Keywords NT-proBNP - bronchopulmonary dysplasia - chronic lung disease - pulmonary arterial
hypertension - tracheobronchomalacia
Pulmonary arterial hypertension (PAH) complicates the course of chronic lung disease
(CLD) in newborns and contributes to later morbidity and mortality during infancy,
especially in the context of bronchopulmonary dysplasia (BPD). Earlier studies showed
that patients with CLD and later-onset PAH represent a very high-risk population that
exhibits increased morbidity and mortality.[1 ] Among infants with BPD, 20 to 40% develop PAH at some point during their initial
hospital course, and PAH is an important risk factor for mortality in this population.[2 ]
[3 ] Echocardiography is often used both to screen for and monitor the progression of
PAH in infants with BPD. However, it has been reported that echocardiographic screening
at 28 days of life fails to identify many late-developing cases of PAH in extremely
low–birth-weight infants.[4 ] There are many causes for failed or late diagnosis of PAH in CLD, such as poor imaging
due to over-inflation caused by CLD, the complexities of evaluating PAH by echocardiography,
and dramatic changes in the hemodynamic status of PAH in CLD due to the patient's
unstable respiratory condition. Recently, N-terminal probrain natriuretic peptide
(NT-proBNP) levels and BNP levels have been useful in screening for PAH in preterm
infants with CLD who are at risk for death.[5 ]
[6 ] However, few studies have elucidated the changes in NT-proBNP levels over time in
CLD complicated by PAH. In this report, we determined the serial changes in NT-proBNP
levels in a 6-month-old male infant with CLD complicated by PAH.
Patient Report
The patient's mother was referred to our department for premature rupture of the membranes
at the 24th week of gestation. An emergency cesarean section was required because
of oligohydramnios and indications of fetal distress. The patient's birth weight was
695 g and his Apgar's scores were 3 and 7 at 1 and 5 minutes, respectively. The patient
was immediately intubated with surfactant and admitted to our newborn intensive care
unit. His respiratory condition was poor and he could not be weaned from mechanical
ventilator support. One month after birth, an X-ray examination was performed, and
the patient was diagnosed with CLD. His oxygenation level was poor. An echocardiogram
revealed no congenital heart disease, but PAH was observed with right atrial enlargement,
right ventricular dilation, and septal flattening ([Fig. 1 ]). He was treated with inhaled nitric oxide (iNO), oral sildenafil, diuretics, and
intravenous and inhaled steroids. Progressive improvement in his respiratory condition
led to subsequent extubation and, at 169 days of age, his weight had increased to
2,568 g. At this time, the patient was discharged and prescribed supplemental oxygen
(1.0 L/min by nasal cannula). At 190 days of age, he was readmitted to our department
due to a viral upper respiratory infection. At 195 days of age, his respiratory condition
and oxygenation level worsened and he developed pulmonary edema. His peripheral capillary
oxygen saturation (SpO2 ) was 67% and he developed cardiopulmonary arrest. We immediately performed successful
cardiopulmonary resuscitation. His clinical course is shown in [Fig. 2 ]. His laboratory findings were: white blood cells, 10,070/µL; C-reactive protein
level, 0.03 mg/dL; and NT-proBNP level, 10,117 pg/mL, as indicated by an Elecsys 2010
analyzer with a chemiluminescent immunoassay kit (Roche Diagnostics, Mannheim, Germany).
The protocol for this assay has been previously described.[7 ] We could not determine the NT-proBNP levels during his stay in the neonatal intensive
care unit because echocardiography performed after he was treated with iNO, oral sildenafil,
and diuretics showed improvement of the characteristic PAH signs (right atrial enlargement,
right ventricular dilation, and septal flattening). After his condition stabilized,
we continued the administration of iNO, catecholamines, and epoprostenol and measured
his NT-proBNP levels two to three times per week. His SpO2 level increased and his respiratory condition improved after treatment, with the
levels of NT-proBNP decreasing to 1,201 pg/mL at 197 days of age. However, echocardiography
indicated that his PAH did not improve; therefore, we added oral bosentan and tadalafil
to his treatment regimen and, at 201 days of age, we were able to discontinue the
iNO. We were not able to wean the patient from mechanical ventilator support and we
transported him to another institution to perform a tracheotomy while maintaining
oral bosentan and tadalafil. During his stay at the other institution, there were
no episodes of pulmonary hypertension. After the tracheotomy was performed, we performed
a bronchoscopy and confirmed a diagnosis of tracheobronchomalacia. High positive-end
expiratory pressure (PEEP) therapy was started for the tracheobronchomalacia and the
patient's respiratory condition was improved. We then started to wean him from mechanical
ventilator support. At the age of approximately 300 days, when the PEEP setting was
decreased from 7 to 6 mm Hg, the patient's NT-proBNP level slightly increased to 1,171
pg/mL at 308 days of age.
Fig. 1 Echocardiography (aortic valve short axis image). Observation of flattening of the
ventricular septum.
Fig. 2 Serial change in NT-proBNP level and the patient's clinical course. Over the course
of treatment, there were six instances during which the NT-proBNP levels increased,
of which three instances were associated with severe cyanosis attacks. iNO, inhaled
nitric oxide; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SpO2 , oxygen saturation of peripheral artery.
However, at 323 days of age, he suddenly experienced a severe cyanosis attack (after
crying), and the suspected cause was PAH or uncontrolled tracheobronchomalacia. Cardiopulmonary
resuscitation was initiated and iNO, catecholamines, and epoprostenol were administered.
High PEEP therapy was performed for tracheobronchomalacia which was difficult to control.
Furthermore, the patient experienced repeated severe cyanosis attacks at 427 days
of age after ending iNO therapy. His NT-proBNP levels were slightly increased and
were always > 1,000 pg/mL when tracheobronchomalacia was hard to manage and he exhibited
unstable respiratory conditions. We continued to administer iNO even when the NT-proBNP
values were < 1,000 pg/mL. At 454 days of age, the patient's NT-proBNP value had slightly
increased and we suspected the re-emergence of an unstable respiratory condition due
to tracheobronchomalacia. After we maintained 10 mm Hg PEEP, his NT-proBNP level decreased.
He was subsequently weaned from iNO therapy and his medication was changed from bosentan
to ambrisentan. Subsequently, his NT-proBNP values decreased to < 1,000 pg/mL and
iNO therapy was stopped at 473 days of age. His respiratory condition, which was caused
by tracheobronchomalacia, gradually stabilized and high PEEP therapy was reduced.
When the patient was 2 years and 2 months of age, we performed cardiac catheterization.
His mean pulmonary arterial pressure was 24 mm Hg and, under treatment with tadalafil
and ambrisentan, there was no evidence of PAH. Furthermore, at 2 years and 4 months
of age, his NT-proBNP value was 350 pg/mL. He was discharged with a home respiratory
machine, supplemental oxygen, and ongoing treatment with tadalafil and ambrisentan.
After discharge, these therapies will be carefully tapered since infants with CLD
have increased risks of mortality due to respiratory failure, unremitting pulmonary
hypertension with cor pulmonale, or acquired infection (pneumonia or sepsis).
Discussion
We determined the serial changes in NT-proBNP levels in a 6-month-old male infant
with CLD complicated by PAH retrospectively. Our patient experienced five cyanotic
attacks, including two requiring CPA. Before his severe cyanotic attacks developed,
the NT-proBNP levels were nearly always slightly increased to > 1,000 pg/mL. The elevated
NT-proBNP was a cause of one CPA, while the others might have been due to the PAH.
When we failed to wean him off the iNO therapy for PAH twice, his NT-proBNP levels
were unstable and exceeded 1,000 pg/mL. Hence, we decided to maintain the iNO therapy
until the NT-proBNP dropped to less than 1000 pg/mL after which the iNO was successfully
stopped.
NT-proBNP is the precursor of brain natriuretic peptide. This peptide is released
from the myocardial tissue of the right and left ventricles when stretched. NT-proBNP
is helpful in diagnosing heart failure; however, it does not distinguish between left
or right ventricular failure. In the present case, NT-proBNP levels increased with
hemodynamic changes associated with PAH and respiratory instability. NT-proBNP and
BNP are two different types of peptides but, as reported previously, there is a strong
correlation between NT-proBNP and BNP levels during childhood.[8 ] It is also possible that the measurement results of these peptides reflect the time
lag between the time of specimen collection and measurement. Since NT-proBNP has a
longer half-life (70 minutes) than atrial NP (12 minutes) or BNP (15 minutes),[9 ] it is likely less influenced by stress on the heart just prior to blood collection.
In adults, NT-proBNP correlates with right ventricle function in PAH and has been
shown to be of prognostic value in PAH.[10 ]
[11 ] In the present case, the serial changes in NT-proBNP levels were observed to correlate
with the patient's respiratory condition and the hemodynamic changes associated with
PAH. While no optimal cut-off value of NT-proBNP, such as 1,000 pg/mL, has been determined,
Cuna et al previously reported that a BNP value of > 220 pg/mL might serve as a prognostic
marker of all-cause mortality in extremely low-birth-weight infants with BPD-associated
PAH.[12 ] Sugimoto et al[8 ] reported a strong correlation between BNP and NT-proBNP levels, where NT-proBNP = 9.080 × BNP0.923 . We speculated that at a threshold of approximately 2000 pg/mL, NT-proBNP might serve
as a prognostic indicator, and that our patient̀s level (< 1000 pg/dL) might be a
safe level at which to control the CLD complicated by PAH. We speculated that the
serial changes in NT-proBNP levels observed in this case were associated with the
patient's PAH with CLD. Furthermore, high levels of NT-proBNP might be useful in predicting
the risk of severe cyanotic attacks.
Echocardiography is often used both to screen for and to monitor the progression of
PAH in infants with CLD. Right ventricular structural or functional abnormalities,
as determined by an echocardiogram, are used as indirect indicators of PAH, including
septal flattening, right atrial enlargement, right ventricular hypertrophy, dilation,
and decreased function. Certain quantitative echocardiographic parameters used to
screen for PAH, such as tricuspid annular plane systolic excursion, tricuspid regurgitant
jet velocity, and/or pulmonary systolic time intervals, are supported by the 2015
guidelines from the American Heart Association.[13 ] However, these parameters have not been validated in preterm infants. There are
several causes for failed or late diagnosis of PH in CLD, such as poor electrocardiogram
quality due to CLD-induced over-inflation, as in the present case. While an echocardiogram
obtained upon admission revealed severe PAH, as indicated by right atrial enlargement,
right ventricular dilation, and septal flattening, we were unable to confirm PAH using
echocardiography due to the unstable respiratory conditions and high PEEP therapy.
Recently, consensus recommendations for the care of children with bronchopulmonary
dysplasia-PAH[14 ] were published. Serial NT-proBNP levels may be useful in monitoring disease progression/regression
and response to therapy and in modulating decision making, but these biomarkers should
be used in conjunction with echocardiography rather than in isolation. We suggest
that NT-proBNP level may be a useful biochemical marker in predicting the presence
of PAH in CLD infants.
Tracheobronchomalacia is an acquired complication of BPD and is more common in infants
and children with classic BPD who are treated with prolonged positive pressure ventilation.
Tracheobronchomalacia is characterized by abnormally compliant, collapsible central
airways and may be associated with barotrauma, chronic or recurrent infection, chronic
aspiration, and endotracheal intubation. Tracheobronchomalacia can improve with age,
as the tracheal cartilage matures and becomes less compliant.[15 ] Our patient was diagnosed with tracheobronchomalacia after undergoing a tracheotomy.
After this diagnosis, he experienced at least two severe cyanotic attacks induced
by PAH. Interestingly, tracheobronchomalacia is easily inducible by PAH, which requires
long-term control by a respiratory machine that in turn, sometimes induces unstable
respiratory conditions, such as desaturation, hypercapnia, and apneic attack.
Conclusion
In conclusion, serial changes in NT-proBNP levels can serve as a surrogate marker
in place of an electrocardiogram. These changes have been shown to have good prognostic
value in patients with PAH associated with CLD. Patients who exhibit higher and unstable
levels of NT-proBNP might be developing a serious respiratory and hemodynamic condition.
As a result, PAH with CLD should be evaluated carefully and the therapeutic strategy
used should be mindful of potential complications, such as tracheobronchomalacia.