Feature Review Article

A review of the natriuretic hormone systems diagnostic and

therapeutic potential in critically ill children*
John M. Costello, MD; Denise M. Goodman, MD, MSc; Thomas P. Green, MD

Objective: To review the natriuretic hormone system and discuss its diagnostic, prognostic, and therapeutic potential in critically ill children.
Data Source: A thorough literature search of MEDLINE was
performed using search terms including heart defects, congenital;
cardiopulmonary bypass, atrial natriuretic factor; natriuretic peptide, brain; carperitide; nesiritide. Preclinical and clinical investigations and review articles were identified that describe the
current understanding of the natriuretic hormone system and its
role in the regulation of vascular tone and fluid balance in healthy
adults and children and in those with underlying cardiac, pulmonary, and renal disease.
Results: A predictable activation of the natriuretic hormone
system occurs in children with congenital heart disease and
congestive heart failure. Further study is needed to confirm preliminary reports that measurement of natriuretic hormone levels
in critically ill children provides diagnostic and prognostic information, as has been demonstrated in adult cardiac populations.
Natriuretic hormone infusions provide favorable hemodynamic

ignificant disturbances in vascular resistance and fluid balance may develop in critically
ill infants and children, secondary to complex interactions between
the primary disease processes, the cardiovascular system, the kidneys, and various
neurohumoral factors. The natriuretic
hormone system participates in the regulation of fluid balance and vascular resistance in healthy humans as well as
those afflicted with a variety of disease

*See also p. 388.

From the Division of Cardiac Intensive Care, Department of Cardiology, Childrens Hospital Boston and
Harvard Medical School, Boston, MA (JMC); and Division of Pulmonary and Critical Care Medicine, Department of Pediatrics, Childrens Memorial Hospital and
Northwestern University Feinberg School of Medicine,
Chicago, IL (DMG, TPG).
The authors have not disclosed any potential conflicts of interest.
Copyright 2006 by the Society of Critical Care
Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
DOI: 10.1097/01.PCC.0000224998.97784.A3

308

changes and symptomatic relief when used in adults with decompensated congestive heart failure, and uncontrolled case
series suggest that similar benefits may exist in children. The
biological activity of the natriuretic hormone system may be
decreased following pediatric cardiopulmonary bypass, and additional studies are needed to determine whether natriuretic hormone infusions provide clinical benefit in the postoperative period. Preliminary reports suggest that natriuretic hormone
infusions cause physiologic improvements in adults with acute
lung injury and asthma but not in those with acute renal failure.
Conclusions: Although important perturbations of the natriuretic
hormone system occur in critically ill infants and children, further
investigation is needed before the measurement of natriuretic peptides and the use of natriuretic hormone infusions are incorporated
into routine practice. (Pediatr Crit Care Med 2006; 7:308 318)
KEY WORDS: natriuretic peptide; brain; atrial natriuretic factor;
heart failure; congestive; heart defects; congenital; cardiopulmonary bypass; diuretics

states. Assays that measure natriuretic

hormone levels and pharmacologic
agents that supplement the natriuretic
hormone system are now available for
clinical use. Thus it is important that
clinicians who care for critically ill infants and children develop an in-depth
understanding of the diagnostic, prognostic, and therapeutic utilities and limitations of the natriuretic hormone system.
The initial section of this review article provides an overview of the mechanisms by which the natriuretic hormone
system participates in the regulation of
fluid balance and vascular resistance. The
literature pertaining to the natriuretic
hormone system in adult and pediatric
patients with congestive heart failure
(CHF) and those recovering from cardiac
surgery and cardiopulmonary bypass
(CPB) is discussed in detail. Investigations of the natriuretic hormone system
in patients with acute renal failure, acute
respiratory distress syndrome, asthma,
and primary pulmonary hypertension are
also reviewed. In each section, topics re-

quiring future investigation are identified.

NATRIURETIC HORMONE
SYSTEM IN HEALTHY HUMANS
The natriuretic hormone system is composed of several structurally and functionally related peptides, primarily produced by
the myocardium, vascular endothelium,
and kidneys, which influence volume homeostasis and vascular tone by binding to
dedicated receptors throughout the cardiovascular and renal systems (Fig. 1). The
1981 landmark observation that the intravenous injection of supernatant from atrial
tissue homogenates caused significant natriuresis and diuresis in rats was soon followed by the isolation of atrial natriuretic
peptide (ANP) from the human cardiac
atrium (1). Stimulated by atrial stretch,
storage granules within cardiac myocytes
release an ANP prohormone that is cleaved
into ANP and three additional hormones,
long-acting natriuretic peptide, vessel dilator, and kaliuretic peptide (Table 1) (2, 3).
On secretion into the circulation, the
Pediatr Crit Care Med 2006 Vol. 7, No. 4

Figure 1. Neurohumoral feedback loop involving the natriuretic hormone system. ANP, atrial natriuretic peptide; BP, blood pressure; BNP, brain natriuretic peptide; CNP, C-type natriuretic peptide;
DNP, Dendroaspis natriuretic peptide; GFR, glomerular filtration rate; LAP, left atrial pressure;
LVEDP, left ventricular end-diastolic pressure; RAAS, renin-angiotensin-aldosterone system; RAP,
right atrial pressure; RVEDP, right ventricular end-diastolic pressure; SNS, sympathetic nervous
system.

diverse biological actions of these peptides in normal humans include attenuation of the renin-angiotensinaldosterone axis and sympathetic
nervous system; suppression of vasopressin release; vasodilation of the systemic, pulmonary, and coronary circulations; and promotion of natriuresis
and diuresis (4 7). Posttranslational
processing of the ANP prohormone in
the kidney differs from that which occurs in the heart, resulting in the renal
production of urodilatin rather than ANP
(3). Urodilatin is mainly produced in the
renal distal tubules in response to sodium

and volume loading and acts in a paracrine

fashion by inhibiting the resorption of sodium in the collecting duct (8).
Brain natriuretic peptide (BNP), so
named because it was first isolated in the
porcine brain, is primarily secreted from
the cardiac ventricles in response to increased wall stress (9). Within myocytes,
pro-BNP is cleaved into the biologically active BNP and an inactive fragment, aminoterminal pro-BNP (NT-proBNP), both of
which are released into the circulation. The
effects of BNP on fluid balance and vascular
tone in healthy humans are similar to those
attributed to ANP (10, 11).

Table 1. The natriuretic hormone family

Peptide

Primary Sites of Synthesis

Primary Stimulus for Release

ANP
LANP
Vessel dilator
Kaliuretic peptide
BNP
CNP
DNP
Urodilatin

Atria, ventricles
Atria, ventricles
Atria, ventricles
Atria, ventricles
Ventricles, atria
Vascular endothelium
Atria, ventricles
Kidney

Atrial stretch
Atrial stretch
Atrial stretch
Atrial stretch
Ventricular wall stress, atrial stretch
ANP, BNP, sheer stress
Atrial stretch, ventricular wall stress
1 Intravascular sodium, volume

ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CNP, C-type natriuretic peptide;
DNP, Dendroaspis natriuretic peptide; LANP, long-acting natriuretic peptide.

Pediatr Crit Care Med 2006 Vol. 7, No. 4

Dendroaspis natriuretic peptide (DNP)

was first isolated from the venom of the
Green Mamba snake (Dendroaspis angusticeps) and subsequently from human
myocardium and plasma (12). In experimental models, DNP appears to possess
similar vasorelaxant, lusitropic, natriuretic, and diuretic properties held by
ANP and BNP (13).
C-type natriuretic peptide (CNP) is
primary synthesized by the vascular endothelium, and its release is triggered by
ANP, BNP, shear stress, and various cytokines and growth factors (14). CNP
plasma levels are often very low or undetectable, and when compared with ANP,
infusions of CNP in healthy humans
cause significantly less hemodynamic effect, neurohumoral suppression, and diuresis (14, 15). CNP primarily acts as a
parahormone that promotes venodilation
and inhibits proliferation of fibroblasts
and vascular smooth muscle cells (14).
Natriuretic hormone receptors are
abundantly distributed in the vascular
endothelium, myocardium, and kidneys,
and ligand binding activates guanylyl cyclase, leading to production of guanosine
3',5'-monophosphate (cGMP) (16, 17).
cGMP-dependent protein kinase subsequently acts on several intracellular substrates to reduce cytosolic calcium, causing vascular smooth muscle and cardiac
myocyte relaxation (18). In the kidney,
natriuretic hormones promote diuresis
by several mechanisms, including increased glomerular filtration rate (19),
enhanced synthesis of prostaglandin E2
leading to inhibition of Na-K-ATPase
(3), and inhibition of sodium resorption
in the collecting duct (8, 20). Indirect
renal influences include inhibition of the
effects of the sympathetic nervous system
and angiotensin II on proximal tubular
sodium absorption, blunted aldosterone
production leading to decreased sodium
resorption at the cortical collecting duct,
and inhibition of vasopressins effect at
the medullary collecting duct (21). Natriuretic hormones also inhibit platelet activation, fibroblast proliferation, and hypertrophy of vascular smooth muscle
cells (18). Natriuretic hormones are primarily removed from the circulation by
binding to clearance receptors and enzymatic degradation by neutral endopeptidases (22, 23), processes that may be inhibited by investigational drugs (24).
Normal pediatric plasma levels for
ANP and BNP can be found in Table 2
(25). When compared with older infants
and children, neonates in the first days of
309

Table 2. Normal human pediatric plasma levels

for atrial natriuretic peptide and brain natriuretic
peptide (in pg/mL; reported as mean SD)a
Age

ANP

BNP

At birth
5 days old
4 months old
1 yr old
5 yr old
10 yr old
16 yr old

129 77
120 62
49 15
49 9
25 12
28 9
31 12

197 170
62 14
21 10
77
73
73
73

ANP, atrial natriuretic peptide; BNP, brain

natriuretic peptide.
a
Natriuretic hormone levels originally reported in fmol/ml (25), but converted to pg/mL
for this table.

life have markedly higher natriuretic hormone plasma levels, perhaps related to
the acute increase in ventricular afterload
that is present following birth. Normal
NT-proBNP levels in neonates, children,
and adolescents have also been published
(26, 27).

THE NATRIURETIC HORMONE

SYSTEM IN CONGESTIVE
HEART FAILURE AND
CONGENITAL HEART DISEASE
Following the onset of myocardial dysfunction, neurohumoral activation occurs that increases vascular resistance
and intravascular volume in order to preserve end-organ perfusion pressure. In
patients with heart failure, plasma levels
of catecholamines, vasopressin, and endothelin are increased, leading to decreased renal blood flow with subsequent
activation of the renin-angiotensinaldosterone axis (28 30). Vasoconstriction and water and salt retention occur
and eventually manifest as CHF. A similar
pattern of neurohumoral activation is
seen in adults with palliated or repaired
congenital heart disease, and the degree
of neurohumoral activation is associated
with worsening New York Heart Association (NYHA) functional class and systemic ventricular function (31). Activation of these neurohumoral systems has
detrimental effects on the failing heart
over time, due to a propensity to cause
progressive myocardial dysfunction, fibrosis, and arrhythmias, and the degree
of neurohumoral activation relates to
mortality (29).
In response to the aforementioned neurohumoral activation and fluid retention, a
compensatory up-regulation of the natri310

uretic hormone system occurs, which promotes vasodilation, natriuresis, and diuresis
(Fig. 1). In adults with systolic ventricular
dysfunction and/or CHF, plasma levels of
ANP, BNP, NT-proBNP, and DNP are elevated, the extent of which is predictive of
NYHA functional class and mortality (9, 29,
3238). In adults with CHF, measurement of
BNP is a superior diagnostic test when compared with ANP and appears to be most useful
when the diagnosis of CHF is clinically suspected but uncertain (3942). The change in
BNP and NT-proBNP levels in response to
inpatient treatment for decompensated CHF
may be a useful adjunct to guide therapy in
adults and is predictive of death or need for
readmission (35, 38, 43). The diagnostic and
prognostic value of BNP levels has also been
described in several other adult populations,
including those with diastolic heart failure,
acute coronary syndromes, aortic stenosis,
and hypertrophic cardiomyopathy and in patients recovering from cardiac surgery (44
48). Determining whether a particular BNP
or NT-proBNP level is normal or elevated in
a given patient depends on a number of variables, including the clinical setting, patient
age and gender, the presence of renal dysfunction or pulmonary disease, intraindividual biological variation, and the assay used
to perform the measurements (4952). The
United States Food and Drug Administration
has approved the measurement of plasma
BNP and NT-proBNP levels to aid in the diagnosis of heart failure in adults.
The diagnostic value of natriuretic hormone levels has been assessed in a variety of
pediatric patients. In 49 children presenting
with respiratory distress, those with CHF had
higher BNP levels compared with those with
primary lung disease (693 502 pg/mL vs.
45 64 pg/mL, p .001), and a cutoff of 40
pg/mL was 84% accurate in differentiating
CHF from pulmonary disease (53). In a similar study of 35 young children requiring hospitalization for respiratory distress, NTproBNP levels measured on admission in
patients with CHF were significantly higher
than those with primary pulmonary disease
or normal controls (CHF group, median
18,452 pg/mL [range 537599,700 pg/mL] vs.
median 311 pg/mL [range 761341 pg/mL]
in the pulmonary group and median 89
pg/mL [range 88292 pg/mL] in controls; p
.001 for the CHF group vs. pulmonary
group and controls) (54). In neonates presenting with respiratory disease, BNP levels
are significantly higher in those with persistent pulmonary hypertension of the newborn
compared with those with normal right ventricular pressure (median 1610 pg/mL [interquartile range 11281745 pg/mL] vs. 137

pg/mL [76327 pg/mL]), and a strong correlation exists between BNP levels and the severity of right ventricular hypertension in the
group with persistent pulmonary hypertension of the newborn (rs .83, p .0001)
(55).
In children with known congenital heart
disease, natriuretic hormone levels vary depending on the type and severity of the lesion.
For example, plasma ANP levels are elevated
in patients with unrepaired atrial or ventricular septal defects with CHF (56, 57). A positive correlation exists between BNP levels
and the ratio of pulmonary to systemic blood
flow, and between BNP levels and mean pulmonary artery pressure, in infants and children with ventricular septal defects (Fig. 2)
(58). In this study, a cutoff of 20 pg/mL had a
sensitivity of 82%, a specificity of 89%, and an
accuracy of 86% for predicting a mean pulmonary artery pressure 20 mm Hg at cardiac catheterization (58). Patients with congenital heart disease and chronic right
ventricular pressure overload have elevated
ANP and BNP levels, which inversely correlate with right ventricular function (59). In
patients with palliated or repaired congenital
heart disease, ANP and BNP levels are elevated and are associated with severity of ventricular dysfunction and NYHA functional
class (31, 60, 61). NT-proBNP levels are elevated in children with CHF, and the degree of
elevation correlates with ventricular ejection
fraction and severity of symptoms (26). In 37
pediatric heart transplant recipients presenting on 59 occasions for echocardiography,
cardiac catheterization, and myocardial biopsy, a cutoff BNP level of 100 pg/mL had
100% sensitivity and negative predictive
value, 78% specificity, but only 45% positive
predictive value for detecting the presence of
graft disease including rejection and transplant coronary artery disease (62).
Natriuretic hormone levels typically
decline in infants and children following
interventions that decrease atrial stretch
and ventricular wall stress. For example,
natriuretic hormone levels are elevated
following initial palliation in children
with single ventricle physiology but are
substantially lower at a median of 30.5
months following the bidirectional Glenn
operation (63). BNP levels fall after successful balloon aortic valvotomy (64), and
NT-proBNP levels decline following successful medical therapy for CHF in young
children (54). Acute changes in natriuretic hormone levels following CPB are
discussed subsequently. Although these
initial reports suggest that the measurement of natriuretic hormone levels in
critically ill children may be useful as
Pediatr Crit Care Med 2006 Vol. 7, No. 4

Figure 2. In children with unrepaired ventricular septal defects, plasma brain natriuretic peptide
(BNP) levels have a moderate correlation with (A) mean pulmonary artery pressure (PAP; r .72) and
(B) pulmonary to systemic flow ratio (Qp/Qs; r .65). Reproduced from Suda et al. (58) with
permission from Blackwell Publishing.

adjunctive tools during diagnostic evaluations and in the assessment of the response to treatment, additional studies
are needed in larger numbers of patients
before such testing is incorporated into
routine practice.
A point-of-care assay for BNP measurement (Triage BNP Test, Biosite Diagnostics, San Diego, CA) and several automated immunoassays (ADVIA Centaur
BNP Assay, Bayer Healthcare, Tarrytown,
NY; AxSYM BNP Test, Abbott Laboratories, Abbott Park, IL; Elecsys proBNP Assay, Roche Diagnostics, Indianapolis, IN)
are now available for clinical use. In
head-to-head comparisons, BNP and NTproBNP measurements have similar accuracy for detecting systolic left ventricular dysfunction, although NT-proBNP
may have an advantage for early ventricular dysfunction (65, 66). Other differences between commercially available assay systems that measure BNP and NTproBNP are summarized in Table 3.

TREATMENT OF HEART
FAILURE WITH NATRIURETIC
HORMONE INFUSIONS
The endogenous biological activity of
the natriuretic hormone system may be
inadequate in patients with severe CHF,
which provides some rationale for the
exogenous administration of natriuretic
hormones. The biological activity of the
natriuretic hormone system may be estimated by determining the molar ratio of
plasma cGMP levels to natriuretic hormone levels (32, 6770). cGMP plasma
concentrations increase in proportion to
ANP levels in mild heart failure, but
cGMP levels plateau despite a further rise
in ANP in severe heart failure, perhaps
Pediatr Crit Care Med 2006 Vol. 7, No. 4

related to down-regulation of natriuretic

peptide receptors (32, 67).
In adults with CHF, ANP and BNP
infusions decrease mean pulmonary artery pressure, pulmonary artery occlusion pressure, and systemic vascular resistance, leading to a secondary increase
in cardiac output (Fig. 3) (4, 7173). The
lusitropic properties of ANP and BNP infusions may be beneficial for patients
with diastolic dysfunction (71, 74 76). It
has been suggested that the pharmacologic responsiveness to ANP infusions are
blunted in adult CHF patients (72, 77),
although no direct comparisons with
BNP infusions have been made in this
patient population.
Nesiritide (Natrecor, Scios, Fremont, CA), a recombinant form of human B-type natriuretic peptide that was
approved by the U.S. Food and Drug
Administration in 2001 for the treatment of acutely decompensated CHF in
adults, is well tolerated and results in
improved hemodynamics and patient
symptoms (78). Several studies suggest
that nesiritide is advantageous when
compared with other inotropic or vasoactive infusions that are commonly
used to treat adults with decompensated CHF. When compared with nitroglycerine, nesiritide has equal or superior effects on hemodynamics and
patient symptoms and a lower incidence of headache (79). When compared with dobutamine, nesiritide use
is associated with a significantly lower
incidence of serious ventricular arrhythmias and cardiac arrest and may
be associated with lower 6-month readmission and mortality rates (80 82).
An analysis of observational data from
the Acute Decompensated Heart Failure

National Registry for 15,230 adults with

decompensated CHF requiring hospitalization and intravenous vasoactive
medications found that the risk factorand propensity score-adjusted odds ratios for in-hospital mortality were significantly lower in patients receiving
nitroglycerine or nesiritide compared
with those receiving dobutamine or
milrinone (83). Dobutamine and milrinone increase intracellular cyclic adenosine monophosphate, leading to increased myocardial contractility and
oxygen consumption, whereas nesiritide has no intrinsic inotropic properties. In patients with decompensated
heart failure, the myocardium is
stressed by altered hemodynamics and
further activation of neurohormones,
cytokines, and oxygen free radicals (84).
Inotropic stimulation during these periods of myocardial energy depletion
may induce subclinical myocardial
ischemia or apoptosis due to sympathetic stimulation and intramyocardial
calcium accumulation (85).
Recent studies have questioned
whether the beneficial effects of nesiritide
infusions on renal function in healthy
humans are present in those with CHF.
In a meta-analysis of five randomized
studies (involving 1269 total adult decompensated CHF patients) that compared nesiritide with either placebo or
active control, nesiritide use was associated with an increased risk of worsening
renal function (defined as an increase in
serum creatinine 0.5 mg/dL at any time
during the hospitalization) when compared with controls (21% vs. 15%; risk
ratio, 1.54; 95% confidence interval,
1.20 1.99; p .001) (86). In this study,
no difference was found in the need for
dialysis. These findings of this metaanalysis generated concern, as worsening
renal function is associated with worse
outcomes in adult heart failure patients.
However, further analysis of data from
these five studies suggested that the increase in creatinine was of clinical importance only in the patients who did not
receive nesiritide. Controls who had an
increase in serum creatinine 0.5 mg/dL
from baseline had a statistically significant 3.4-fold increase in the risk of dying
within 30 days of hospitalization compared with control patients without an
increase in serum creatinine ( p .005).
Among patients treated with nesiritide,
however, those with elevated serum creatinine levels had a nonsignificant 1.1fold increase in 30-day mortality risk
311

Table 3. Comparison of commercially available assays for measurement of brain natriuretic peptide and N-terminal fragment BNP

Assay
Range of detection (pg/mL)
Total coefficient of variation (%)
Point-of-care testing
Interaction with nesiritide
Half-life of peptide (minutes)
Peptide stable at room
temperature 4 hours
Specimen

NT-proBNP

BNP

BNP

BNP

Elecsys NT-proBNP
E170 (Roche)

Triage BNP Test

(Biosite)

AxSYM BNP Assay

(Abbott)

ADVIA Centaur
BNP assay (Bayer)

535,000
3.65.8
No
No
120
Yes

55,000
9.912.2
Yes
Yes
20
No

24,000
6.59.4
No
Yes
20
No

25,000
2.34.7
No
Yes
20
No

Plasma or serum

Whole blood or
plasma

Whole blood or
plasma

Plasma

BNP, brain natriuretic peptide; NT-proBNP, N-terminal pro-brain natriuretic peptide.

compared with those without elevated serum creatinine levels ( p .722), suggesting a protective effect of the drug
(87).
Although theoretically attractive for
use in patients with decompensated CHF
and renal dysfunction, in a recent doubleblind placebo-controlled, crossover study
of 15 hospitalized adults with decompensated CHF, fluid overload, and mild renal
insufficiency that was worse than baseline, a 24-hr nesiritide infusion did not
improve glomerular filtration rate, effective renal plasma flow, urine output, or

sodium excretion (88). However, the

small sample size, timing of patient enrollment, and lack of a washout period
between study drug infusions all must be
considered when interpreting these findings (89).
The effect of nesiritide use on mortality in adult heart failure patients is unknown and the subject of ongoing controversy (90 92). A recently published
pooled analysis of three randomized trials
involving 862 total adult decompensated
CHF patients found that, when compared
with patients receiving non-inotrope-

Figure 3. Effects of nesiritide on pulmonary artery occlusion pressure (in mmHg), cardiac index (in
L/min/m2), systemic systolic blood pressure (in mmHg), and systemic vascular resistance (in dyne/
sec/cm5) in adult heart failure patients. Reproduced from Mills et al. (73) with permission from The
American College of Cardiology Foundation. Open squares, placebo; filled circles, 0.015 g/kg/min;
filled triangles, 0.03 g/kg/min; open circles, 0.06 g/kg/min. BL, baseline; postinf, postinfusion.

312

based control therapies, those given nesiritide tended to have a higher incidence
of death within 30 days (7.2% vs. 4%; risk
ratio, 1.74; 95% confidence interval,
0.973.12; p .059) (93). In contrast, a
subsequent risk-adjusted analysis of all
available nesiritide trials with 30-day and
6-month mortality data found no difference in mortality rates between patients
receiving nesiritide and controls (94).
Given these concerns about the effect
of nesiritide use on renal function and
mortality, an expert panel of adult cardiology experts was convened to review
available safety and efficacy data, issue
recommendations for the use of nesiritide, and provide guidance for further
clinical development of this drug (95). A
large randomized clinical trial designed
to assess the impact of nesiritide on mortality in adults with acute decompensated
heart failure will begin enrolling patients
in Europe in early 2006 (96).
In several small, uncontrolled case series, investigators have reported that nesiritide infusions in children with decompensated CHF are well tolerated, decrease
central venous pressure, and improve
urine output, appetite, and functional
status (9799). Many of the patients in
these reports were concurrently receiving
conventional inotropic and diuretic
agents. Clinical trials designed to assess
the pharmacokinetics, safety, and efficacy
of nesiritide infusions in children are
needed before this drug can be recommended for routine use. Until such studies are completed, it seems reasonable to
consider a trial of nesiritide in carefully
selected children with decompensated
CHF when conventional therapies are ineffective.
The recommended adult dosing regimen for nesiritide is a bolus of 2 g/kg
Pediatr Crit Care Med 2006 Vol. 7, No. 4

Figure 4. In infants and children undergoing a variety of procedures involving cardiopulmonary bypass
(CBP), brain natriuretic peptide (BNP) levels increase in the early postoperative period (*significant
change vs. preoperative). Reproduced from Costello et al. (70) with permission from the American
Academy for Thoracic Surgery. Baseline, following induction of anesthesia and before CPB; all other
time points are post-CPB. ICU, intensive care unit; POD, postoperative day.

followed by a continuous infusion of 0.01

g/kg/min. After 3 hrs, if clinically indicated, a repeat bolus of 1 g/kg may be
administered and the infusion increased
by increments of 0.005 g/kg/min up to a
maximum dose of 0.03 g/kg/min. Doserelated hypotension, azotemia, and bradycardia have been reported in adults. As
with any vasodilator, ventricular preload
should be optimized before the initiation
of nesiritide, and it should not be used if
overt cardiogenic shock exists. Although
the half-life of nesiritide is relatively
short (18 mins), its hemodynamic effects
may last for several hours. Natriuretic
hormone infusions do not require dose
adjustment in the setting of hepatic or
renal insufficiency. Currently, nesiritide
is the only natriuretic hormone infusion
available for clinical use in the United
States. Alpha-human ANP (carperitide,
HANP Injection 1000, Daiichi Suntory
Pharma Company, Tokyo, Japan) has
been approved for clinical use for decompensated CHF in Japan since 1995 (100),
and phase II trials are ongoing in the
United States. Enrollment was recently
completed in Europe for a phase II clinical trial of urodilatin (Ularitide, CardioPep Pharma GmbH, Hanover, Germany)
in adults with decompensated CHF.

THE NATRIURETIC HORMONE

SYSTEM AND
CARDIOPULMONARY BYPASS
Following CPB, systemic and pulmonary vascular resistances are typically increased, related in part to the release of
Pediatr Crit Care Med 2006 Vol. 7, No. 4

catecholamines, vasopressin, endothelin,

and activation of the renin-angiotensinaldosterone system (101107). This neurohumoral response, along with inflammation, endothelial dysfunction, and
hemodilution, also leads to generalized
fluid retention. As disturbances in neurohumoral and endothelial regulation of
vascular tone and fluid balance following
CPB are somewhat similar to those seen
with CHF, it is intuitively attractive to
investigate the natriuretic hormone system in the postoperative period.
Predictable changes in natriuretic
hormone levels occur during and following CPB in infants, children, and adults.
Natriuretic hormone levels fall during
CPB due to underfilling of the atria, hypothermia, dilution, and exclusion of the
heart from the circulation (69, 108). Operations that result in increased atrial
stretch are associated with an immediate
postoperative rise in ANP levels, such as
the atriopulmonary Fontan operation
(102, 109). In contrast, ANP levels also
fall, at least transiently, after extracardiac
total cavopulmonary connection Fontan
completion, in which the atria are excluded from the systemic venous circulation (110, 111). In patients with complete
atrioventricular canal or large ventricular
septal defects and CHF, we and others
have shown that ANP levels are elevated
preoperatively but decline significantly by
24 hrs following surgery (68, 69). A similar decline in ANP levels has been reported within 24 hrs of mitral valve surgery in adults, which is likely related to
lower left atrial pressure (112).

In the early postoperative period, BNP

levels rise following CPB in adults, and
the extent of rise is inversely related to
indices of ventricular function (113, 114).
BNP levels increase, at least transiently,
in children following repair of tetralogy
of Fallot and the total cavopulmonary
connection Fontan operation (110). We
have documented an early postoperative
rise in BNP levels following repair of intracardiac left to right shunts in five infants (69). In a subsequent study of 25
infants and children undergoing a variety
of cardiac surgical procedures, BNP levels
increased in the early postoperative period (Fig. 4), and the extent of rise in BNP
levels correlated with longer CPB time
(rs .4, p .043) (70). The utility of BNP
levels for predicting morbidity and mortality following congenital heart surgery
requires investigation in a larger number
of patients undergoing similar procedures.
Emerging evidence suggests that the
biological activity of the natriuretic hormone system is inadequate following
CPB, as has been reported in advanced
CHF. In adults undergoing mitral valve
surgery, the molar ratio of cGMP to ANP
is inversely associated with the duration
of CPB, postoperative atrial filling pressure, and pulmonary vascular resistance
(115). In pediatric patients, Seghaye et al.
(68) reported that a longer CPB time was
associated with lower molar ratio of
cGMP/ANP. We suggest that inclusion of
multiple natriuretic peptide levels in the
calculation of biological activity may be
more appropriate, as they all activate natriuretic peptide receptors to increase
production of cGMP. In our initial investigation of five infants following CPB, the
molar ratio of cGMP/(ANP BNP
DNP) significantly decreased within the
first 24 hrs after surgery (69). In a subsequent larger study, we also observed a
transient decrease in the biological activity of the natriuretic hormone system
(Fig. 5) (70). The underlying mechanism
for decreased biological activity following
CPB is unknown, but potential contributing factors include receptor downregulation, alterations in signal transduction, increased phosphodiesterase
activity, and hypothermia (67, 116 118).
As cGMP also serves as the second
messenger for nitric oxide, the use of
plasma cGMP levels in the assessment of
natriuretic hormone system biological
activity warrants discussion. In smooth
muscle cells, both natriuretic hormones
and nitric oxide increase intracellular
313

THE NATRIURETIC HORMONE

SYSTEM AND RENAL FAILURE

Figure 5. The biological activity of the natriuretic hormone system transiently decreases in infants and
children following cardiopulmonary bypass (CPB) (*significant change vs. preoperative). Reproduced
from Costello et al. (70) with permission from the American Academy for Thoracic Surgery. Baseline,
following induction of anesthesia and before CPB; all other time points are post-CPB. ICU, intensive
care unit; POD, postoperative day.

cGMP concentrations. However, some investigations suggest that plasma levels of

cGMP are predominantly determined by
natriuretic hormone activity on endothelial cells (119). Plasma levels of nitrites
and nitrates, markers of endogenous nitric oxide production, do not correlate
with plasma cGMP levels following pediatric CPB (68), and exogenous infusion of
the nitric oxide donor sodium nitroprusside does not raise plasma cGMP levels
(119). Administration of inhaled nitric
oxide, however, increases plasma cGMP
levels (107). Although the relative influence of natriuretic hormones and nitric
oxide on plasma cGMP levels requires
further investigation, the aforementioned
studies support the notion that, in the
absence of the use of inhaled nitric oxide,
plasma levels of cGMP may be used as a
marker of natriuretic hormone system
activity.
Preliminary studies in humans suggest
that provision of exogenous natriuretic hormones may improve hemodynamics and end
organ function following CPB. Compared
with controls, adult coronary artery bypass
graft patients receiving a 24-hr continuous
infusion of ANP had improved loading conditions and cardiac index, improved respiratory
and renal function, and suppression of the
renin-angiotensin-aldosterone axis (120). In
adults undergoing elective open heart surgery, a 72-hr infusion of ANP, when compared with placebo, was associated with improved postoperative hemodynamics,
suppression of renin and aldosterone levels,
and lower fluid, diuretic, and potassium supplementation requirements (121). Following
314

the atriopulmonary Fontan operation in children, a 1-hr infusion of ANP was well tolerated and improved cardiac loading conditions, cardiac index, and urine output; these
variables returned to baseline once the infusion was discontinued (109). Small, uncontrolled case series in adults suggest that nesiritide provides hemodynamic and renal
benefit for selected patients (122125). In
small, uncontrolled pediatric case series,
postoperative nesiritide use was reportedly
well tolerated (126) and associated with lower
central venous pressure and improved urine
output (99, 127). As is the case with pediatric
heart failure patients, the perioperative use of
nesiritide requires prospective investigation
in children. These studies should determine
whether nesiritide or other natriuretic hormone infusions alter the neurohumoral response to CPB as well as the need for conventional inotropic, vasoactive, and diuretic
agents. In isolated heart and whole animal
models of myocardial ischemia-reperfusion,
and in adults undergoing percutaneous coronary reperfusion for acute myocardial infarction, provision of exogenous natriuretic
hormones limits myocardial ischemia reperfusion injury (128132). It is not known
whether the administration of natriuretic
hormones before removal of the aortic crossclamp during pediatric cardiac surgery will
minimize ischemia reperfusion injury. Natriuretic peptide infusions have beneficial effects
on pulmonary function and gas exchange in
animal models and adult patients with acute
lung injury (133, 134), and these properties
should be investigated following cardiopulmonary bypass.

Natriuretic hormone levels are elevated in

the plasma of patients with renal failure,
likely related to salt and water retention and
left ventricular hypertrophy (135, 136). Although preliminary studies in animal models
and adult humans with ischemic or nephrotoxic acute renal failure found that ANP or
urodilitin infusions improved creatinine
clearance and decreased the need for hemodialysis (3, 137), no benefit was found in subsequent large, randomized, double-blind, placebo-controlled trials in adults with acute
tubular necrosis (138140). ANP also was not
beneficial for preventing radio-contrastinduced nephropathy in adults with stable
chronic renal failure (141). BNP infusions
have not been formally evaluated in patients
with acute renal failure. The preliminary data
appear somewhat more promising for renal
insufficiency following cardiac surgery, perhaps related to the controlled nature of the
insult. In animal models of renal ischemiareperfusion injury, infusions of ANP preserved glomerular filtration rate and minimized histologic injury when compared with
placebo (142, 143). Small, uncontrolled studies in adults with acute renal impairment
following CPB suggest that both ANP and
BNP infusions improved renal function (124,
144, 145). Given the current concerns about
nesiritide use and renal function in adults,
and in the absence of randomized studies
demonstrating clinical benefit (3), the use of
natriuretic hormone infusions cannot be recommended for the prevention or treatment
of renal failure in critically ill children.

THE NATRIURETIC HORMONE

SYSTEM, ACUTE LUNG INJURY,
AND ASTHMA
ANP and BNP levels are elevated in patients with acute lung injury, likely related
to myocardial dysfunction and abnormal
cardiac loading conditions (51, 146, 147).
When compared with furosemide and placebo in animal models of acute lung injury,
ANP infusions result in improved gas exchange, reduced pulmonary artery pressure, and better diuresis (133, 148), perhaps due to cGMP-mediated reduction in
endothelial permeability leading to a reduction of extravascular lung water (133). In a
randomized study of 40 adults with acute
lung injury, ANP infusion, when compared
with placebo, resulted in improved oxygenation, lung compliance, lung injury score,
and urine output (134). Enrollment has
recently been completed in a multiplePediatr Crit Care Med 2006 Vol. 7, No. 4

center phase II study evaluating the use of

carperitide in adults with respiratory distress syndrome.
In asthmatics, the ability of natriuretic
peptides to promote bronchial smooth
muscle relaxation by increasing intracellular levels of cGMP has been investigated. In a randomized, double-blind,
placebo-controlled clinical trial in stable
asthmatic adults, indexes of pulmonary
function improved to a similar extent
with intravenous infusion of urodilatin
and inhaled albuterol (149). Furthermore, combination therapy with albuterol and urodilatin provided maximal efficacy when compared with separate
administration of the two drugs (149). No
data are currently available regarding the
use of natriuretic hormones as bronchodilators in adults or children with status
asthmaticus.

THE NATRIURETIC HORMONE

SYSTEM AND PULMONARY
HYPERTENSION
ANP and BNP levels are elevated in
adults with primary and secondary pulmonary hypertension and correlate with the
extent of elevation of mean pulmonary artery pressure and pulmonary vascular resistance (150 152). BNP levels are predictive of mortality in adults with pulmonary
hypertension (151, 153). ANP levels are elevated in premature infants with bronchopulmonary dysplasia, and BNP levels are
elevated in term infants with persistent pulmonary hypertension (55, 154). Pediatric
experience using natriuretic hormones infusions for treatment of pulmonary hypertension is limited. Ivy et al. (155) found that
only three of eight patients with repaired
congenital heart disease had a significant
reduction in mean pulmonary artery pressure and pulmonary vascular resistance
with an infusion of ANP, whereas five of
eight patients responded to inhaled nitric
oxide. These investigators concluded that
although some children responded to ANP,
inhaled nitric oxide might be the preferred
agent in this setting because of its efficacy
and selective pulmonary vasodilation (155).

CONCLUSIONS
The natriuretic hormone system, an
important regulator of fluid balance and
vascular tone, is activated in a predictable
fashion in infants and children with significant structural or myopathic heart
disease. Additional studies are needed to
determine the diagnostic and prognostic
Pediatr Crit Care Med 2006 Vol. 7, No. 4

value of routine measurement of natriuretic hormone levels in critically ill children. The biological activity of the system
is disturbed following CPB, and carefully
designed clinical trials are needed to determine whether the use of natriuretic
hormone infusions will provide meaningful benefit in children undergoing cardiac
surgery or treatment for decompensated
CHF or other critical illnesses.

ACKNOWLEDGMENTS
Emily Flynn-McIntosh and Emily Harris from the Department of Cardiology at
Childrens Hospital Boston assisted with
the figures used in this manuscript.

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