India has a high rate of neonatal mortality, with 750,000 newborn deaths in 2013, the highest number for any country [1]. Mechanical ventilation (MV) is often necessary to support the breathing of critically ill children in the Neonatal Intensive Care Unit (NICU), particularly those with respiratory distress syndrome, meconium aspiration syndrome, sepsis, congenital diaphragmatic hernia, persistent pulmonary hypertension of the newborn, or severe air leak syndromes. MV delivers oxygen-rich air to the baby's lungs and helps keep the air sacs open, allowing for better gas exchange and easier breathing [2,3]. However, MV can also lead to various complications, such as air leaks, chronic lung disease, barotrauma, volu-trauma, atelectasis, retinopathy of prematurity, infections, lung injury, hypotension, and gastrointestinal perforation. To reduce these risks, lung-protective ventilation strategies and close monitoring are necessary [4].

While MV can greatly improve the survival of critically ill neonates, it is expensive and requires significant resources. Developing countries like India, where resources are limited, need careful planning and implementation of MV. To improve outcomes for neonates who require ventilator care in the NICU, it is essential to identify the factors that influence their outcomes. Most of the data on ventilated sick neonates come from developed countries, so more research is needed to understand the clinical profiles and outcomes of neonates in developing countries like India. The high rate of neonatal mortality in India highlights the urgent need to address this issue and improve access to and implementation of life-saving interventions like mechanical ventilation in neonatal care. We undertook this study in a zest to explore the factors responsible for neonatal mortality in NICU patients with a hope that it will translate into designing of better care plans in such patients.

This was a prospective observational study, clinical profile, complications and outcomes of 150 consecutive neonates admitted into the NICU and put onto MV, were enrolled. Proper history, family history, physical examination was done at presentation to the hospital and relevant clinical, birth related, and anthropometric parameters were duly noted. A written informed consent was obtained from the parents/ guardians of all the study subjects. Enrollment of the patients into the study was done after approval from the Institutional Ethics Committee (approval number 3427/D-26/2020).

Statistical Analysis

Data was analyzed using SPSSv.26. All categorical data was summarized using frequency and percentages, all continuous data was described using mean and standard deviation. To study the association of clinical parameters between survivors and non-survivors, independent sample t test was applied for the continuous measurements after checking normality assumption and Chi square test or Fishers exact test was applied for categorical observations based on the expected frequency. Multivariate analysis (MVA) done using cox regression analysis was used to arrive at factors having a significant impact on the clinical outcome of the ventilated neonates. P-value was considered significant at 5% level of significance for all comparisons.

Out of the total 150 neonates enrolled in the study, 99 (66%) were males and 51 (34%) of them were females. Normal vaginal delivery was the predominant mode of delivery in the study cohort accounting for 93 (62%) of the neonates. Fifty-seven neonates (38%) were delivered after Lower segment caesarean section. The mean gestational age of the study cohort was 34.5 weeks ± 3.22 (95% CI) and the median gestational age was 35 weeks (IQR= 32-37 weeks).

Out of the total study cohort of 150 neonates, 92 patients (61%) were born preterm (before 37 weeks), 58 patients (39%) of the patients were born at term. Out of the 92 patients born preterm, 4 (4.3%) neonates were extremely preterm (less than 28 weeks of gestation), 25 (27.2%) neonates were very preterm (between 28-32 weeks of gestation) and 63 (68.5%) neonates were moderate to late preterm (between 32-37 weeks of gestation). For the study definition, the neonates born in the institute where the study was conducted were labelled as inborn and the ones born out of the facility were labelled as out born. Out of the total 150 patients enrolled into the study cohort, 73 (48.7%) were inborn and 77 (51.3%) of the patients were out born.

The study included 150 patients, out of which 109 (73%) were appropriate for gestational age, 38 (25%) were small for gestational age, and 3 were large for gestational age. There was no significant association between appropriateness for gestational age and clinical outcome. Patients were categorized based on birth weight into ELBW, VLBW, LBW, and NBW categories, with 11 (7%), 32 (22%), 63 (42%), and 44 (29%) falling into each category, respectively. There was a significant association between birth weight categories and clinical outcome (P value =0.003). The mean age at presentation to the institute was 1.42 ± 1.754 (95%CI) days, and the median age was 1 day (IQR=1-1 days).

APGAR scores were obtained at 1 and 5 minutes after birth for inborn neonates and from previous medical records for outborn patients. The mean APGAR score at 1 minute was 6.59±0.778 (95% CI) and at 5 minutes was 7.88± 0.723 (95%CI). The median APGAR score at 1 minute was 7 (IQR= 6-7) and at 5 minutes was 7 (IQR= 7.75-8). Downes score was used to assess the severity of respiratory distress, with a median score of 6 and most patients (n=121) falling into the moderate distress category. Approximately 19% of patients were categorized into the severe distress category.

The mean age (in hours) of the study cohort at the time of mechanical ventilation was 39.4 hours± 86.43 (95% CI). The median age of the child at the time of ventilation was 5 hours (IQR= 2.75-29.2). The most common indication (approx. 49%) for mechanical ventilation in the neonates under study was respiratory distress syndrome (RDS). Birth asphyxia (27%) and meconium aspiration syndrome (9%) were the second and third most common indication for mechanical ventilation in the study cohort. The details of the ventilation parameters of the patients in this study have been summarised in Table 1.

Table 1: Table summarising the ventilation parameters of the study cohort.

In the study cohort, 65 (43%) patients were given steroids and amongst the patients who received steroids, 37/65 (57%) patients expired. A total of 85 patients were not given steroids during their course of treatment and amongst them only 13 (15%) expired whereas 62 (73%) of them were discharged. The chi square test of independence showed a significant association between steroid use and clinical outcome (P value= <0.001). In the study cohort, 34 (23%) patients were given surfactants and amongst the patients who received surfactant, 11/34 (32%) patients expired. A total of 116 patients were not given surfactant during their course of treatment and amongst them only 39 (34%) expired whereas 65 (55%) of them were discharged. The chi square test of independence did not show a significant association between surfactant use and clinical outcome (P value= 0.247). In the study population under analysis, a total of 20 (13%) patients developed DIC during their treatment course. Amongst these patients who developed DIC, 14/20 (70%) of the patients expired and in comparison, amongst the patients who did not develop DIC, 36/130 (27%) of the patients expired and approximately 64% of the patients were successfully discharged. The chi square test of independence showed a significant association between presence of DIC status or not and clinical outcome (P value= <0.001). In the study population under analysis, a total of 73 (49%) patients developed shock during their treatment course. Amongst these patients who developed shock, 39/73 (53%) of the patients expired and in comparison, amongst the patients who did not develop shock, 11/77 (14%) of the patients expired and approximately 77% of the patients were successfully discharged. The chi square test of independence showed a significant association between presence of shock status or not and clinical outcome (P value= 0.003).

Out of the total 150 patients enrolled in the study, a total of 16 (10.6%) of the patients developed complications during mechanical ventilation. The treatment complications have been summarised in Figure 1. Treatment outcomes of the study cohort have been shown in Figure 2.

Figure 1: Complications related to ventilation in the study cohort.

Figure 2: Figure showing treatment outcomes in the patients enrolled in the study.

The estimated survival fraction at the end of one month was 57% and median survival was not reached due to insufficient number of events (Figure 3).  A univariate analysis (UVA) and multivariate analysis (MVA) were done including all the clinicopathological variables to find out their impact on clinical outcome using cox regression analysis. The variables found to have significant impact on outcome of the child in UVA were taken into MVA. On multivariate analysis only APGAR score at 5 minutes, presence, or absence of shock and FiO2 showed statistically significant impact on the clinical outcome (Table 2 and Table 3).

Figure 3: Kaplan Meier curve showing the survival stats of the entire cohort.

Table 2: Table highlighting the results of Univariate Analysis.

Table 3: Table highlighting the results of Multivariate analysis.

Mechanical ventilation is necessary for newborns who are suffering from perinatal hypoxia or birth asphyxia, or who have developed life-threatening conditions such as apnoea, worsening respiratory distress, and potential respiratory failure or heart failure. The availability of mechanical ventilation has greatly improved the survival of critically ill newborns in neonatal intensive care units.

Our study highlighted that APGAR score at 5 minutes was a significant predictor of clinical outcomes in ventilated neonates. Oliveira retrospective analysis showed a positive association between APGAR score and mortality in the study cohort. For neonates with birth weight less than 1000g, the strength of association of APGAR score at 1 minute < 4 with mortality was 3 times higher than in the 1000-1500g birth weight category and 35 times more than the >3000g birth weight category [5]. Similarly, Casey emphasized the significance of APGAR scores for new-born assessment in their retrospective cohort study of approximately 152,000 patients. They found that premature infants born between 26 to 36 weeks of gestation with a low five-minute Apgar score (0 to 3) had a higher neonatal death rate compared to full-term infants born at 37 weeks or later. Additionally, the risk of death for full-term infants with a low Apgar score was much higher than those with a pH level of 7.0 or lower [6].

Fraction of inspired oxygen used in our ventilated patients was another important parameter that drove the clinical outcomes in the study. In a study reporting clinical profile and outcomes in mechanically ventilated patients it was seen that mean PIP max (cm of H2O) in survivors was 16.52±1.12 as compared to 18.06±1.18 in the neonates that did not survive (P value=<0.001). The authors also reported that PEEP max and FiO2 were numerically lower in survivors, 5.47±0.51 versus 5.59±0.61 (P value=0.491) and 0.69±0.10 versus 0.75±0.13 (P value=0.091), respectively [3].

Development of shock in the ventilated patients in our study was another significant factor influencing the survival on multivariate analysis. Similar to our study, a prospective study exploring the clinical profile and outcomes in mechanically ventilated patients, reported that presence or absence of shock during mechanical ventilation was a significant factor (82.4% versus 17.6% in expired and surviving patients respectively) influencing survivorship, P value= <0.0002) [3,10].

The mortality rate in our study was 33% and out of the total 150 patients enrolled in the study, 88 (58.7%) patients were discharged in a stable clinical condition. Our study mortality rates were significantly less as compared to a study by Thakkar which reported an overall mortality rate of 52%. In their study Low birth weight, circulatory disturbances, pneumothorax, pulmonary haemorrhage, and high initial oxygen requirements were independent risk factors for mortality [7]. In another study, Yadav reported a neonatal mortality rate of 60%.  In their study on neonates requiring mechanical ventilation, survival was significantly related to gestational age, intrauterine growth pattern, and APGAR score at birth, with higher survival rates observed in neonates with higher gestational age, appropriate growth patterns, and APGAR scores greater than 7 [8,9].

Although our study investigated various factors related to mechanical ventilation in neonates and identified predictors of mortality, but it had several limitations. These included a small sample size and being conducted in a single center that primarily serves as a referral center for tertiary care, making it difficult to generalize the findings to the broader population. Therefore, it is recommended that future studies should be conducted on a larger scale and involve multiple centres to obtain a more comprehensive understanding of the subject.

The present study showed that the APGAR score at 5 minutes, presence of shock during NICU stay and the FiO2 used had a significant impact on the neonatal mortality. This study brings to light the key concepts of management in the ventilated neonates, and we hope that it is helpful in designing better care plans in this population especially in the developing countries with a resource crunch.

It’s a single institution prospective study and the results and findings of this study need to be validated on a multi-institutional level.

Authors and Contributions

Ranvir Kaur: Conceptualisation, Data collection, Statistical Analysis, Drafting of the Manuscript

Manmeet Kaur Sodhi: Conceptualisation, Drafting and editing of the manuscript.

Jaspal Singh: Drafting and editing of the manuscript.

Neeraj Sehgal: Drafting and editing of the manuscript.

Research Funding and Grants: None.

Disclosure of Interest: None.

1. India achieves significant landmarks in reduction of Child Mortality n. d.
2. Keszler M, Mammel MC. Basic modes of synchronized ventilation. In: Assist. Vent. Neonate an evidence-based approach to newborn respir. Care. Sixth edition. 2017.
3. Keszler M, Chatburn RL. Overview of assisted ventilation. In: Assist. Vent. Neonate an evidence-based approach to newborn Respir. Care. Sixth edition. 2017.
4. Pierson DJ. Complications associated with mechanical ventilation. Crit Care Clin. 1990; 6: 711-724.
5. Oliveira TG de, Freire PV, Moreira FT. Apgar score and neonatal mortality in a hospital located in the southern area of Sao Paulo city, Brazil. Einstein (Sao Paulo). 2012; 10: 22-28.
6. Casey BM, McIntire DD, Leveno KJ. The Continuing Value of the Apgar score for the Assessment of Newborn Infants. Obstetric and Gynecologic Survey. 2001; 56: 406-407.
7. Thakkar PA, Pansuriya HG, Bharani S, Taneja KK. Clinical profile, outcome and risk factors for mortality of neonates requiring mechanical ventilation at tertiary care centre of Central Gujarat, India. J Nepal Paediatric Society. 2021; 41: 29-34.
8. Yadav M, Chauhan G, Bhardwaj AK, Sharma PD. Clinico-etiological pattern and outcome of neonates requiring mechanical ventilation: Study in a tertiary care center. Indian J Crit Care Med. 2018; 22: 361-363.
9. Shaikh MA, Bedmutha RH. Study of clinical profile and short-term outcome of neonates requiring assisted mechanical ventilation. Med Pulse International J Pediatrics. 2021; 18: 13-16.
10. Dekate P, Damke S, Meshram R. Clinical Profile and Short-Term Outcome of Neonates Requiring Assisted Mechanical Ventilation. New Indian J Pediatrics. 2019; 8: 42.