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Original article
Duration of mechanical ventilation and neurodevelopment in preterm infants
  1. Roos J S Vliegenthart1,
  2. Anton H van Kaam1,2,
  3. Cornelieke S H Aarnoudse-Moens3,
  4. Aleid G van Wassenaer1,
  5. Wes Onland1
  1. 1 Neonatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
  2. 2 Neonatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
  3. 3 Psychosocial Department, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
  1. Correspondence to Roos J S Vliegenthart, Neonatology, Emma Children’s Hospital/Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands; r.j.vliegenthart{at}amc.nl

Abstract

Objective To investigate the association between invasive mechanical ventilation (IMV) duration and long-term neurodevelopmental outcomes in preterm infants in an era of restricted IMV.

Design Retrospective cohort study.

Setting Single neonatal intensive care unit in Amsterdam.

Patients All ventilated patients with a gestational age between 24 and 30 weeks born between 2010 and 2015.

Main outcome measures Neurodevelopmental impairment (NDI) at 24 months corrected age (CA). Data on patient characteristics, respiratory management, neonatal morbidities, mortality and bronchopulmonary dysplasia were collected. The relationship between IMV duration and NDI was determined by multivariate logistic regression analysis.

Results During the study period, 368 admitted infants received IMV for a median duration of 2 days. Moderate and severe bronchopulmonary dysplasia was diagnosed in 33% of the infant. Multivariate regression analysis with adjustment for gestational age, small for gestational age and socioeconomic status showed a significant association between every day of IMV and NDI at 24 months CA (adjusted OR [aOR] 1.08, 95% CI 1.004 to 1.16, p=0.04). This association only reached borderline significance when also adjusting for severe neonatal morbidity (aOR 1.08, 95% CI 1.00 to 1.17, p=0.05).

Conclusion Even in an era of restricted IMV, every additional day of IMV in preterm infants is strongly associated with an increased risk of NDI at 24 months CA. Limiting IMV should be an important focus in the treatment of preterm infants.

  • mechanical ventilation
  • bronchopulmonary dysplasia
  • neurodevelopmental outcome

https://doi.org/10.1136/archdischild-2018-315993

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    What is already known on this topic?

    • Protracted ventilation in preterm infants is associated with neurodevelopmental impairment at 18-24 months of age.

    • A restrictive invasive ventilation policy in preterm infants is feasible and associated with less neurodevelopmental impairment at 24 months corrected age.

    What this study adds?

    • Even in an era of restrictive invasive ventilation policy, every additional day of invasive mechanical ventilation increases the risk on neurodevelopmental impairment at 24 months.

    • Limiting invasive mechanical ventilation should be an important focus in the treatment of preterm infants.

    Introduction

    Despite the increasing use of non-invasive respiratory support, the majority of preterm infants still need invasive mechanical ventilation (IMV) at some point in time during their admission.1 Although IMV will often restore gas exchange, it is also associated with serious pulmonary adverse events such as air leak syndrome, ventilator-acquired pneumonia2 and bronchopulmonary dysplasia.3 Furthermore, protracted IMV increases the risk for neurodevelopmental impairment later in life.4 In a cohort of preterm infants born between 1995 and 1998 with a birth weight <1000 g and ventilated for a median duration of 18 days, Walsh et al reported that the duration of ventilation was a significant risk factor for a 1.18 on neurodevelopmental impairment assessed at 18 months corrected age (OR 1.18, 95% CI 1.14 to 1.22) per additional week of IMV.5

    Recently, a more restrictive ventilation policy in preterm infants has been advocated.6 Studies have shown that such a policy is feasible and can greatly reduce the number of IMV days in preterm infants.6 7 A recent study by our group reported a median duration of IMV <1 day in a cohort of patients with a gestational age <28 weeks, which is considerably lower than the 18 IMV days reported in the study by Walsh et al.8 Such a restricted IMV policy also seems to be associated with improved neurodevelopmental outcomes at 24 months corrected age.9

    It is unclear whether the reported association between the duration of IMV and neurodevelopmental impairment by Walsh et al still exists in the current era of restrictive IMV and if so, to what extent. Therefore, the aim of this study was to determine the association between IMV duration and neurodevelopmental impairment at 24 months corrected age in a cohort of ventilated preterm infants subjected to a restrictive IMV policy.

    Patients and methods

    Study design

    In this retrospective cohort study, all preterm infants who received any respiratory support were included with a gestational age between 24 and 30 weeks, admitted to the neonatal intensive care unit (NICU) of the Amsterdam UMC within 24 hours after birth, and born between January 2010 and December 2015. Since January 2010, the restricted ventilation policy was implemented in the NICU of the Amsterdam UMC as previously described.9 Infants with congenital anomalies were excluded. To investigate the objective of the current study, only the infants who did not receive any invasive mechanical ventilation were excluded. However, in the supplemental file of the manuscript, the analyses including the total population, including the infants who never received any invasive mechanical ventilation are displayed.

    Data collection

    A predefined set of demographics, patient characteristics and outcome measures were collected (online supplement 1). All surviving infants were invited to follow-up assessment at 24 months corrected age, which included a standardised neurological examination by a trained paediatrician and assessment of the composite cognitive score (CCS) and composite motor score (CMS) of the Bayley Scales of Infant and Toddler Development (BSID)10 performed by a trained developmental psychologist. Hearing and vision data were collected by parental information on results of visits to audiology and/or ophthalmology if applicable and observation during assessment. The data of these assessments were prospectively collected and retrospectively drawn for the current study. Until January 2015, the third edition of the BSID was used with the American scoring system. From January 2015 onwards, the third edition of the BSID was used with the Dutch scoring system. With the norming process of the Dutch version of the Bayley it became apparent that at the age of 2 there was a 4-point difference between BSID outcomes based on American and Dutch norms. Therefore, we subtracted 4 points of the CCS that were based on the American norms, while the CMS based on the American norms needed no adaptation to the Dutch norms.11 The Dutch version of the Bayley did not include a communication score of the BSID III at time of assessment. During all follow-up visits, the norm score of the specific corrected age was used. Cerebral palsy (CP) was defined according to international standards.12 Neurodevelopmental impairment at 24 months corrected age was defined as having a CCS or CMS < −1 SD (eg, a score <85 points), any CP, hearing loss despite amplification and/or visual impairment leading to blindness or light perception only in one or both eyes.

    Data analysis

    Patient characteristics were reported as means with SD or medians with IQR, depending on their distribution. Differences between assessed infants and those lost to follow-up at 24 months corrected age were analysed with independent t-test, Χ2 test or their non-parametric equivalents, depending on the distribution. If outcome measures at 24 months corrected age had >5% missing values, imputation of missing data was performed 10 times, combining them with Rubin’s rules.13 14 The relationship between days of IMV and each component of neurodevelopmental impairment was assessed using logistic regression analysis. To correct for confounders, predefined covariates were added to the logistic regression analysis. The first corrected model consisted of the covariates gestational age, small for gestational age and socioeconomic status. In the second corrected model, the postnatal complications intraventricular haemorrhage (IVH)≥grade III, necrotising enterocolitis (NEC)≥grade II and culture-proven sepsis were also added to the model. A sensitivity analysis was performed in infants with a birth weight between 501 and 1000 g only, to compare our results with the population reported by Walsh et al.5 Additional analyses comparing ventilated versus non-ventilated infants can be found in the online supplement 2. A difference with a p value of <0.05 was considered to be statistically significant. All statistical analyses were performed with IBM SPSS Statistics for Windows, V.24 (IBM, Armonk, New York, USA).

    Results

    Patient characteristics

    During the study period, 656 eligible infants were admitted, of which 27 infants were excluded because they were transferred to our hospital >24 hours after birth or because they had a congenital anomaly (figure 1). Of the remaining infants, 261 infants (42%) did not receive any IMV during their admission, and were excluded from the analyses. The patient characteristics of the remaining 368 infants are displayed in table 1. Included infants had a median gestational age of 27.0 weeks (IQR 25.6–28.3), a median birth weight of 890 g (IQR 735–1090) and 20% were small for gestational age. The majority (89%) received antenatal steroids.

    Figure 1
    Figure 1

    Flow chart. NICU, neonatal intensive care unit; PMA, postmenstrual age; CA, corrected age.

    View this table:
    Table 1

    Patient characteristics

    Respiratory characteristics and outcome

    The respiratory characteristics are displayed in table 2. The median duration of IMV was 2.1 days (IQR 0.8–6.0), with 29% of the infants receiving IMV <24 hours. A total of 80 infants (22%) were ventilated longer than a week, while only 26 infants (7%) were ventilated for >2 weeks. The mortality rate in this selected high-risk subpopulation at 36 weeks postmenstrual age was 35%. In those infants alive at 36 weeks postmenstrual age, 33% had moderate or severe bronchopulmonary dysplasia.

    View this table:
    Table 2

    Respiratory characteristics

    Neurodevelopmental outcomes

    Analyses comparing the ventilated and non-ventilated infants showed a clear difference in mortality rates, but not in long-term neurodevelopmental outcomes (online supplement tab1e S2). Analyses of the ventilated infants only show that 193 (85%) of the surviving infants were assessed at a median of 24 months corrected age (IQR 23–24) (figure 1). Multiple imputation for missing values was performed for the variables CCS and CMS, CP, hearing and visual impairment. Analyses of the patient characteristics showed that compared with those infants assessed at 24 months corrected age, the infants lost to follow-up had comparable neonatal characteristics and morbidities.

    Neurodevelopmental impairment was present in 40 (22%) infants assessed at 24 months corrected age (table 3). Figure 2 shows the frequency of neurodevelopmental impairment and mortality per additional day of IMV at 24 months corrected age. Overall, the rates of an CCS/CMS<−2 SD, CP and sensory impairment were low, with only 10 infants having a neurodevelopmental impairment below −2 SD.

    Figure 2
    Figure 2

    Overview of neurodevelopmental impairment and mortality, classified by the number of cumulative ventilated days.

    View this table:
    Table 3

    Long-term neurodevelopmental outcomes

    Logistic regression analysis with multiple imputation showed that the OR of neurodevelopmental impairment at 24 months corrected age was 1.07 per day IMV (95% CI 1.004 to 1.13, p=0.04) and the effect estimate did not change after adjusting for gestational age, small for gestational age, socioeconomic status, IVH≥grade III, NEC≥grade II and sepsis (table 4). However, the association became borderline significant in the second adjustment model including all confounders (adjusted OR [aOR] 1.08, 95% CI 1.00 to 1.17, p=0.05). The increased OR for neurodevelopmental impairment was mainly driven by an increase in the components CCS below −1 SD (aOR 1.08 per day IMV, 95% CI 0.99 to 1.17, p=0.08) and CMS below −1 SD (aOR 1.10 per day IMV, 95% CI 1.01 to 1.20, p=0.02). There was no significant association between IMV days and CP, visual or hearing impairment. Subgroup analysis of infants with a birth weight between 501 and 1000 g showed an increase in neurodevelopmental impairment per additional day IMV (aOR 1.08, 95% CI 1.00 to 1.16, p=0.04).

    View this table:
    Table 4

    OR indicating the association between duration of mechanical ventilation and the outcome measure in the pooled imputed cohort

    The OR of death or neurodevelopmental impairment at 24 months corrected age was 1.04 per day IMV (95% CI 1.001 to 1.09, p=0.05), but did not significantly increase after correcting for all confounders (aOR 1.01, 95% CI 0.97 to 1.06, p=0.70). Subgroup analysis of the infants with a birth weight between 501 and 1000 g showed an increased OR of 1.06 (95% CI 1.01 to 1.11, p=0.02) per additional day IMV on the outcome death or neurodevelopmental impairment at 24 months corrected age.

    Discussion

    This study shows that in a population of ventilated preterm infants in an era of restrictive IMV policy, the risk on neurodevelopmental impairment at 24 months corrected age was 1.07 higher per additional day of mechanical ventilation.

    IMV was adopted in the 70s as the primary mode of respiratory support in preterm infants with (imminent) respiratory failure. Despite the increasing body of evidence that IMV was associated with the development of bronchopulmonary dysplasia, it remained the primary mode of support for many decades. In this era, Walsh et al investigated the effect of IMV on neurodevelopmental outcome in a cohort of preterm infants born between 1995 and 1998 with a birth weight between 501 and 1000 g.5 These infants received IMV for a median duration of 18 days in the total cohort, increasing to 23 IMV days in those infants surviving infants up to 18 months corrected age. The authors showed that duration of ventilation was a significant risk factor for neurodevelopmental impairment with an OR of 1.18 per week IMV in this population. More than 20 years after this study, respiratory support policies in preterm infants have changed dramatically. High-quality studies have shown that restricting the (primary) use of IMV in favour of non-invasive support improves outcome in preterm infants.15 16 As a result, a more restrictive IMV policy has been implemented in many units, but up to now it remained unclear if and how such a policy affected the previously reported association between IMV and neurodevelopmental impairment.

    Our study shows that adopting a restricted IMV policy has a profound effect on duration of IMV, which was reduced to a median of 2 days, with only 22% of the infants ventilated for >1 week. More importantly, our study also shows that, despite this reduction in IMV days, the association between IMV duration and neurodevelopmental impairment is still present with an OR of 1.07 per additional day IMV in the current study compared with an OR of 1.18 per week IMV described by Walsh et al.5

    This increased risk IMV poses on neurodevelopmental impairment at 24 months corrected age might be explained by several factors. First, IMV might be an indicator for severity of disease. When using a restrictive ventilation policy, it is conceivable that the most severely ill patients, who have the highest risk of neurodevelopmental impairment, are in need of IMV.17 Second, IMV duration is considered a risk factor for bronchopulmonary dysplasia, as recently confirmed by a large cohort study.18 That study showed that the odds for developing bronchopulmonary dysplasia were already 5.7 times higher in a group of preterm infants who were ventilated for 8–14 days compared with infants receiving IMV for ≤7 days. Bronchopulmonary dysplasia itself also is associated with an increased risk on neurodevelopmental impairment.4 19 Finally, IMV itself might cause brain injury by inducing white matter damage. A study in preterm baboons20 showed that 5 days of IMV resulted in more cerebral injury compared with 1 day of IMV.

    The increased risk on neurodevelopmental impairment was mainly determined by the components CCS and CMS, but not CP. This finding is in accordance with the study by Walsh et al, which showed that the proportion of infants with a mental and psychomotor development index < −2 SD gradually increased over the first 28 days of ventilation, while the proportion of infants developing CP only started to increase when ventilated >28 days. Nowadays, preterm infants have a higher risk of developing minor neurological dysfunction caused by diffuse white matter damage,21 instead of CP, caused by damage to the corticospinal tract.22

    The effect size of IMV on neurodevelopmental impairment was considerable higher in the present study (OR 1.07 per IMV day) compared with the study by Walsh et al (OR 1.18 per IMV week). There may be several explanations for this difference. First, and probably most important, Walsh et al used a more strict definition of neurodevelopmental impairment with a higher severity of almost all its components. The third version of the BSID is shown to overestimate development, leading to underidentification of developmental delay.23 Therefore, a less strict definition of neurodevelopmental impairment was used in the current study. Second, the different versions of the BSID used in the present study and by Walsh et al may also have contributed to differences in categorisation of severity of neurodevelopmental impairment. Finally, the effect of IMV on neurodevelopmental impairment may have changed as treatment of prematurity has evolved over time, as illustrated by the shift from CP to minor neurological dysfunction.

    We found a relative high rate of NEC in this cohort. This might partly be explained by the selection of ventilated infants only, and the fact that in that time period no donor milk or probiotics were administered. Although there is no evidence supporting a relationship between non-invasive ventilation and increased risk on NEC,24 future studies should monitor this outcome. Furthermore, the incidence of culture-proven sepsis in this cohort study might be considered unusually high. However, this observation is probably explained by the selection of the mechanically ventilated study population. Respiratory insufficiency is one of the main clinical symptoms of infection in preterm infants.

    This study has several limitations. We collected data retrospectively, which may have limited the quality of evidence. One of the consequences of this retrospective design was the different BSID scoring systems that were used over time. Although flawless conversion cannot be guaranteed, we corrected for the different BSID scoring systems based on published studies.11 Another consequence of the retrospective design was the 15% missing follow-up data at 24 months corrected age. However, multiple imputation analyses has been shown to be an accurate method to address this problem and the relationship between IMV duration and neurodevelopmental impairment was consistent in the pooled imputed data analyses.25 There was no difference between the infants assessed and lost to follow-up, therefore, confounding by indication was unlikely to influence the association between IMV duration and neurodevelopmental outcome. Regarding generalisability, active treatment is only offered in the Netherlands to infants born at ≥24 weeks of gestation. The results may be different when including infants born <24 weeks gestation. The fact that the presence and magnitude of the association between IMV duration and neurodevelopmental impairment did not change in a subgroup analysis with a birth weight between 500 and 1000 g, seems to indicate that the impact on generalisability is probably small.

    Conclusion

    In conclusion, the duration of IMV is negatively correlated with long-term neurodevelopmental outcome at 24 months corrected age in ventilated preterm infants in an era of restrictive invasive mechanical ventilation. Given the results of this study, every additional day of IMV should be prevented as much as possible and therefore, physicians should weigh the necessity for mechanical ventilation on a daily basis. Future research should focus on therapies reducing the need for invasive mechanical ventilation.

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    Footnotes

    • Contributors Conception and study design: RJSV, AHvanK, WO. Collection, analysis and interpretation of data: RJSV, AHvanK, CSHA-M, AGvanW, WO. Drafting the manuscript for important intellectual content: RJSV, AHvanK, WO. Decision to submit the paper for publication: RJSV, AHvanK, CSHA-M, AGvanW, WO. RJSV wrote the first draft of the manuscript. No payment was given to anyone to produce the manuscript. All authors approved the final version to be published. RJSV will act as corresponding author for this paper.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Ethics approval The institutional review board approved this study.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement All available data are presented in the included manuscript. Therefore, no data sharing statement is neccessary.

    • Patient consent for publication Not required.