Efficacy of cycled environmental light and noise during initial hospitalisation for improved cognitive outcomes at 2 years in infants born extremely or very preterm: Study protocol for the prospective, randomised, open, blinded endpoint controlled multicentre CIRCA DIEM trial

Very preterm infants (<32 w gestation) will be randomised to either standard environmental care (control) or a cycled environment (light and noise) from birth until discharge. The intervention group will receive cycled environmental light and noise to simulate day/night-time environments using a pragmatic 14 hour day (6 am – 8 pm), 10 hour night (8 pm – 6 am) cycle. Daytime intervention will include exposure to light including removal of cot-covers if present, to achieve lighting within the range of 300-600 lux, whilst avoiding direct bright light to the infant’s eyes. Nocturnal intervention will include repositioning of cot-covers, application of light-occlusive eye-masks; and silicone ear-plugs. Eye-masks and ear-plugs will remain in position during any medical procedures or overnight cares unless removal is necessary for medical reasons. Similar cycling of cot-blankets in combination with cycled light was used previously in a small trial without adverse effects. Hand-held light meters will be used by nursing staff to check light levels to ensure daylight lux targets are achieved and maintained (intervention group) or level of ambient lighting recorded (control group). Lux/noise levels will be documented for full days at Day 7, 14, 28 and 56 (if applicable). Eye-masks will continue to be used for phototherapy and ear protection for high-frequency ventilation as per normal nursery protocols (normally short-term). Respiratory stimulants (e.g. caffeine) will be regulated to 8 am dosing for all infants, when prescribed, to avoid pharmacologic confounding on circadian rhythm development. Similarly, if postnatal glucocorticoids are prescribed for severe lung disease, they will be given at 6 am/6 pm to reduce nocturnal disruption. Eye-masks are already used in Australian NICUs as short-term protection from phototherapy light. Similarly, many units use noise protection (ear muffs) to protect the infant from noisy ventilators (e.g. high-frequency oscillators). Silicone ear plugs are more effective at reducing noise than the routine ear muffs used in many neonatal units. The interventions (eye masks and silicone ear plugs) are medically safe for neonates and acceptable to NICU staff. Standardised eye masks and silicone earplugs will be supplied, and applied during each period by the nurse caring for the infant. Protocol adherence to the intervention will be monitored by inspection of hospital and clinical record form logs, direct observation by trials staff, and auditing of light and sound records. NICU nursing staff will receive training to demonstrate the correct application of both the eye-masks and the ear-plugs. Some infants in the CIRCA DIEM study will be involved in substudies that aim to explore underlying mechanisms and additional outcomes related to the intervention. a) the Biological substudy aims to understand if the study intervention (cycled light and noise) is effective in creating a circadian rhythm in salivary hormones (cortisol and melatonin) and in sleep and activity patterns. Infants are eligible for the Biological substudy if they are enrolled in the parent CIRCA DIEM study, were recruited to the study at King Edward Memorial Hospital, and informed parental assent was provided for substudy participation. Enrolled infants have saliva swabs collected at 4-6 timepoints throughout the day at baseline, 7 d, 14 d, 28 d, 56 d (if < 28 w gestation) and at 36 w postmenstrual age (PMA). Sleep activity behaviours are obtained at the same timepoints with an actiwatch attached to one of their lower limbs. b) the MRI substudy will be conducted in those infants who have a routine MRI performed around the expected delivery date. There are no additional procedures for sub-study participants other than parents will need to provide informed consent for the MRI images to be examined by experienced trial investigators. c) the Sleep substudy will evaluate sleep behaviours of CIRCA DIEM study babies and those of their primary caregiver prior to hospital discharge and at 2 months and 6 months following discharge home. This substudy is only performed in those infants recruited in West Australian hospitals. Sleep diaries are completed for infant and primary caregiver and sleep/activity data obtained from actiwatch placed around the limbs of infant and parent. Saliva is also collected from the babies (morning and night) to ascertain if their sleep behaviours align with a circadian rhythm in salivary melatonin. d) The Social Communication Substudy will explore whether there is an impact of cycled light and noise during hospitalisation on risk for developing Autism Spectrum Disorder. Infants are eligible for the substudy if they are identified as at risk for a behavioural disorder on the CSBS survey that all CIRCA DIEM study infants are asked to complete at 22 months, and their parents provide informed assent to their participation in the substudy. Infants enrolled in the Social Communication Substudy will have an additional assessment (The Autism Diagnostic Observation Schedule - Toddler Module (ADOS-T)) performed at approximately 2 years corrected postnatal age.