• 
• 

Three Part Question

In [very low birth weight preterm infants], is [there good evidence that keeping their SpO2 alarm limits lower than convention, in effect providing less supplementary oxygen], [beneficial/ detrimental towards their long term eye and lung development]?

Clinical Scenario

A very low birth weight baby is born at 27 weeks gestation.She is now fully stable and 10 days old requiring low flow oxygen via the nasal prongs, is on full enteral feeds. Her Hb is slightly low at 13, her biochemistry is otherwise normal. Her saturation alarm limits are kept at mid 80s to low 90s, which is the local policy. Is there good evidence that this reduces complications to her eyes and future development of chronic lung disease or may actually be harmful by inducing an element of chronic hypoxia?

Search Strategy

Medline using pubmed interface, Ovid online, My Athens, Cochrane Reviews acessed 18th April 2008
Search using words,alarm limits, oxygen saturation in preterm infants, Retinopathy of Prematurity, Bronchopulmonary dysplasia,

Search Outcome

For the following words the following hits were obtained:
1) Alarm limits, oxygen saturation - 246 hits were obtained
2) Retinopathy of Prematurity and alarm limits, Bronchopulmonary Dysplasia - 196 hits were obtained
A total of 9 relevant studies were identified.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Vanderveen et al Oct 2006 USA	Oximetry alarm limits were lowered to 85%-93% for all infants born after 1st June 2003,with a birth weight of < 1250g &/ or gestational age 28 weeksor less, maintained until 32 weeks post menstrual age or until oxygen saturations were consistently greater than 93% in room air.	Prospective Observational Study, ROP data was collected in the year after the oximeter policy change to the preceeding 3 years.	Retinopathy of Prematurity rates	5.6% of infants developed Prethreshold ROPafter policy change compared with17.5% infants in the 3yr epoch, p=0.01	Does not identify those babies who developed threshold ROP, or the ones who needed LASER treatment, hence the study may be falsely reassuring,
				4.2% of eyes versus 16.7% of eyes deveploped prethreshold ROP in the yera after policy change compared with 16.7% in the 3 year epoch, p=0.001
Wright KW et al 2006 USA	Very Low birth weight Premature infants from 3 NICUs- Cedars- Sinai Medical centre, Los Angeles Good Samaritan Hospital, and National University Hospital Singapore. A Physiologic reduced oxygen protocol ( PROP) was implemented to keep oxygen saturation values by pulse oximeter between 83% & 93%.	Prospective Observational study	incidence of Threshold ROP, in the year before & after implementation of PROP.	The incidence of Threshold ROP decreased in each centre: CSMC- 3.3% to 0.0%,GSH- 14.8% to 4.9%, NUH- 6.7% to 0.0%
				Overall reduction was from 7.3% to 1.3%, p< 0.05
Askie LM et al 4th Sept 2003 Australia	358 infants born at less than 30 weeks gestationwho remained dependent on supplemental oxygen at 32 weeks of post menstrual age were randomly assigned to a target functional oxygen saturation of either 91- 94% or 95-98%, this target was maintained for the duration of the supplemental oxygen therapy.	Multi center, double blind, randomized, controlled trial	Outcome was assessed at a corrected age of 1 year including growth , mean weight, lenght, head circumference, weight below 10th centile	No significant difference demonstrated	This study targets infants who remained oxygen dependent after 32 weeks of postmenstrual age, hence difficult to extrapolate to the immediate newborn period. The pulmonary & eye outcomes were not intended as primary outcomes.
			Presence of major developmental abnormality- blindness, cerebral palsyor a general quotient of <77	24% in the 91-94% group vs 23% in the 95- 98% group, p=0.85
			Duration of oxygen therapy, assisted ventilation, hospital stay, frequency of home based oxygen therapy	The 95-98% group received oxygen for a median of 40 days vs 18 days in the 91-94% group, p= <0.001, and the 95-98% group similarly had a higher rate of dependence on on supplemental oxygen and home based oxygen therapy
			Retinopathy of Prematurity	No significant difference
			Rehospitalisations during the 1st year	No significant difference
			Causes of deaths	6 deaths due to pulmonary causes in the 95-98% group vs 1 in the 91-94% group, p=0.12
W Tin, et al March 2001 UK	295 babies who survived infancy after delivery before 28 weeks of gestation in the north of England in 1990- 1994.All these babies were in 1 of the 5 Neonatal units where the policy towards monitoring the oxygen saturation varied but other care policies were similar. 4 different practices of oxygen monitoring were identified as 2 units had very similar policies.The oxygen saturation limits were liberal approach- 88-98%, 85-95%, restrictive approach-84-94% and 70-90%	Retrospective Observational Study of the case notes of all the babies mentioned in the patient group.	One year survivors	No significant difference in the survival rates 53% in liberal approach to 52% in restrictive approach	Not a randomised controlled study, no long term cognitive and neurodevelopmental follow up data on the outcomes of the children kept relatively hypoxic, other factors confounding results leading to bias.
			One year survivors with cerebral palsy	17% in liberal to 15% in restrictive approach, no statistical difference
			One year survivors with threshold Retinopathy of prematurity	27.2% in liberal approach to 6.2% in restrictive approach, 4 times higher rate in liberal approach
			Duration of ventilation	31.4 days in liberal approach vs 13.9 days in the restrictive approach
			Oxygen requirement at a postmenstrual age of 36 weeks	46% of liberal approach vs 18% of restrictive approach
STOP- ROP Multicenter Study Group Feb 2000 USA	Premature infants with confirmed prethreshold ROP in at least 1 eye and median pulse oximetry < 94% saturation were randomise to a conventional oxygen arm with pulse oximetry targeted at 89% - 94% or a supplemental arm with pulse oximetry at 96% to 99% for atleast 2 weeks and until both eyes were at study end points. 649 infants ( 325 conventional and 324 supplemental) were enrolled from 30 centers over 5 years. Weekly eye examinations were conducted until ophthalmic endpoint.	Randomised Controlled multicenter trial.	Adverse Ophthalmic end point defined as reaching threshold criteria for laser or cryotherapy in atleast 1 study eye	41% in supplemental arm vs 48% in conventional arm, odds ratio( supplemental vs conventional) was 0.72	Study group not done in the immediate neonatal period but in established prethreshold ROP, hence difficult to extrapolate to the immediate neonatal period.
			Favourable ophthalmic end point- Regression of the ROP into zone IIIfor 2 consecutive weekly examinations or full retinal vascularization.
			At 3 months after due date, ophthalmic findings	Similar rates of severe sequelae in both treatment arms, infants without plus disease found to be more responsive to supplemental therapy.
			At 3 months Pulmonary Status	Pneumonia & Exacerbations of chronic lung disease ocurred in 13.2% supplemental arm vs 8.5% in the conventional arm
			Rates of rehospitalization	6.8% conventional vs 12.7% supplemental
			On oxygen at 50 weeks of postmenstrual age	37% Conventional vs 46.8% supplemental
			On Diuretics at 50 weeks of postmenstrual age	24% conventional vs 36% supplemental
			Growth & Development	No significant difference between the 2 arms.

Comment(s)

There seems to be little doubt that reducing the upper limit of oxygen saturation alarm limit thereby effectively reducing hyperoxaemia in the early neonatal period in the extremely low birth weight infants, reduces the risk of developing retinopathy of prematurity. There is good indirect evidence from randomised controlled studies namely the BOOST trial by Lisa M Askie et al and the STOP- ROP trial ( as outlined in the previous section ),that hyperoxaemia also affects the lungs adversely. There is however no good evidence of neurodevelopmental outcomes from chronic hyperoxaemia/ hypoxia.

Clinical Bottom Line

Prolonged hyperoxaemia should be avoided, hence the upper limit of the SpO2 alarm limit should be low to mid 90's, however evidence regarding the lower limit of the SpO2 alarm is currently not free from controversy. We must await multi-centre trials to establish this fact.

References

1. Vanderveen DK, Lower Oxygen Saturation alarm limits decrease the severity of retinopathy of prematurity J AAPOS Oct, 2006: 445-8
2. Wright KW, Sami D, Thompson L, Ramanathan R, Joseph R, Farzavandi S A Physiologic reduced oxygen protocol decreases the incidence of threshold retinopathy of prematurity. Trans AM Ophthalmol Soc "006, 104:78- 84
3. Askie LM, Henderson- smart et al Oxygen Saturation targets and outcomes in extremely preterm infants New England Journal Of Medicine 4th september 2003
4. Tin w, D Milligan et al Pulse oximetry, severe retinopathy and outcome at 1year in babies of less than 28 weeks gestation Archives of Diseases of Childhood March 2001, F106- 110
5. STOP- ROP Multicenter study group Supplemental Therapeutic oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP), A Randomised Controlled Trial I : Primary Outcomes Paediatrics Feb 2000, 295-310