Your patient is sitting in front of you about to undergo major surgery. You get a ‘sniff’, that they may have heart failure in their background history and you want reassurance that they are safe to undergo the procedure. Then, you see the BNP level in the blood profile, it’s elevated….what now?!!

What is BNP?

Brain natriuretic peptide (BNP) is a member of a family of four human natriuretic peptides that share a common 17-peptide ring structure. The first was identified in 1983 and named atrial natriuretic peptide (ANP).

ANP is a 28-amino acid polypeptide resulting from the C-terminal end of the prohormone proANP. The source is largely in the cardiac atria, and ANP is quickly secreted in response to atrial stretching and distension. Normal hearts secrete extremely small amounts of ANP, but elevated levels are found in patients with left ventricular (LV) hypertrophy and mitral valve disease.

ANP was discovered first, but in 1988, a closely related molecule was identified in pig brains, hence the rather misnomer of BRAIN in the nomenclature. Concentrations of BNP were found to be higher and thus offered a more measurable biomarker of increased ventricular filling pressure and LV dysfunction.

BNP is stored as a 108 amino acid polypeptide precursor (proBNP). This is stored in secretory granules in both ventricles and, to a lesser extent, in the atria. In Vivo, cleavage of the prohormone proBNP produces biologically active 32 amino acid BNP as well as biologically inert 76 amino acid N-terminal pro-BNP (NT-proBNP). The 2 fragments are secreted into the plasma in equimolar amounts and increased levels are present in both symptomatic and asymptomatic ventricular dysfunction. This has led to their clinical evaluation and use in the diagnosis / management of heart failure. NT-proBNP has a correspondingly prolonged half-life of 60-120 minutes and is more stable in the lab. As a result, plasma levels of NT-proBNP tend to be 3-5 times higher than BNP levels. Clearance of NT-proBNP is thought to be primarily renal. Therefore, the renal clearance of NT-proBNP confounds its diagnostic utility in patients with renal insufficiency.

What does it do?

High ventricular filling pressures stimulate the release of ANP and BNP. Both peptides have diuretic, natriuretic, and antihypertensive effects, which they exert by inhibiting the renin-angiotensin-aldosterone system. They also have systemic and renal sympathetic activity, with effects on endothelia secretion. In addition, BNP may provide a protective effect against the detrimental fibrosis and remodeling that occurs in progressive heart failure.
Patients with heart failure often have elevated catecholamines and increased angiotensin II secretion and BNP may act to reduce the hypertensive and sodium retention in these patients.

How is it measured?

There has been a gradual introduction of point of care assays, however the mainstay is lab based testing of NT-ProBNP.

Concentrations are reported in numerous units with a range of 5-1300pg/mL or 1.4 to 376 pmol/L

BNP and NT-proBNP levels are roughly similar in the general population, but there is up to 40% variation due to genetic factors. Age, sex and BMI can also vary the levels, (NT-proBNP is increased with age and is higher in women). Oddly increased BMI and obesity reduces BNP and NT-proBNP.

In Ventricular dysfunction, (particularly LVF due to its increased number of myocytes) however, NT-proBNP rises at an increased rate compared to BNP, so levels cannot be easily converted between the two.

Estimated cost is £25 per test

What else can elevate BNP levels?

Renal failure
- Inverse relationship between GFR and BNP levels. BNP is removed by a receptor and enzyme system, (neutral endopeptidase) and also through passive excretion.
- NT-proBNP is cleared mainly by the kidney and so it rises in isolated renal failure without LV dysfunction.
Obesity
- Unclear what causes the decreased levels.
- Despite the lower values with obesity, higher plasma BNP values within any body mass index category is associated with worse outcomes
Medication
- Many used to treat heart failure can alter BNP levels. Diuretics such as spironolactone and AT-1/AT-2 receptor blockers, can all reduce natriuretic peptide concentrations.
  - Therefore, many patients with chronic stable heart failure will have BNP levels in the normal diagnostic range (i.e., BNP level less than 100 pg per mL [100 ng per L]).
- Digoxin and some beta blockers appear to increase natriuretic peptide concentrations.
Exercise
- Causes a short-term increase in BNP levels, although only small changes (i.e., increase of 0.9 percent in patients without heart failure, 3.8 percent in patients with New York Heart Association [NYHA] class I or II heart failure, and 15 percent in patients with NYHA class III to IV heart failure) are detectable one hour after exercise.
Other heart conditions
- Coronary ischemia
- Prior heart failure
- Heart muscle disease
- Left ventricular hypertrophy
- Restrictive myopathies
- Apical ballooning syndrome
- Myocarditis
- Toxic insults, like chemotherapy
- Valvular heart disease
- Cardiac Surgery
- Cardioversion
- Atrial fibrillation or flutter
- Congenital heart diseasePulmonary heart disease
Respiratory
- Sleep apnea
- Pulmonary embolism
- Pulmonary hypertension
- Pneumonia
Others
- High output (shunts)
- Anemia
- Critical illness
- Bacterial sepsis
- Burns
- ARDS
- Stroke

Does BNP level predict symptoms?

Not always. As with a lot of tests, patients with high BNP may be asymptomatic and some symptomatic HF patients may have low levels. In one study, 26% of symptomatic patients had ‘normal’ levels. Of these patients, more were likely to by young and female with cardiomyopathy of non-ischaemic origin.

What may be more useful is using levels to track course of disease and treatment.

Check out the study below which discusses ‘normal’ levels

Can we use it to prognosticate?

Chronic HF

Systematic reviews have shown every 100 pg/ml increase in BNP increased relative risk of death by 35%. In another, modelling levels of BNP was a better indicator of risk and a better predictor of survival than NYHA class and LVEF. It has been shown that prior to discharge, persistently elevated BNP levels are independent predictors of readmission and death.

Acute HF

The ADHERE registry was used here.

A near linear relationship was shown between BNP quartiles and in-hospital mortality.
BNP values were categorized according to quartiles.

Quartiles 1 to 4: <430, 430 to 839, 840 to 1729, and ≥1739 pg/mL respectively.
- There was a near linear relationship between BNP quartiles and in-hospital mortality.
Quartiles 1 to 4: 1.9, 2.8, 3.8, and 6 percent respectively.

NT-proBNP and prognosis?

Plasma NT-proBNP correlates with prognosis in patients with acute and chronic HF. In some studies, NT-proBNP had a greater prognostic value for all-cause mortality.

How does this relate to anaesthetic practice and risk?

The burning question. What do you do with the patient who has rather borderline symptomatology who is undergoing major non-cardiac surgery and has an elevated BNP level? Cancellation may not be the answer as a ‘mirror signal manoeuvre’ response.

Both pre and post-operative increased levels of natriuretic peptides are associated with increased risk of perioperative complications. Specifically, they are associated with increased risk of adverse cardiovascular events at 30 days (death, cardiac death, and non-fatal MI at 30 days).

The addition of postoperative NP to a risk prediction model containing pre-operative NP improved risk classification at 30 and ≥180 days. Elevated postoperative NP was the strongest independent predictor of the primary outcome at both time points. While it appears that BNP measured either before or shortly after surgery has prognostic information, the implications of this finding are uncertain.

What does the evidence tell us?

There have been numerous trials and meta analyses, many of which should be considered with caution because as ever, confounders are in abundance amongst the patient cohorts.

Meta-analysis 1

15 studies
4856 patients
Mixed types of surgery
Study level data

Summary and conclusions:

BNP strongly predicts peri‐operative short term
- MACE
- Cardiac mortality
- All cause mortality
- BNP predicts post‐operative long term
- All cause mortality

Limitations:
• BNP cut offs were study specific: this biases towards a favourable result.
• Study‐level, unadjusted data used
• Cannot specify optimal cut off for BNP
• Does not prove BNP is better than other preoperative assessment methods
• Cannot specify optimal treatment if BNP +ve.

Meta-analysis 2

18 trials
2477 patients
Mixed types of surgery
Pre and post‐operative BNP/NT-proBNP considered
In depth precise and risk factor profiling
Multiple Outcome measures looked at including MACE, cardiac mortality and all cause mortality
BNP / NT‐proBNP thresholds
- Pre‐operative BNP threshold 92 ng/L
- NT‐proBNP 300 ng/L

Summary and conclusions:

Confirms previous meta‐analyses
BNP is good as a negative predictor of Major adverse cardiac events
Post‐operative BNP has the highest predictive value, and is better than other risk factors
Adds to traditional risk assessment

Even GUIDE-IT can’t give the answer in proven failure!

In high-risk patients with HFrEF, a strategy of NT-proBNP–guided therapy was not more effective than a usual care strategy in improving outcomes.

Who should we ask for a BNP on?

The European Society of Cardiology (ESC) and European Society of Anesthesiology (ESA) recommended using B-type natriuretic peptide (BNP) or amino terminal-proBNP (NT-proBNP) for independent perioperative prognosis in high-risk cardiac patients undergoing non-cardiac surgery (see flow chart). Much of this involves the use off the Lee RCRI (Revised Cardiac risk index).

What lies ahead of us then?

It would be useful to compare BNP to CPEX guided prognostication.
Studies comparing BNP guided therapy to conventional management are also lacking, bar those done within specific non-surgical settings and with GUIDE-IT above.

Summary

Exactly who to do BNP on varies depending on the guideline. The AHA advises caution with this, as there is poor/controversial evidence in existence as per the trial below.

It certainly does not lie as a routine test within the current NICE pre-operative tests guideline. It may, as discussed above in this article, be useful in predicting risk. The area we believe BNP measurements to be useful is in guidance of further treatment and further pre-operative testing/ monitoring.

Further research is needed to compare treatment based on BNP in comparison to conventional therapy.

However, whether admission, discharge, or change from admission to discharge levels of natriuretic peptides is the most important predictor of long-term outcomes is still being investigated. The final thing is, cancelling patients purely on a BNP level, may not quite be the right thing to do. As we have seen, there are so many other factors within the patient pathological set that can raise levels aside from direct heart conditions that will lead to ‘death on the table’. The key; mindfulness of these, safe anaesthesia, involved appropriate POCUS and parallel advice from cardiology colleagues where required.

Written by: Dr Matt Beadle (Core Anaesthesia and ICM Trainee)

Senior editor: Jonny Wilkinson