• 
• 

Three Part Question

Is [Brain natriuretic peptide (BNP or NT-proBNP)] a useful biomarker for [differentiating between a cardiac or respiratory aetiology of respiratory distress] in [children and neonates]?

Clinical Scenario

A 6-week-old presents to the emergency department with respiratory distress with no significant clinical findings suggesting a cardiac or respiratory cause at this point in time. You plan to take bloods and wonder whether Brain Natriuretic peptide (BNP) would be a useful biomarker to detect cardiac disease in this case.

Search Strategy

Searched Pubmed database on 28th June 2018
(BNP OR Brain natriuretic peptide) AND neonate OR children AND cardiac OR respiratory distress

Search Outcome

41 Papers from search
16 papers identified and abstracts read.
2 articles could not be found in english, 3 additional papers were read from the references

14 papers were considered good quality and most relevant

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Markovic-Sovtic, G. et al. November 2014 Serbia	Term neonates with respiratory distress 62 patients (38 with congenital heart disease and 24 with pulmonary disease)	Prospective cohort study	NT-proBNP level in control	Average level of 8.21 with strong correlation to gestational age with a rise during 1st week of life	Non-randomised study using registry data. Small number of patients enrolled Grouped all congenital heart disease together Not standardised sampling times as clinical decision
			NT-proBNP level in RD	Significantly higher levels 9.65 average (p<0.001)
			NT-proBNP level between heart disease and pulmonary disease	9.72 in cardiac disease and 9.54 in respiratory disease both higher than controls. Pulmonary hypertension and severity of RD independent of aetiology was associated with higher BNP
Sahingozlu T, et al. May 2015 Turkey	68 infants aged 1-26 months presenting with respiratory distress and bronchiolitis 19(28%) were found to have congenital heart disease	Prospective cohort study	BNP in infants with respiratory distress	Study group had average BNP level of 320.7 compared to 11.6 so significantly higher (p<0.004)	Non-randomised study using registry data. Small numbers in the study Did control for respiratory severity and correlated with clinical improvement Excluded neonates
			BNP in infants with cardiac disease compared to controls	BNP level with cardiac disease was 841.2 compared to 118.9 (p<0.001) and particularly higher for heart failure 1122.1 compared to 112.9 (p<0.001)
Lechner, E. et al. May 2013 Austria	40 neonates with duct dependent CHD 40 neonates with respiratory distress but no CHD	Prospective single centre cohort study	NT-proBNP level on 1st, 2nd, 3rd and 5th day of life	Day 1 3048 n cardiac compared to 6011 (p<0.03) Day 2 14191 in cardiac compared to 4872 (p<0.001) Day 3 17790 in cardiac compared to 3524 (p<0.001) Day 5 17015 in cardiac compared to 3524 (p<0.001) Cannot differentiate on day 1 but after this point neonates with cardiac disease had significantly higher BNP levels	Non-randomised study using registry data. Different timing for sampling within the 24hr windows. May have particularly affected Day 1 as the CHD group tended to have earlier samples taken Most CHD diagnosed prenatally so did not present critically ill CHD patients given prostaglandin that has vasoactive properties which may enhance BNP synthesis but NT-proBNP may be more reliable
Cohen S, et al. May 2005 Israel	Infants aged 1-36 months (median 10 months) presenting with respiratory distress 17 with heart failure, 18 acute lung disease and 13 healthy	Prospective cohort study	Nt-proBNP levels	BNP was higher in infants with heart failure (median 18452) compared to infants with lung disease (median 311) with significant difference in the level before and after treatment	Non-randomised study using registry data. Small number of infants Grouped all causes of heart failure Excluded neonates
Koulouri, S. et al. July 2004 USA	51 infants and children with respiratory distress 49 were eligible for analysis 23 with CHD and 26 with primary respiratory disease	Prospective cohort study	BNP levels in CHD vs respiratory disease	Patients with CHD had significantly higher BNP levels compared to non-cardiac (693 vs. 64 p<0.001) Cut off at 40pg/ml had an 84% accuracy CHD with left ventricular systolic dysfunction had higher BNP level than volume overload	Non-randomised study using registry data. Same number of patients Some analysis of separate lesions by effect
Maher KO, et al. June 2008 USA	33 patients with newly diagnosed congenital heart disease or acquired heart disease after evaluation in acute setting 70 control patients with respiratory or infectious complaints	Prospective cohort study	BNP level in cardiac patients compared to control population	Mean age of cardiac cohort 33.6 months. Mean BNP level of 3290 Non-cardiac had a mean age of 23.1 month and BNP level of 17.4 with no overlap to cardiac group	Non-randomised study using registry data. Age difference between the two groups – may not matter as BNP levels consistently low during normal childhood Small number of patients Grouped both acquired and congenital heart disease
Sezgin, E. et al. October 2010 Turkey	71 children (1 month to 17.5yrs) with dyspnoea 41 had heart failure – 25 due to cardiac disease, 16 due to pulmonary disease and 35 had pulmonary disease without heart failure Control group 32 children	Prospective cohort study	NT-proBNP levels in the groups	Children with cardiac failure had significantly higher NT-proBNP levels than those without (mean 11,029 vs. 336.8 p<0.05). Those with failure due to cardiac reasons had higher BNP than those with pulmonary disease but this difference was not statistically significant (Mean 13,585 vs. 6397.7 p>0.05) BNP level was also higher in the respiratory group than in the control group but this was not statistically significant (Mean 336.8 vs. 153)	Non-randomised study using registry data. Mixture of congenital cardiac defects (19) and acquired myocarditis (2) and acute rheumatic carditis (1) Small numbers in each group
Hammerer-Lercher, R et al. June 2006 Austria	142 patients aged 33-1070 days (excluded infants <28 days). Infants could be presenting with any problem 23 patients had CHD	Prospective cohort study with subgroup matched analysis	BNP levels in CHD vs. other infants	Significant increase in BNP levels in infants with cardiac disease (3681 vs. 241 p<0.0001) Infants with signs of heart failure had higher BNP than those with CHD but without failure (median 8307 vs. 2850 p=0.02)	Non-randomised study using registry data. Small number of patients with cardiac disease Not specific to respiratory distress as included all infants presenting to ED Selected population excluding neonates when many cardiac conditions may present to the ED
			ROC curve analysis for diagnostic performance of NT-proBNP	Good performance with sensitivity 74%, specificity 95%, accuracy 92% with optimal cut off at 2000ng/l
Ross RD December 2012 USA	Studies covering all age groups with a section specifically for paediatrics	Literature review	BNP with symptoms of HF	Good marker of clinical severity and worsening systolic function
			Specific cut-offs for Ross I to IV scoring system for HF	Sugimoto et al. found very sensitive and specific cut off points for BNP for Ross I to IV BNP levels can predict need for circulatory support, heart transplantation and death. Trend is most useful
Welisch E, et al. September 2011 Canada	Children	Literature review	Focus on NT-proBNP levels as more stable and longer half life	Good correlation between BNP and NT-proBNP levels
				Cyanosis does not affect BNP levels but reduced renal function leads to higher BNP
				BNP rise specific to kawasaki’s with cardiac involvement BNP levels higher with patent ductus arteriosus and correlated with closure
Amiram Nir and Nadera Nasser June 2005 Israel	Children and neonates	Literature review		BNP levels raise for first few days after birth Remain constant through childhood
				Elevated in children with congestive heart failure and volume overload Related to functional capacity (negative correlation with ejection fraction)
				Limited evidence for use in cyanotic, obstructive and inflammatory heart conditions disease progression
Samuel N, et al. December 2014 Israel	18 children with known CHD presenting with bronchiolitis	Prospective single-cohort study	Relation of BNP to heart failure	7 cases were diagnosed with heart failure with a median BNP of 783 compared to 59 in those without heart failure Positive predictive value 0.83 (0.28-0.95)	Non-randomised study using registry data. Small number of cases No control group Known diagnosis of CHD and bronchiolitis diagnosis only Narrow inclusion criteria
Lee S. et al. July 2015 South Korea	138 Children in 3 groups Group 1 (94 patients) – Kawasaki Group 2 (44 patients) – Kawasaki plus respiratory symptoms Group 3 (50 patients) – febrile with respiratory symptoms	Prospective cohort study	ESR, ALT, AST, serum total protein, albumin, CRP and NT-proBNP	No significant differences between the levels of most markers including NT-proBNP for children with Kawasaki with or without respiratory symptoms. NT-proBNP level was higher in Group 2 compared to group 3 (698 vs. 156)	Non-randomised study using registry data. Select group for Kawasaki disease as a particular acquired heart problem Smaller number for kawasaki’s plus respiratory features Diagnosis is mostly clinical so could be flawed as not all had the cardiac features including coronary dilation on echo
			Echo results between group 1 and 2	No differences in ejection fraction and fractional shortening between group 1 and 2
Sugimoto et al. April 2010 Japan	181 children with CHF and 232 healthy children aged 4 months to 14 yrs	Prospective cohort study	NT-proBNP and BNP levels in healthy vs. CHF patients under 3yrs	Median levels of NT-proBNP in under 3yrs was 102.3 in healthy children and >219 in children with heart failure and increased with grade of heart failure Cut off at 31.2 had an 83% sensitivity and specificity of 83.6% for HF grade >II	Non-randomised study using registry data. Uses Ross scoring for classification of heart failure Not in emergency department setting with children with known HF Youngest child was 4 months old Small numbers for each lesion
			Severity of CHF and NT-proBNP and BNP levels in over 3yrs	For those over 3yrs healthy was 63.2 whilst children with heart failure was 89.4 and above also correlating with severity of HF A cut off at 438.4 had a Sensitivity of 88.7% and specificity of 91.8%

Comment(s)

Several studies analysed BNP or NT-proBNP levels in different age groups. It is worth noting that each different assay has a different data range when comparing the studies. Most studies used NT-proBNP rather than BNP as it is other research has showed its reliability and stability in infants/children. Although each study is based on a small number of neonates or children the clear majority report significant difference (p<0.004-p<0.001) in the BNP level between those with heart disease and those without. Some studies found an increase with respiratory distress alone but the BNP level for respiratory distress due to cardiac disease was consistently higher than those with respiratory disease. In one study when respiratory disease had led to heart failure, the BNP was higher but not statistically significant in those with cardiac related heart failure. Increased NT-proBNP level has been associated with the grade of heart failure. The levels are also consistent with acquired as well as congenital heart disease with many studies, such as the example by Lee et al. Shown above, focusing on Kawasaki’s disease. One exception was in the first week of life when the BNP level is higher in all infants and differentiation between cardiac or respiratory cause of distress was less distinct than in older infants (p<0.03 on first day of life between cardiac and respiratory cause of distress).

Clinical Bottom Line

Measurement of NT-proBNP level in infants and children is a useful biomarker in the differentiation between respiratory and cardiac disease as a cause of respiratory distress. NT-proBNP can be used in neonates but there is more overlap between the levels in those with cardiac and respiratory disease particularly during the first few days-1st week of life when BNP levels are high in all infants.

References

1. Markovic-Sovtic, G. et al. N-terminal pro-brain natriuretic peptide in the assessment of respiratory distress in term neonates. Paediatric international 2014; Volume 56, Issue 3, 373-7
2. Sahingozlu T, et al. Brain natriuretic peptide: the reason of respiratory distress is heart disease or lung disease? American Journal of Emergency Medicine 2015; Volume 33, Issue 5, 697-700
3. Lechner E, et al. Aminoterminal pro-B-type natriuretic peptide: heart or lung disease in the neonate? Pediatric Critical Care Medicine 2013; Volume 14, Issue 4, 396-402
4. Cohen S, et al. Amino-terminal pro-brain-type natriuretic peptide: heart or lung disease in pediatric respiratory distress? Pediatrics 2005; Volume 115, Issue 5, 1347-50
5. Koulouri S, et al. Utility of B-type natriuretic peptide in differentiating congestive heart failure from lung disease in pediatric patients with respiratory distress. Pediatric Cardiology 2004; Volume 25, Issue 4, 341-6
6. Maher KO, et al. B-type natriuretic peptide in the emergency diagnosis of critical heart disease in children. Pediatrics 2008; Volume 121, Issue 6, e1484-8
7. Sezgin Evim M, et al. The value of serum N-terminal pro-brain natriuretic peptide levels in the differential diagnosis and follow-up of congestive cardiac failure and respiratory distress due to pulmonary aetiologies Cardiology of the Young 2010; Volume 20, Issue 5, 495-504
8. Hammerer-Lercher, R et al. Utility of N-terminal pro-B-type natriuretic peptide to differentiate cardiac diseases from noncardiac diseases in young pediatric patients. Clinical Chemistry 2006; Volume 52, Issue 71, 1415-1419
9. Ross RD The Ross classification for heart failure in children after 25 years: a review and an age-stratified revision. Paediatric Cardiology 2012; Volume 33, Issue 8, 1295-300
10. Welisch E, et al. N-terminal pro-brain natriuretic peptide level as a screening tool for cardiac involvement in paediatric diseases of extracardiac origin. Clinical research in cardiology 2011; Volume 100, Issue 9, 723-30
11. Nir A, and Nasser, N. Clinical value of NT-ProBNP and BNP in paediatric cardiology. Journal of Cardiac Failure 2005; Volume 11, Issue 5, S76-80
12. Samuel N, et al. Diagnosing heart failure in children with congenital heart disease and respiratory syncytial virus bronchiolitis. American Journal of Emergency Medicine 2014; Volume 32, Issue 12, 1510-2
13. Lee SB, et al. Cardiac Function in Kawasaki Disease Patients with Respiratory Symptoms. Korean Circulation Journal 2015; Volume 45, Issue 4, 317-24
14. Sugimoto M, et al The role of N-terminal pro-B type natriuretic peptide in the diagnosis of congestive heart failure in children. Circulation Journal 2010; Volume 74, Issue 5, 998–1005