BPD children, pulmonary outcome,

long term lung function, prevention

and follow-up guidelines

Anne Greenough

Division of Asthma, Allergy and Lung Biology

King’s College London School of Medicine

MRC & Asthma UK Centre in

Allergic Mechanisms of Asthma

Bronchopulmonary dysplasia

• Oxygen dependency beyond 28 days, then assessed at 36wks PMA - mild (air), moderate (<30%) or severe (>30% and/or positive pressure support)

Jobe and Bancalari AJRCCM 2001

• 77% of 4866 infants <32 weeks gestational age and birthweight<1000gms developed BPD

Ehrenkranz et al Pediatr 2005

• Review of 5115 infants born between 1994 and 2002 demonstrated the risk of BPD remained constant

Smith et al J Pediatr 2005

Quality of life of families caring for

preterm infants requiring home oxygen • 10 premature infants requiring home oxygen, 10 who had required home oxygen

and 10 who had never required home oxygen

• Parental quality of life questionnaires – SF-36

• Regression analysis controlling for GA, PA, birthweight, residence demonstrated the home oxygen group were significantly worse re:

- little desire to go out

- hard to find a reliable carer

- see family and friends less often

- fatigue

McLean et al J Paediatr Child health 2000

• 186 BPD children: health related quality of life of care givers related to respiratory symptoms and acute care usage

McGrath- Morrow et al Pediatr Pulmonol 2012

Home oxygen status and health care

utilisation in children <2 years of age

Home oxygen No home p

oxygen

n 88 147

Admissions

n per baby 2 (0-20) 1 (0-20) <0.05

duration (days) 7 (0-131) 3 (0-282) <0.01

OPD 10 (1-27) 8 (0-41) <0.05

Cost of care (£) 6802 4881 <0.01

Greenough et al ADC 2002

Home oxygen and healthcare utilisation

in BPD children aged 2-5 years home oxygen no home oxygen p

n 70 120

OPD (n) 8 (0-39) 5 (0-39) 0.0021

Visits to specialist 3 (0-104) 1 (0-62) 0.0023

Wheezed

>once a week 13% 3% 0.0486

Used an inhaler 81% 57% <0.0001

Cost of care (£) 10683 4044 <0.0001

Greenough et al ADC 2006

Home oxygen and healthcare utilisation

in BPD children aged 5-7 years

• 160 children with BPD, 65 had home oxygen.

• The “home oxygen” group had:

more outpatient attendances (p=0.0168)

more respiratory outpatient attendances (p=0.0032)

greater cost of prescriptions (0.0409)

• But not more wheeze/cough or greater lung function

abnormalities

Greenough et al EJPed 2011

Rehospitalisation of BPD infants

• BPD infants <32 weeks GA had twice as many rehospitalisations as term controls: (53% versus 26%)

Gross et al J Pediatr 1998

• 235 BPD infants

- only 27% were never admitted

- 27% had >3 admissions (maximum 20!)

Greenough et al ADC 2001

Mean number of days in hospital 30

20

10

0

Mean

nu

mb

er

of

days

<1 1 2 3 4 Years of life

Proven RSV

Bronchiolitis

Other respiratory

No/other admission

LBW and respiratory disease

in adulthood

• 4674 VLBW and LBW 18-27 year olds

• 18445 controls

• Respiratory hospitalisations:

- LBW OR 1.34 (1.17-1.53) p<0.005

- VLBW OR 1.83 (1.28-2.62) p=0.001

• Association remained after adjustment for sex

maternal age, race, residence and marital status

Walter et al AJRCCM 2009

Mean number of ‘respiratory’

prescriptions 6

4

2

0

Me

an

nu

mb

er

of

pre

scri

pti

on

s

<1 1 2 3 4 Years of life

Proven RSV

Bronchiolitis

Other respiratory

No/other admission

Respiratory morbidity

At 6 and 12 months, 492 infants < 29 weeks GA:

• 27% coughed (6%> once a week)

• 20% wheezed (3% > once a week)

• 14% had taken bronchodilators and 8% inhaled steroids

• BPD was a risk factor for wheeze (OR 2.74) and need for medication (2.36)

• Male gender was a risk factor for every adverse outcome

Greenough et al ADC 2004

Between 2003-2008 all infants <32weeks - geographical area

• Higher readmission rate for boys (p<0.0001), mainly due to respiratory problems (p=0.003)

Neubauer et al Acta Pediatr 2012

Gender and risk for adverse outcomes

male female

Birth weight (gms) 870 843

Died/O2 dep at 38 weeks PMA* 72% 61%

Major cranial abnormality * 20% 12%

Hospital stay (days)* 97 86

Any disability * 53% 39%

Cognitive delay* 35% 19%

Bronchodilators/steroids* 48% 31%

* p<0.05

Peacock et al Pediatr Res 2012

Small for gestational age

• 174 of 797 < 29 weeks GA

• 92% exposed to steroids and 97% surfactant

• OR 3.23 Oxygen dependency at 36weeks PMA

• OR 3.07 Pulmonary haemorrhage

• OR 3.32 Death

• OR 1.43 Respiratory admissions

• OR 1.32 Chest medicines

Peacock et al Pediatr Res 2013

Respiratory morbidity

In years 2-5 (BPD infants):

• 28% coughed and 7% wheezed > once a week

• on average 10 visits to the GP (max 68)

Greenough et al ADC 2004

219 extremely prematurely born children versus 169 classmate controls at 11 years of age had more

• chest wall deformities

• respiratory symptoms

• asthma (25 versus 13%, p<0.01)

• abnormal spirometry (56% versus 9%)

Fawkie et al AJRCCM 2010

Gender differences in respiratory

symptoms in 19 year old adults

• 690 adults GA<32 weeks and BW <1500 gms

• European community respiratory health survey questionnaire

• BPD women compared to controls:

- wheezing without a cold 35% versus 13%

- doctor diagnosed asthma 24% versus 5%

- shortness of breath on exercise 43% versus 16%

• Prevalence of symptoms in BPD men were comparable with the controls.

Vrijlandt et al Respir Research 2005

Relationship of wheezing at follow-up

to lung function

111 infants mean gestational age 26.3 weeks; 63% BPD

Wheeze No wheeze

60 51

FRChe:FRCpleth 0.83 (0.13) 0.91(0.11) 0.001

Raw 3.34 (1.58) 2.65 (0.96) 0.02

Tptef:Te 0.24 (0.08) 0.28 (0.11) 0.04

Days of wheeze correlated to FRChe:FRCpleth (p=0.015)

Broughton et al ADC 2007

Longitudinal follow-up

these data suggest persistent airflow limitation

Filippone et al Lancet 2003

Gas transfer at rest and during exercise

• 10 BPD, 10 preterms without BPD and 10 healthy term born children

• Gas transfer (DLCO) studied at 6-9 years

• BPD survivors had reduced DLCO and alveolar volume (VA) at rest

• During exercise, unlike the other groups, the BPD children had no increase in DLCO/VA

• The impaired gas transfer may reflect reduced alveolar surface area

Mitchell et al AJRCCM 1998

Airway function at 21 years after

preterm birth • Ex preterm, median GA 31.5 wks, no surfactant

• Healthy controls

• 7-9yrs: excess respiratory symptoms, airways

obstruction and AHR

• 21 yrs: excess respiratory symptoms (p=0.01), but

no significant differences in spirometry or AHR

• Low incidence of BPD, maternal smokers

• There was evidence of lung function tracking

Narang et al ARJCCM 2008

Lung function and exercise capacity

in young adults

• 42 <32 weeks GA and/or birthweight<1500 gms

• Healthy controls all studied at 19years of age

• Prematurely born young adults:

- more likely to smoke

- greater airways obstruction

- lower CO diffusing capacity

- lower exercise level (impaired fitness)

Vrijlandt et al AJRCCM 2006

PREDISPOSED INFANT

Immaturity

Antenatal inflammation

Family History

SEVERE LUNG DISEASE

PDA/Fluid overload

PIE

HIGH LEVEL OF

RESPIRATORY SUPPORT

Baro/volutrauma

Oxygen Support

Bronchopulmonary dysplasia

CONTRIBUTARY

FACTORS

Infection

Surfactant

abnormalities

Disturbance of

elastase/protease

Corticosteroids < 96 hours

21 trials 3072 infants RR (95% CI)

O2 dep at 28 days 0.85 (0.79, 0.92)

O2 dep at 36 wks 0.69 (0.60, 0.80)

Failure to extubate by day 7 0.76 (0.66, 0.88)

Hyperglycaemia 1.36 (1.23, 1.51)

Hypertension 1.84 (1.54, 2.21)

GI bleeding 1.85 (1.34, 2.55)

Intestinal perforation 1.68 (1.16, 2.44)

Developmental delay 1.68 (1.08, 2.61)

Abnormal neurological exam 1.81 (1.33, 2.47)

Corticosteroids (7-14 days)

7 trials – 669 infants

RR (95% CI)

O2 dep at 28 days 0.87 (0.81,0.94)

O2 dep at 36 weeks 0.62 (0.47,0.82)

Infection 1.35 (1.06,1.71)

Hyperglycaemia 1.51 (1.21, 1.90)

Hypertension 2.73 (1.25, 5.95)

Cerebral palsy 1.03 (0.47, 2.24)

Corticosteroids > 3 weeks

9 trials of 562 infants

RR (95% CI)

O2 dep at 36 weeks 0.76 (0.58, 1.00)

Late rescue 0.40 (0.28, 0.57)

Home oxygen 0.66 (0.47, 0.92)

Hypertension 2.61 (1.29, 5.26)

Cerebral palsy 1.20 (0.77, 1.85)

Impact of postnatal corticosteroids

on cerebral palsy

20 trials including 2064 infants

RR (95% CI)

All trials 1.45 (1.13-1.87)

Early treatment 1.70 (1.20-2.42)

Late treatment 1.20 (0.83 -1.74)

Doyle et al Pediatrics 2005

Impact of less postnatal steroids

Israel VLBW network –infants 24 -32 weeks GA:

1997-8 2003-4 p

Steroid use 23.5% 11% <0.005

O2 at 28 days 29.1% 38.6% <0.001

O2 at 36 weeks 12.9% 18.7% <0.001

Shinwell et al ADC 2007

Low dose dexamethasone

70 infants GA < 28 weeks and BW < 1000 gms

dexamethasone 0.89mk/kg (10 days) or placebo

OR (95% CI)

Extubation by 10 days 11.2 (3.2-39)

O2 dep at 36 weeks 0.58 (0.13-2.66)

No difference in death or major disability at 2 years

Doyle et al Pediatrics 2006, 2007

Bronchodilators - treatment

On the NICU

• In ventilated infants short term improvements in lung

function

• Spacer device short term improvements in gas exchange

• No faster weaning

At follow-up

Bronchodilators in randomised trials:

• improved lung function

• reduced symptom score

in wheezy prems with/without BPD

Diuretics > 3 weeks after birth

• 6 randomised trials of frusemide

- single dose improves lung mechanics

- chronic administration improved lung mechanics and oxygenation

• 8 randomised trials of aerosolised frusemide

- transiently improved lung mechanics

• 6 randomised trials of thiazide and spironolactone

- 4 week treatment improved lung compliance and

reduced the need for frusemide

Cochrane reviews

Nephrocalcinosis

• Longest course and largest doses of intravenous

frusemide

• Other risk factors include dehydration, TPN,

candidiasis and a family history

• Can result in haematuria and UTI

• Long term follow-up has highlighted chronic

tubular and glomerular dysfunction

Inhaled nitric oxide

• Improves angiogenesis and alveolarisation

through enhanced signalling mediated by VEGF

• Reduction in lung inflammation

• Reduction in neutrophil infiltration

• Protection against antioxidant lung injury

EUNO

• 800 infants 24-28+6 weeks GA and BW>500gm

• Requiring surfactant or CPAP <24 hours of age

• 5ppm iNO or placebo for at least 7 days

• BPD RR 0.83 (0.58-1.17)

• No differences in two year outcomes

Mercier et al Lancet 2010, Paediatrics 2013

Inhaled NO

• BPD reduction - 2 positive RCTs

- 4 negative RCTs

• Dosage 5-10ppm

• ?started later 7days

• ? Duration >7days

• Not effective in severe or mild respiratory failure

• Black and Hispanic but not white infants

Sosenko and Bancalari Lancet 2010

Reduction in oxygen toxicity?

• Superoxide dismutase

• Pentoxifylline

• Azithromycin/clarithromycin

• Melatonin

• Alpha-1-protease inhibitor

• N-acetyl cysteine

• Allopurinol

• Cimetidine

Caffeine therapy for apnoea of prematurity

• 2006 infants 500-1250 gms

BPD 0.63 (0.52, 0.78)

PDA treatment 0.67 (0.54, 0.82)

Cerebral palsy 0.58 (0.39, 0.87)

Schmidt et al NEJM 2006, 2007

• Infants on IPPV more neurodevelopmental benefits and starting earlier associated with a greater reduction in IPPV days

Davis et al J Pediatr 2010

• At 5 years, there was no significant difference in survival without disability between the two groups

Schmidt et al JAMA 2012

Prophylactic HFO

17 published prophylactic trials ( < 12 hours) (n=3652)

• BPD at 36 weeks PMA or discharge in survivors

RR 0.89 (0.81 – 0.99)

• Death by 36 weeks PMA RR 0.98 (0.83 – 1.14)

• Death or BPD at 36 weeks PMA or discharge

RR 0.90 (0.78-1.03)

• Pulmonary airleak RR 1.19 (1.05-1.34)

• 3-4 IVH RR 1.11 (0.95-1.30)

• PVL RR 1.10 (0.85-1.43)

Cools et al Cochrane review 2010

UKOS Trial

• Infants between 23 weeks and 28 +6 weeks gestational

age, CMV or HFOV within 60 minutes of birth

CMV HFO

n 397 400

Died 26% 25%

Survived O2

dependant at 36 weeks 41% 41%

Airleak 18% 16%

Cerebral abnormality 25% 17%

Johnson et al NEJM 2002

Pulmonary function at one year

Means and 95% CI of the differences in the means:

CMV HFOV (95%CI diff)

Respiratory rate (bpm) 31.2 33.9 (-6.1,0.7)

TGV (mls/kg) 26.9 26.5 (-2.5,3.4)

FRC (mls/kg) 24.1 23.5 (-2.1,3.2)

FRC:TGV 0.90 0.90 (-0.06,0.06)

Resistance (cmH2O/l/s) 33 34 (-8,6)

Thomas et al ARJCCM 2003

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Crown-heel length (cm)

Effect of preterm delivery on airway function

Worsening V’maxFRC in infants with BPD

• 36 infants mean birthweight 837 (152) gms and gestational age 26.8 (1.7) gms

• BW < 1250gms, IPPV>7 days, BPD

• Initial ventilation: IPPV or HFOV in the youngest and smallest infants

• Evaluated at 6 and 12 months

• Maximum flow at functional residual capacity

(V’maxFRC)

Hofhuis et al AJRCCM 2002

UKOS follow-up study

• Does HFO protect small airway function as

assessed when children were aged 11-14 years?

• Respiratory health quality of life and functional

questionnaires filled in by the children, parents

and teachers

• Comprehensive cardiopulmonary function

assessments

Follow-up guidelines

• BPD children require long term follow-up with

lung function assessment

• Those who required home oxygen may need more

intensive follow-up when pre-schoolers

• Those who had chronic diuretic therapy should

have regular renal follow-up until resolution

• Therapies should only be continued if

demonstrated to have ongoing efficacy