Long Cases

Neonatal intensive care unit graduate: chronic lung disease/bronchopulmonary dysplasia (CLD/BPD)

Chronic lung disease (CLD) in the neonatal intensive care unit (NICU) graduate is defined as an oxygen requirement beyond 36 weeks’ post-conceptual age; the term ‘CLD’ is used interchangeably with the term describing the pathology of the condition, bronchopulmonary dysplasia (BPD). The term ‘new BPD’ is now used to replace the ‘old BPD’ definition based on the work of Northway. CLD results predominantly from positive pressure ventilation of functionally immature lungs.

An increasingly large number of children with CLD are available for long-case participation. Many have had postnatal steroid therapy for prevention and/or treatment of CLD, but now evidence has accumulated that the risks of steroid therapy used postnatally in babies with CLD outweighs the possible benefits. Decreased dexamethasone use between 1997 and 2006 was associated with increased BPD incidence in babies born at 23–28 weeks’ gestation.

Recent progress has been made in the understanding and management of BPD. There is now a consensus-validated description of diagnostic criteria for BPD and its severity. In the last few years, a genetic component to BPD has been identified, with establishment of a familial tendency and heritability in twin studies; this suggests that genetic factors are as important in BPD as they are in adults for hypertension, cancer or psychiatric disease. As yet, however, there are no identifiable reproducible allelic associations to the susceptibility to BPD, although ongoing research is attempting to identify specific candidate genes involved in the pathogenic pathways of BPD.

Of the many strategies aimed specifically at reducing the incidence of BPD, including respiratory care, pharmacological or nutritional therapy, few have demonstrated efficacy. The only effective therapy widely accepted is surfactant (by default), as it reduces days of ventilation and reduces BPD in some groups (e.g. the extremely low birth weight [ELBW] ventilated group). There is level-1 evidence of efficacy for two other therapies, neither of which are widely used: parenteral vitamin A supplementation and corticosteroids. Unfortunately, the use of the latter has been associated with hypertension, hyperglycaemia, hypertrophic cardiomyopathy and abnormal neurological examination/neurodevelopmental impairment.

It is worth noting what does not work: Cochrane reviews note that evidence does not support the use of the following for preventing BPD: (a) medications—corticosteroids (in premmies at low risk of BPD), inhaled corticosteroids, inhaled nitric oxide, superoxide dismutase (SOD), glutathione or its precursors, cimetidine, macrolides (treating Ureaplasma colonisation), diuretics; (b) ventilatory strategies—high-frequency ventilation; (c) nutritional strategies—standard versus ‘aggressive’ (higher concentration of lipid, amino-acid and glucose) parenteral nutrition.

There are two other treatments that have been found to help reduce BPD, although this was not their primary goal: caffeine (for treating apnoea of prematurity), and ‘aggressive’ phototherapy for treating hyperbilirubinaemia in extremely low birth weight (ELBW) babies (under 1000 g). Caffeine citrate decreases the rate of BPD in premature babies who do not need prolonged intubation; it also decreases requirement for treatment for patent ductus arteriosus (PDA) (drug or surgical), and it decreases retinopathy of prematurity (ROP). Several studies have reported ‘non-invasive’ (meaning without an endotracheal tube) ventilation, such as bubble CPAP, to decrease BPD.

In babies less than 1000 g, up to 30% develop BPD. It is not known how much of BPD is iatrogenic and how much is unpreventable. Pulmonary immaturity (yet to develop protectants: surfactants; antioxidants; proteinase inhibitors) is the number one risk factor for BPD; other risk factors include neonatal sepsis, fetal growth restriction, Caucasian race, male gender and family history of asthma. Some have termed BPD a ‘neo-iatro-epidemic’.

Currently (2010) neonates born at 23–26 weeks’ gestation survive; this is 8–10 weeks more premature than the original babies with BPD. Lung injury mechanisms have altered. BPD as initially described (which will be termed ‘old’) occurred in moderately premature babies treated with pressure-limited time-cycled ventilators and a high oxygen concentration for significant time intervals. Since the late 1980s, with ubiquitous use of antenatal steroids, and the advent of gentler ventilating strategies (‘gentilation’), a ‘new’ BPD has emerged.

‘New’ BPD occurs in the context of multi-hit insults to the developmentally immature lung (especially under 26 weeks’ gestation), positioned between canalicular and saccular phases of lung growth (at 23–30 weeks). There is the intrinsic problem of developmental arrest of alveologenesis and vasculogenesis, with dysregulated angiogenesis, resulting in large simplified alveoli and dysmorphic lung vasculature, in addition to a premature anti-oxidant system, surfactant deficiency, and a very compliant chest wall; these intrinsic qualities increase susceptibility to the noxious effects of extrinsic problems. These extrinsic problems include mechanical ventilation and ventilator-induced lung injury (which include barotrauma [from pressure], volutrauma [from overdistension], atelectotrauma [from insufficient tidal volume], biotrauma [from infection, inflammation] and rheotrauma [from inappropriate airway flow]; these alter the integrated morphogenic programme of pulmonary development. Other inhibitors of alveolarisation and lung growth include oxygen toxicity, intrauterine, lung and systemic infections, and cytokine exposure. BPD is still the most prevalent sequel of preterm birth. Requirement for treatment with supplemental oxygen at 36 weeks’ postmenstrual age (PMA) is the commonest accepted definition of BPD at present (2010).

More very premature babies are surviving, and more survivors will develop BPD. Premmie survivors with ‘new’ BPD, compared to survivors without BPD, have higher rates of neurological problems, including (i) cerebral palsy, (ii) specific movement disorders, (iii) poor fine and gross-motor skills, (iv) impairments in hearing, vision and visuospatial perception, (v) delayed development of speech and language (receptive and expressive), (vi) lower cognitive abilities, (vii) attentional impairments, (viii) memory and learning problems, (ix) difficulty with executive skills and (x) behavioural problems.

Premmies are at increased risk of neurodevelopmental impairment, but BPD is an independent additional risk factor. Some aspects of this could be attributed to postnatal steroids, some to recurrent desaturation/hypoxia and some to poor growth. BPD is associated with global developmental impairment, the severity of which correlates with that of the BPD.

Around 50% of BPD survivors are re-hospitalised in the first 2 years of life. Rates of bronchial hyperresponsiveness are higher in BPD survivors than in ex-premmies of similar size and age without BPD until they enter school age. BPD survivors have more respiratory tract infections in childhood, and BPD survivors at 18 years have worse lung-function variables reflecting airflow than non-BPD ex-premmies.

BPD usually occurs in infants under 30 weeks’ gestation, with birth weights of under 1500 g. BPD is a multi-system disorder; associated conditions include pulmonary hypertension, neurodevelopmental delay, hearing impairments and retinopathy of prematurity. Survivors of BPD, at any age, have lower spirometry values reflecting airflow; the mean FEV₁ values in BPD survivors approximate the lower limit of the normal range of controls. However, these data do not reflect those with ‘new’ BPD. Unfortunately, almost 30% of people born prematurely smoke as young adults, which causes a steeper age-related decline in lung function. BPD is no longer a disease of childhood, as BPD survivors may have obstructive lung disease that persists into adulthood. Lung abnormalities that may persist into adulthood include airway obstruction, airway hyperreactivity, bronchiectasis and emphysema.

The single most significant predictor of CLD developing is low gestational age. Complications of CLD may include pulmonary hypertension (if oxygenation not maintained), recurrent hospitalisation with lower respiratory infections such as RSV, and bronchial hyper-reactivity. The lungs of a baby with CLD have low compliance, with increased work of breathing.

Chest Inspection Breathing pattern Respiratory rate Chest deformity Scars Palpation: •Tracheal position •Apex position •Palpable pulmonary valve closure •Right-ventricular overactivity Percussion can be deferred until after auscultation, as it may cause crying in younger infants Auscultation Lungs Heart Percussion For hyperinflation, consolidation After the above, palpate the liver for ptosis (hyperinflation) and percuss for liver span (hepatomegaly from congestive cardiac failure [CCF]) Upper limbs Hands: scars of previous intravenous cannulae Nails Pulse Blood pressure: hypertension (renovascular hypertension due to umbilical catheter, corticosteroid use or renal dysfunction) Head Eyes Nose: deformity due to prolonged intubation Lower limbs Palpate for ankle oedema (CCF) Other Temperature chart (infection)

CCF = congestive cardiac failure; PDA = patent ductus arteriosus; ROP = retinopathy of prematurity.

Management

Adequate oxygenation (and nutrition discussed below) is the most important factor for growth and development. Home oxygen is usually administered via nasal prongs. Low-flow oxygen (less than 2 litres/min) can be provided via various different-sized cylinders. All families must be supplied with cylinders: size E, which are small and portable, and size C, which are larger and to be kept at home.

Oxygen is needed if the child’s PO₂ in air is below 60 torrs. The aim is for the oxygen saturation (SaO₂) to be between 94% and 98% in the awake and asleep phases. Aiming for higher levels may worsen lung disease, and does not necessarily improve long-term growth or development. The actual range is controversial. Neonatologists generally use a lower limit of 90%, but respiratory physicians generally use a higher range (>94%), which is probably reflective of the age of infants and hence the risk of ROP. In the early phase, a lower SaO₂ is usually accepted, but upon discharge when infants are well over the corrected term of gestation, a higher minimal SaO₂ is usually used. Oxygen administration is associated with increased weight gain, decreased pulmonary hypertension, decreased SIDS-like events, and decreased morbidity and mortality. Home oxygen therapy avoids prolonged and expensive hospitalisation.

At discharge from NICU, the average requirement for CLD is low-flow subnasal oxygen at 250–1000 mL/min. The median duration of oxygen requirement is 6–10 months. Weaning should occur very slowly, over about 12 weeks, guided by regular saturation monitoring. An intercurrent acute respiratory tract infection may require reinstitution of oxygen.

Increased oxygen is needed during increased activity, feeding and sleeping (rapid eye movement sleep is associated with increased activity and irregular breathing, and carries a risk of hypoxia), so that monitoring of these times indicates when the child is able to cope in air. Oxygen is discontinued first when awake, then eventually when asleep. These children may be admitted to hospital overnight, for oximetry off oxygen while asleep. If the saturation level is consistently below 94%, oxygen therapy is still required; if it stays at or above 97%, then oxygen can probably be discontinued. Alternatively, as an outpatient, a period of oximetry for one hour when awake demonstrating saturations consistently above 97% indicates that supplemental oxygen is no longer required. Once oxygen is discontinued, weight gain is watched closely over the ensuing few weeks to ensure that adequate growth is occurring. As above, note variation of acceptability of minimum SaO₂.

Cystic fibrosis (CF)

This is a common long case and it is expected to be handled well. CF is becoming an adult disease with, currently, some 45% of CF patients in Australia being adults. Survival continues to increase, with overall mean survival in Australia at the time of writing (2010) at around 40 years (males older, females younger). This improved survival is the result of standard care, intervening earlier and aggressively treating every respiratory exacerbation, optimised by the ability to eradicate Pseudomonas (in 1998, 44% colonised with Pseudomonas, versus 12% in 2007), the optimal use of mucolytics (pulmozyme, hypertonic saline 6%), utilising the anti-inflammatory effects of azithromycin, and recognition of the utility of segregation clinics (Pseudomonas and non-Pseudomonas, MRSA and non-MRSA, cepacia and non-cepacia). Increasingly, CF is recognised as an ‘antibiotic deficiency disease’; BAL studies have shown a veritable bacterial pathogen soup, in airways of patients as young as 3 months: Staphylococcus aureus (comes early and stays); Pseudomonas aeruginosa (comes early and stays); Haemophilus influenzae (declines in later year); E. coli, Streptococcus pneumoniae, Klebsiella species and Enterobacter. Discussion in the long case could well centre around aspects other than lung disease, as longer survival has led to more patients developing complications such as cystic fibrosis related diabetes (CFRD) and musculoskeletal disorders.