Automatic Oxygen Control for Reducing Extremes of Oxygen Saturation (AreOS): A Randomised Control Trial

Study Overview
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Brief Summary
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Oxygen treatment is common in babies born early (preterm) and requiring intensive care. Having too much or too little oxygen can increase the risk of damage to the eyes and lungs, and contribute to death or disability. Preterm infants because of their immaturity experience episodes of low oxygen levels. The low oxygen episodes are primarily due to pauses in their breathing (Apnoea of prematurity) and immaturity of their lung. These episodes persist for weeks. The lower the gestation at birth the longer the duration of these events. Studies have shown that these episodes of low oxygen saturations especially if frequent and prolonged is associated with poor developmental outcome, severe eye disease and lung disease. Traditionally, the oxygen delivery is manually adjusted when infant has low oxygen saturation. However previous studies have shown despite the best efforts the oxygen level can only be maintained less than half of the time and nearly a one-fifth of the time infant spends in low oxygen levels and nearly one third of the time in high oxygen levels. Now it is possible to maintain oxygen level in target range by using automatic control of oxygen delivery. With the proposed study, we would like to study the efficacy of automatic control of oxygen delivery in reducing the time spent in low oxygen levels.

Detailed Description
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Supplemental oxygen remains by far the most commonly used 'drug' in neonatal intensive care units. The goal of oxygen therapy is to maintain normal oxygenation while minimizing hypoxemia and hypoxemia. Preterm infants are particularly vulnerable to oxygen toxicity and oxidative stress leading to retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), and periventricular leukomalacia (PVL)[1]. It's also well known that preterm infants experience hypoxic events which are primarily linked to cardiovascular instability and apnea of prematurity. These events vary as the infant matures. Martin R et al showed in their study that these hypoxic events peaked around 2-4 weeks and decreases by 6-8 weeks in preterm infants (2). Exposure to prolonged and frequent hypoxemic episodes has been associated with increased morbidity and mortality [3-5]. Prolonged hypoxic events (Saturation less than 80% for more than 1 minute) have been associated with severe ROP and impaired neurodevelopmental outcome in survivors (2, 5). Peripheral oxygen saturation monitoring is standard of care in preterm infants. Traditionally oxygen saturation (SpO2) targeting is carried out by manual adjustment of fraction of inspired oxygen (FiO2) by the caregiver based on the monitored oxygen saturation. However, in practice this is only partially achieved during routine care[6]. Hagadorn et al conducted a study in 14 centers and showed that preterm infants under 28 weeks' gestation receiving oxygen spent on average only 48% of the time with SpO2 within the prescribed target range, about 36% of the time above and 16% of the time with SpO2 below the target range [7]. Preterm infants have frequent fluctuations in SpO2 due to their cardio-respiratory instability requiring frequent adjustments of FiO2 [7]. Consequently, these particularly vulnerable infants spend significant time with SpO2 outside intended range and are often exposed to extremes of hypoxemia and hyperoxaemia. It is now possible to have automated control of inspired oxygen using a device (CLiO2™) incorporated in Avea® ventilator. The device continuously monitors the oxygen saturation and adjusts the oxygen delivery to maintain oxygen saturation within the target range. The safety, feasibility and efficacy of this device have already been established [9-14]. There has been further improvement in the algorithm of the pulse oximeter incorporated in Avea® ventilator to achieve a better normative distribution around the median SpO2 value[15]. Automated control of FiO2 significantly improves compliance of oxygen saturation targeting and significantly reduces exposure to hypoxemia as well as hyperoxaemia [9-14, 16,]. Automatic control of oxygen delivery is available in both invasive and non-invasive mode of ventilation (17). The Avea ventilators are equipped with Automatic Oxygen control with invasive as well as non-invasive mode of ventilation. Previous studies looking at the efficacy of automated oxygen control mostly have been a crossover model and the study duration less than 48 hours. As previously mentioned, preterm infants experience hypoxic events for few weeks before cardiopulmonary maturation is established. Hence, it's important to study these events over a longer period of time. The objective of this randomised controlled trial is to evaluate the efficacy of the automatic oxygen control function in reducing the time spent in extremes of oxygen saturations (less than 80%), in preterm infants for the entire period of their respiratory support on invasive or non-invasive mode of ventilation.

Official Title
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Automatic Oxygen Control for Reducing Extremes of Oxygen Saturation (AreOS): A Randomised Control Trial

Conditions
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Prematurity

Intervention / Treatment
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* Device: Automatic Oxygen control
* Other: Manual Oxygen Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Preterm infants less than 33 weeks (23+0 to 32+6 weeks) • Receiving invasive or non-invasive mode of respiratory support Exclusion Criteria: Infants more than or equal to 33 weeks Preterm infants with congenital anomalies Infants on a non-conventional mode of invasive or non-invasive ventilation

Ages Eligible for Study
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Minimum Age: 23 Weeks
Maximum Age: 32 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Automatic Oxygen Control<br>Infants randomized to this arm will be monitored using automatic oxygen control system on the ventilator. When infants oxygen saturation are out of the target range the ventilator will adjust the oxygen delivery depending on the saturation of the infant to bring the saturation int he target range. | Device: Automatic Oxygen control<br>* The CLiO device is integral to the Avea infant ventilator and allows automated OXYGEN adjustment aiming to maintain SpO2 within assigned target range using neonatal pulse oximeter. When first started it adopts the FiO2 previously set by the clinician as the initial 'Baseline FiO2' level. Thereafter, the changes to the FiO2 and their frequency depend on whether SpO2 is below, above or within the target range, the trend in SpO2 and all changes are proportionate to the 'Baseline FiO2' level.<br>|
| Active Comparator: Manual oxygen control<br>Infants randomized to this arm will be receive oxygen delivery adjustments manually by the nursing and medical team taking care of the infants. When the infants oxygen saturation are out of the target range, the staff will manually adjust the oxygen delivery. | Other: Manual Oxygen Control<br>* In the manual arm the oxygen is adjusted manually by the clinical team.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| proportion of time spent in extreme saturation ( less than or equal to 80%) | The primary outcome of this study is proportion of time spent in extreme saturation (less than or equal to 80%) in preterm infants <33 weeks receiving invasive or non-invasive form of respiratory support. | Through study completion, an average of 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of time spent in target saturation | Proportion of the time spent in target saturation of 90-95% | Through study completion, an average of 8 weeks | 
| Proportion of time spent in saturation more than or equal to 98% | The proportion of time spent in more than or equal to 98% through the entire period of respiratory support | Through study completion, an average of 8 weeks | 
| Number of episodes of prolonged hypoxemia (SpO2 less than 80% for more than 60 sec) | Toatal number of episodes of prolonged hypoxemia through the respiratory support | Through study completion, an average of 8 weeks | 
| Brochopulmonary Dysplasia at 36 weeks PMA | Oxygen supplementation or need for respiratory support at 36 weeks PMA | Upto 36 weeks post menstrual age | 
| Oxygen need at day 28 | Need for oxygen on day 28 | 4 weeks | 
| Severe Retinopathy of Prematurity | Severe ROP requiring treatment | Upto 36 weeks post menstrual age | 
| Periventricular Leuckomalacia | PVL diagnosed by Brain imaging through their stay in the NICU | Upto 36 weeks post menstrual age | 
| Total number of days on supplemental oxygen less than 30% | The total number of days the infant has spent in the oxygen less than 30% | Upto 36 weeks post menstrual age | 
| Length of hospital day | Total duration of stay in Neonatal Unit | Upto 36 weeks post menstrual age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preterm Infants, Automatic oxygen control, Respiratory support