Also, ROC analysis in the subgroups of infants with GA of 28–31 weeks and 22–27 week. has not revealed a significant deviation in the subgroup thresholds from the value obtained for the whole cohort of infants with GA of 22–31 weeks.

Like Choi et al. [5], we have found a significant negative effect of prolonged ventilation on the survival of VLBW infants, although there are conflicting data on this effect [5 , 26]. Several studies identified prolonged duration of MV as a risk factor for short and long-term complications in neonates of different gestational age in general [13] and VLBW infants in particular [5 , 11–13]. Continuous MV during the first 48 hours of life increased the probability of developing BPD in preterm infants with GA of <34 weeks and birth weight <1500 grams [11]. It was found that prolonged ventilation for weeks increased neonatal morbidity and its severity [4, 12]. Duration of MV was significantly correlated with increased ventilation-perfusion mismatch at 37 weeks of PMA in preterm infants with BPD [27], independently associated with reduced lung volume and lung growth during infancy [28], and history of asthma and higher incidence of bronchial hyperresponsiveness in later childhood [29]. Also, it was revealed a significant association between every additional day of invasive MV and neurodevelopmental impairment at 24-month CA in preterm infants with GA of 24–30 weeks [30].

At the same time, it is well known that even a short period of MV can produce volutrauma and activate a pro-inflammatory cascade leading to lung and brain injury [22, 24]. The question that remains unanswered is how long is too long? Our study provides an estimate for the possible threshold in the population of VLBW infants in a lower-middle-income country.

According to our results, BPD occurred significantly more often in infants who needed prolonged MV and treatment with antibiotics, had a lower GA, hsPDA, and sepsis. In our population of the sickest very preterm infants who required MV, development of BPD was not associated either with antenatal risk factors, maternal chorioamnionitis and intrauterine growth, or with the need for endotracheal intubation at birth, and lower Apgar scores. Despite the sound theory, the association between clinical chorioamnionitis and BPD development is still controversial [31], albeit such a relationship seems well defined for postnatal infections [32]. Prolonged antibiotic treatment has also been associated with BPD development in other studies [33]. It is well known that a large left-to-right PDA shunt significantly increases the risk of developing BPD or death [34]. The results of a recent meta-analysis suggested that in five out of nine studies that predicted BPD development the hsPDA or PDA was significantly more likely in infants who developed BPD [34]. The low incidence of BPD in our patients can be explained not only by our practice of using non-invasive respiratory support extensively and avoiding MV as much as possible but also by a relatively high mortality and decreased survival of the most immature infants to a PMA of 36 weeks.

Thus, considering adverse outcomes that are associated with the duration of MV it is essential to determine newborns at risk for developing BPD and other complications as early as possible.

We identified that duration of MV longer than 60.5 hours was a significant risk factor for morbidity and mortality, which potentially impacted outcomes in preterm infants with GA of less than 32 weeks. Enhancing extubation attempts during the first three days of life to minimize ventilation injury can improve outcomes in VLBW infants with RDS [9]. However, this approach could be of limited practical value for the tiniest extremely preterm infants who often need prolonged MV to survive [36]. Application of more effective methods of MV and post-extubation non-invasive respiratory support can shorten duration of ventilation [37] or prevent reintubation [38, 39] and additional anti-inflammatory treatment may be used to try to decrease the incidence and severity of BPD in this population [7].

One of the features of this study is the description of the large cohort of VLBW infants from a lower-middle-income country, raising the question of whether a similar critical period of MV exists for similar cohorts of VLBW infants in developed countries. Recent data from Norway indicated that extremely preterm infants with GA of 22–25 weeks might need a much longer initial period of MV ranging from 35 to 12 days, respectively [36].

The study has several limitations. First, it was retrospective by design and used a structured computer database, limiting our ability to assess and present more information about our patients. Importantly, we analyzed the total duration of MV, without being able to further evaluate the effects of its initial period of varying duration. At the same time, the established MV duration threshold of 60.5 hours, which was rather short, with a high probability could be attributed to the initial periods of MV during the early neonatal period. We could not investigate the independent impact of specific ventilation parameters on study outcomes either. Second, the study covered a relatively long period during which some changes in clinical practice did occur, making our cohort more heterogeneous. Third, the long-term outcomes have not been assessed. However, despite these limitations, the multivariable logistic regression models in our population of VLBW infants demonstrated good performance and confirmed the reliable predictive value of the established threshold duration of MV for the future formation of BPD and other adverse outcomes. Validation of such a threshold in similar cohorts of VLBW infants could be a future direction of research with both theoretical and practical value.

5 Conclusions

Footnotes

Acknowledgments

The study was conducted without any specific financial support.

Conflicts of interest

None declared.

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