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