What is BOOST - II UK

This is a double blind randomised controlled trial to compare the effects of targeting arterial oxygen saturations at levels of 85–89% versus 91–95% in babies born at less than 28 weeks gestation

Why are these treatments so interesting?

In the UK and Ireland most Neonatal Intensive Care Units (NICUs) run arterial saturation levels (SpO2) on their premature babies between 85% and 95%. Some believe that the higher end of this range is best, others use the lower end

What is SpO2 anyway?

• The haemoglobin, or red blood cells, combine with oxygen and carry it from the lungs to the tissues where it is used in cell metabolism.

• When haemoglobin combines with oxygen it is called oxyhaemoglobin

• (SpO2) is a measurement of how much of the total haemoglobin passing through the arteries has combined with oxygen to become oxyhaemoglobin

It is expressed as a percentage

• oxyhaemoglobin

• SpO2 = ---------------------------- x 100

• total haemoglobin

How is SpO2 measured?

• A machine, called a pulse oximiter, shines red and infrared light from a small projector through the body, usually a hand or foot in a baby.

• A detector, on the opposite side of the limb measures exactly how much light has managed to shine through

How does the pulse oximeter work?

• By measuring how much red and infrared light gets through the machine can calculate how much of the heamoglobin has been combined with oxygen to become oxyhaemoglobin

• If there is not enough oxyhaemoglobin too little oxygen will get to the tissues and normal cell metabolism will not take place

What is the normal SpO2?• Healthy adults have

an of SpO2 close to 100%

• In utero babies grow normally with an SpO2 of around 70%. At this time they are getting food and oxygen from their mothers, through the placenta

Why not keep babys’ SpO2 at these levels?

• After birth they need more oxygen when they have to take on some of the functions of the uterus and the placenta, e.g.. breath and keep warm. This is because more cell metabolism must take place

• When born prematurely they often need help to breath, and their underdeveloped lungs sometimes need extra oxygen so that they can exchange enough gas to keep their (SpO2) at a level which will enable them to grow and develop, but too much oxygen can be damaging…

ORGANS WHICH CAN BE DAMAGED BY OXYGEN

Lung injury Cause - a combination of

O2 toxicity and oxidative

stress,

barotrauma, volutrauma

inflammatory activation

and other processes

Jobe & Bancalari Am J Respir Crit Care Med 2001;163:1723

Hyperoxia and Brain Injury• High O2 levels cause the blood

vessels in the brain to constrict1

• Constricted blood vessels lead to

lower Cerebral Blood Flow (CBF) 2

• Low CBF is associated with injury to

brain tissue 3

• Associated with Periventricular

leucomalacia (PVL)

1 Niijima S et al. Arch Dis Child 1988;63:1126–30 2 Lundstrom K et al. Arch Dis Child 1995;73:F813 Haynes R et al. J Neuropathol Exp Neurol 2003;62:441

Cerebral Palsy

PVL may explain why

hyperoxia is a risk factor for

cerebral palsy.

Collins MP et al. Pediatr Res.

2001;50:712

The retina and retinopathy• Develops from 16w to term• Very sensitive to O2 • High or very variable O2 levels:

– Cause retinal ischaemia– Stop blood vessel growth

• Causing secondary overgrowth of blood vessels

• These new & fragile vessels may rupture causing damage and scarring

• Severe cases - retinal detachment may • cause total blindness

What is current practice?

• In the UK and Ireland

• Most NICUs aim for SpO2 between 85% and 95%

• Some believe that the higher end of this range is

best, others use the lower end but…

when we asked 40 units what saturation limits they usethey said:

NICUs wishing to join BOOST-II UK

“…there has never been

a shred of convincing

evidence to guide limits

for the rational use of

supplemental oxygen in

the care of extremely

premature infants”

Silverman WA. A cautionary tale about supplemental oxygen: the albatross of neonatal medicine. Pediatrics 2004;113:394–6

Bill Silverman

Facts and Figuresfrom the UK and Ireland

• over three thousand babies are born each year at less than 28 weeks gestation.

• two thirds of these very premature babies now survive to discharge

• most grow poorly in the first year after birth and many have respiratory problems which require further hospital admission.

• a quarter have at least one major disability at two years of age

• many of these have cerebral palsy. • developmental progress, even in those with no physical

disability, is a standard deviation below that of babies born at term

We do not know how much of this damage is done by using the wrong SpO2 levels so we need a study to guide our use

of oxygen

Babies are eligible if….

they are less than 28 weeks’ gestation at birth and

they are less than 12 hours old (24 hours old if the baby is outborn) and

the clinician and parents are substantially uncertain which SpO2 is better and

the parent(s) have given written informed consent to their baby’s participation

Exclusion Criteria

Recruitment is not appropriate if there is no realistic prospect of survival, or follow up is unlikely to be possible.

Randomisation

Randomisation is via a secure website at the National Perinatal Epidemiology Unit (NPEU) in Oxford. A telephone back-up system will be available 24 hours a day.

How will blinding take place?

• The oximeters will be modified by the manufacturer to display and store a figure that is either 3% above or 3% below the ‘true’ oxygen saturation between 85% and 95% as computed by the machines’ internal algorithm. Outside of these limits the oximeter will display the true value. Staff will aim for an oximeter reading of between 88 and 92%. This will, therefore, generate two trial groups - one for which oxygen saturation is maintained at 85–89%, and one for which it is maintained at 91–95%.

Low and high reading machines

80 85 90 95 100

80

85

90

95

100

Standard monitorLow reading (-3%)High reading (+3%)

Readout SpO2

Tru

e S

pO

2

6%

Readout Sp02

Tru

e S

pO

2

240 monitors will be customised for use in the study

but

If the baby’s SpO2 level is not kept within the range specified in the protocol (88-92%) for approximately 40% of the time, and between 85 and 95% for

approximately 70% of the time while the baby is on oxygen there will not be seperation between the two study groups, and the study will not work

Trips to stay “on target”

• Titrate the FiO2 level as seldom as possible• If baby’s SpO2 drifts out of the targeted range

give it a few moments to see if it will correct its self

• Only change the FiO2 level by 5% at a time, then leave for a few moments to see what the trend is

• If you are adjusting the oxygen level often of have changed the by FiO2 more than 15% consider that the baby’s condition has changed and report it to the senior nurse or doctor

DATA

Data collected on the Masimo monitors will be downloaded every 28 days by local link nurses and sent back to the BOOST – II UK co-ordinating centre.As the study is only concerned with what happens when a baby is actually receiving oxygen we need to know when a baby is “on” and “off” oxygen

The Oxygen Log

22-100% Oxygen, or “a trickle” is “on” oxygen

21% or room air is “off”

The co-ordinating centre only wants to know “on” or “off”. They are not concerned about “what percentage”

Please fill in the oxygen as accurately as you can. The success of this study depends on you

Primary Outcomes

Death or serious neurosensory disability at 2 years corrected for prematurity.Neurodisability is defined as any of the following: a Mental Development Index (MDI) of less than 70 using the Bayley Scale of Infant Development; severe visual loss (legally certifiable as blind or partially sighted); not walking unaided at 2 years (corrected for prematurity) because of cerebral palsy; deafness requiring hearing aids.

Secondary outcomesRespiratory outcomes: – days of endotracheal intubation – days of nasal continuous positive airway pressure – supplemental oxygen at a postmenstrual age of 36 weeks – days of oxygen prior to discharge home, and – days in oxygen after discharge home

ROP, plus disease, stage 3 and 4 disease Patent ductus arteriosus requiring medical or surgical treatmentNecrotising enterocolitis, Bells stage 3 or 4Changes in weight and head circumference from birth to 36 weeks’ postmenstrual age, and 2 years after delivery was due Retinal structure when last seen for ophthalmic review

Secondary outcomes at 2 years of age

• Re-admissions to hospital until 2 years after delivery was due (and their cause)

• Cerebral palsy (and its severity) • Visual disability • Deafness • Developmental delay using the Bayley Test MDI • Other disability not classifiable as neurosensory in

origin • All postneonatal (>27 day) deaths, together with

their immediate and underlying cause

Follow-up

After the baby is discharged staff at the study co-ordinating centre at NPEU will keep in touch with the parents and will arrange for follow-up when the child would have been 2 years old if it was born at term.