natriuretic hormone

Feature Review Article

A review of the natriuretic hormone systems diagnostic andtherapeutic potential in critically ill children*

John M. Costello, MD; Denise M. Goodman, MD, MSc; Thomas P. Green, MD

Significant disturbances in vas-cular resistance and fluid bal-ance may develop in criticallyill infants and children, sec-ondary to complex interactions betweenthe primary disease processes, the cardio-vascular system, the kidneys, and variousneurohumoral factors. The natriuretichormone system participates in the reg-ulation of fluid balance and vascular re-sistance in healthy humans as well asthose afflicted with a variety of disease

states. Assays that measure natriuretichormone levels and pharmacologicagents that supplement the natriuretichormone system are now available forclinical use. Thus it is important thatclinicians who care for critically ill in-fants and children develop an in-depthunderstanding of the diagnostic, prog-nostic, and therapeutic utilities and lim-itations of the natriuretic hormone sys-tem.

The initial section of this review arti-cle provides an overview of the mecha-nisms by which the natriuretic hormonesystem participates in the regulation offluid balance and vascular resistance. Theliterature pertaining to the natriuretichormone system in adult and pediatricpatients with congestive heart failure(CHF) and those recovering from cardiacsurgery and cardiopulmonary bypass(CPB) is discussed in detail. Investiga-tions of the natriuretic hormone systemin patients with acute renal failure, acuterespiratory distress syndrome, asthma,and primary pulmonary hypertension arealso reviewed. In each section, topics re-

quiring future investigation are identi-fied.

NATRIURETIC HORMONESYSTEM IN HEALTHY HUMANS

The natriuretic hormone system is com-posed of several structurally and function-ally related peptides, primarily produced bythe myocardium, vascular endothelium,and kidneys, which influence volume ho-meostasis and vascular tone by binding todedicated receptors throughout the cardio-vascular and renal systems (Fig. 1). The1981 landmark observation that the intra-venous injection of supernatant from atrialtissue homogenates caused significant na-triuresis and diuresis in rats was soon fol-lowed by the isolation of atrial natriureticpeptide (ANP) from the human cardiacatrium (1). Stimulated by atrial stretch,storage granules within cardiac myocytesrelease an ANP prohormone that is cleavedinto ANP and three additional hormones,long-acting natriuretic peptide, vessel dila-tor, and kaliuretic peptide (Table 1) (2, 3).On secretion into the circulation, the

*See also p. 388.From the Division of Cardiac Intensive Care, De-

partment of Cardiology, Childrens Hospital Boston andHarvard Medical School, Boston, MA (JMC); and Divi-sion of Pulmonary and Critical Care Medicine, Depart-ment of Pediatrics, Childrens Memorial Hospital andNorthwestern University Feinberg School of Medicine,Chicago, IL (DMG, TPG).

The authors have not disclosed any potential con-flicts of interest.

Copyright 2006 by the Society of Critical CareMedicine and the World Federation of Pediatric Inten-sive and Critical Care Societies

DOI: 10.1097/01.PCC.0000224998.97784.A3

Objective: To review the natriuretic hormone system and dis-cuss its diagnostic, prognostic, and therapeutic potential in crit-ically ill children.

Data Source: A thorough literature search of MEDLINE wasperformed using search terms including heart defects, congenital;cardiopulmonary bypass, atrial natriuretic factor; natriuretic pep-tide, brain; carperitide; nesiritide. Preclinical and clinical investi-gations and review articles were identified that describe thecurrent understanding of the natriuretic hormone system and itsrole in the regulation of vascular tone and fluid balance in healthyadults and children and in those with underlying cardiac, pulmo-nary, and renal disease.

Results: A predictable activation of the natriuretic hormonesystem occurs in children with congenital heart disease andcongestive heart failure. Further study is needed to confirm pre-liminary reports that measurement of natriuretic hormone levelsin critically ill children provides diagnostic and prognostic infor-mation, as has been demonstrated in adult cardiac populations.Natriuretic hormone infusions provide favorable hemodynamic

changes and symptomatic relief when used in adults with de-compensated congestive heart failure, and uncontrolled caseseries suggest that similar benefits may exist in children. Thebiological activity of the natriuretic hormone system may bedecreased following pediatric cardiopulmonary bypass, and ad-ditional studies are needed to determine whether natriuretic hor-mone infusions provide clinical benefit in the postoperative pe-riod. Preliminary reports suggest that natriuretic hormoneinfusions cause physiologic improvements in adults with acutelung injury and asthma but not in those with acute renal failure.

Conclusions: Although important perturbations of the natriuretichormone system occur in critically ill infants and children, furtherinvestigation is needed before the measurement of natriuretic pep-tides and the use of natriuretic hormone infusions are incorporatedinto routine practice. (Pediatr Crit Care Med 2006; 7:308318)

KEY WORDS: natriuretic peptide; brain; atrial natriuretic factor;heart failure; congestive; heart defects; congenital; cardiopulmo-nary bypass; diuretics

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

diverse biological actions of these pep-tides in normal humans include atten-uation of the renin-angiotensin-aldosterone axis and sympatheticnervous system; suppression of vaso-pressin release; vasodilation of the sys-temic, pulmonary, and coronary circu-lations; and promotion of natriuresisand diuresis (4 7). Posttranslationalprocessing of the ANP prohormone inthe kidney differs from that which oc-curs in the heart, resulting in the renalproduction of urodilatin rather than ANP(3). Urodilatin is mainly produced in therenal distal tubules in response to sodium

and volume loading and acts in a paracrinefashion by inhibiting the resorption of so-dium in the collecting duct (8).

Brain natriuretic peptide (BNP), sonamed because it was first isolated in theporcine brain, is primarily secreted fromthe cardiac ventricles in response to in-creased wall stress (9). Within myocytes,pro-BNP is cleaved into the biologically ac-tive BNP and an inactive fragment, amino-terminal pro-BNP (NT-proBNP), both ofwhich are released into the circulation. Theeffects of BNP on fluid balance and vasculartone in healthy humans are similar to thoseattributed to ANP (10, 11).

Dendroaspis natriuretic peptide (DNP)was first isolated from the venom of theGreen Mamba snake (Dendroaspis angus-ticeps) and subsequently from humanmyocardium and plasma (12). In experi-mental models, DNP appears to possesssimilar vasorelaxant, lusitropic, natri-uretic, and diuretic properties held byANP and BNP (13).

C-type natriuretic peptide (CNP) isprimary synthesized by the vascular en-dothelium, and its release is triggered byANP, BNP, shear stress, and various cyto-kines and growth factors (14). CNPplasma levels are often very low or unde-tectable, and when compared with ANP,infusions of CNP in healthy humanscause significantly less hemodynamic ef-fect, neurohumoral suppression, and di-uresis (14, 15). CNP primarily acts as aparahormone that promotes venodilationand inhibits proliferation of fibroblastsand vascular smooth muscle cells (14).

Natriuretic hormone receptors areabundantly distributed in the vascularendothelium, myocardium, and kidneys,and ligand binding activates guanylyl cy-clase, leading to production of guanosine3',5'-monophosphate (cGMP) (16, 17).cGMP-dependent protein kinase subse-quently acts on several intracellular sub-strates to reduce cytosolic calcium, caus-ing vascular smooth muscle and cardiacmyocyte relaxation (18). In the kidney,natriuretic hormones promote diuresisby several mechanisms, including in-creased glomerular filtration rate (19),enhanced synthesis of prostaglandin E2leading to inhibition of Na-K-ATPase(3), and inhibition of sodium resorptionin the collecting duct (8, 20). Indirectrenal influences include inhibition of theeffects of the sympathetic nervous systemand angiotensin II on proximal tubularsodium absorption, blunted aldosteroneproduction leading to decreased sodiumresorption at the cortical collecting duct,and inhibition of vasopressins effect atthe medullary collecting duct (21). Natri-uretic hormones also inhibit platelet ac-tivation, fibroblast proliferation, and hy-pertrophy of vascular smooth musclecells (18). Natriuretic hormones are pri-marily removed from the circulation bybinding to clearance receptors and enzy-matic degradation by neutral endopepti-dases (22, 23), processes that may be in-hibited by investigational drugs (24).

Normal pediatric plasma levels forANP and BNP can be found in Table 2(25). When compared with older infantsand children, neonates in the first days of

Table 1. The natriuretic hormone family

Peptide Primary Sites of Synthesis Primary Stimulus for Release

ANP Atria, ventricles Atrial stretchLANP Atria, ventricles Atrial stretchVessel dilator Atria, ventricles Atrial stretchKaliuretic peptide Atria, ventricles Atrial stretchBNP Ventricles, atria Ventricular wall stress, atrial stretchCNP Vascular endothelium ANP, BNP, sheer stressDNP Atria, ventricles Atrial stretch, ventricular wall stressUrodilatin Kidney 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.

Figure 1. Neurohumoral feedback loop involving the natriuretic hormone system. ANP, atrial natri-uretic 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 nervoussystem.

309Pediatr Crit Care Med 2006 Vol. 7, No. 4

life have markedly higher natriuretic hor-mone plasma levels, perhaps related tothe acute increase in ventricular afterloadthat is present following birth. NormalNT-proBNP levels in neonates, children,and adolescents have also been published(26, 27).

THE NATRIURETIC HORMONESYSTEM IN CONGESTIVEHEART FAILURE ANDCONGENITAL HEART DISEASE

Following the onset of myocardial dys-function, neurohumoral activation oc-curs that increases vascular resistanceand intravascular volume in order to pre-serve end-organ perfusion pressure. Inpatients with heart failure, plasma levelsof catecholamines, vasopressin, and en-dothelin are increased, leading to de-creased renal blood flow with subsequentactivation of the renin-angiotensin-aldosterone axis (2830). Vasoconstric-tion and water and salt retention occurand eventually manifest as CHF. A similarpattern of neurohumoral activation isseen in adults with palliated or repairedcongenital heart disease, and the degreeof neurohumoral activation is associatedwith worsening New York Heart Associa-tion (NYHA) functional class and sys-temic ventricular function (31). Activa-tion of these neurohumoral systems hasdetrimental effects on the failing heartover time, due to a propensity to causeprogressive myocardial dysfunction, fi-brosis, and arrhythmias, and the degreeof neurohumoral activation relates tomortality (29).

In response to the aforementioned neuro-humoral activation and fluid retention, acompensatory up-regulation of the natri-

uretic hormone system occurs, which pro-motes vasodilation, natriuresis, and diuresis(Fig. 1). In adults with systolic ventriculardysfunction and/or CHF, plasma levels ofANP, BNP, NT-proBNP, and DNP are ele-vated, the extent of which is predictive ofNYHA functional class and mortality (9, 29,3238). In adults with CHF, measurement ofBNP is a superior diagnostic test when com-paredwith ANP and appears to bemost usefulwhen the diagnosis of CHF is clinically sus-pected but uncertain (3942). The change inBNP and NT-proBNP levels in response toinpatient treatment for decompensated CHFmay be a useful adjunct to guide therapy inadults and is predictive of death or need forreadmission (35, 38, 43). The diagnostic andprognostic value of BNP levels has also beendescribed in several other adult populations,including those with diastolic heart failure,acute coronary syndromes, aortic stenosis,and hypertrophic cardiomyopathy and in pa-tients recovering from cardiac surgery (4448). Determining whether a particular BNPor NT-proBNP level is normal or elevated ina given patient depends on a number of vari-ables, including the clinical setting, patientage and gender, the presence of renal dys-function or pulmonary disease, intraindi-vidual biological variation, and the assay usedto perform the measurements (4952). TheUnited States Food and Drug Administrationhas approved the measurement of plasmaBNP and NT-proBNP levels to aid in the di-agnosis of heart failure in adults.

The diagnostic value of natriuretic hor-mone levels has been assessed in a variety ofpediatric patients. In 49 children presentingwith respiratory distress, those with CHF hadhigher BNP levels compared with those withprimary lung disease (693 502 pg/mL vs.45 64 pg/mL, p .001), and a cutoff of 40pg/mL was 84% accurate in differentiatingCHF from pulmonary disease (53). In a sim-ilar study of 35 young children requiring hos-pitalization for respiratory distress, NT-proBNP levels measured on admission inpatients with CHF were significantly higherthan those with primary pulmonary diseaseor normal controls (CHF group, median18,452 pg/mL [range 537599,700 pg/mL] vs.median 311 pg/mL [range 761341 pg/mL]in the pulmonary group and median 89pg/mL [range 88292 pg/mL] in controls; p .001 for the CHF group vs. pulmonarygroup and controls) (54). In neonates pre-senting with respiratory disease, BNP levelsare significantly higher in those with persis-tent pulmonary hypertension of the newborncompared with those with normal right ven-tricular pressure (median 1610 pg/mL [inter-quartile range 11281745 pg/mL] vs. 137

pg/mL [76327 pg/mL]), and a strong corre-lation exists between BNP levels and the se-verity of right ventricular hypertension in thegroup with persistent pulmonary hyperten-sion of the newborn (rs .83, p .0001)(55).

In children with known congenital heartdisease, natriuretic hormone levels vary de-pending on the type and severity of the lesion.For example, plasma ANP levels are elevatedin patients with unrepaired atrial or ventric-ular septal defects with CHF (56, 57). A pos-itive correlation exists between BNP levelsand the ratio of pulmonary to systemic bloodflow, and between BNP levels and mean pul-monary artery pressure, in infants and chil-dren with ventricular septal defects (Fig. 2)(58). In this study, a cutoff of 20 pg/mL had asensitivity of 82%, a specificity of 89%, and anaccuracy of 86% for predicting a mean pul-monary artery pressure 20 mm Hg at car-diac catheterization (58). Patients with con-genital heart disease and chronic rightventricular pressure overload have elevatedANP and BNP levels, which inversely corre-late with right ventricular function (59). Inpatients with palliated or repaired congenitalheart disease, ANP and BNP levels are ele-vated and are associated with severity of ven-tricular dysfunction and NYHA functionalclass (31, 60, 61). NT-proBNP levels are ele-vated in children with CHF, and the degree ofelevation correlates with ventricular ejectionfraction and severity of symptoms (26). In 37pediatric heart transplant recipients present-ing on 59 occasions for echocardiography,cardiac catheterization, and myocardial bi-opsy, a cutoff BNP level of 100 pg/mL had100% sensitivity and negative predictivevalue, 78% specificity, but only 45% positivepredictive value for detecting the presence ofgraft disease including rejection and trans-plant coronary artery disease (62).

Natriuretic hormone levels typicallydecline in infants and children followinginterventions that decrease atrial stretchand ventricular wall stress. For example,natriuretic hormone levels are elevatedfollowing initial palliation in childrenwith single ventricle physiology but aresubstantially lower at a median of 30.5months following the bidirectional Glennoperation (63). BNP levels fall after suc-cessful balloon aortic valvotomy (64), andNT-proBNP levels decline following suc-cessful medical therapy for CHF in youngchildren (54). Acute changes in natri-uretic hormone levels following CPB arediscussed subsequently. Although theseinitial reports suggest that the measure-ment of natriuretic hormone levels incritically ill children may be useful as

Table 2. Normal human pediatric plasma levelsfor atrial natriuretic peptide and brain natriureticpeptide (in pg/mL; reported as mean SD)a

Age ANP BNP

At birth 129 77 197 1705 days old 120 62 62 144 months old 49 15 21 101 yr old 49 9 7 75 yr old 25 12 7 310 yr old 28 9 7 316 yr old 31 12 7 3

ANP, atrial natriuretic peptide; BNP, brainnatriuretic peptide.

a Natriuretic hormone levels originally re-ported in fmol/ml (25), but converted to pg/mLfor this table.


adjunctive tools during diagnostic evalu-ations and in the assessment of the re-sponse to treatment, additional studiesare needed in larger numbers of patientsbefore such testing is incorporated intoroutine practice.

A point-of-care assay for BNP mea-surement (Triage BNP Test, Biosite Diag-nostics, San Diego, CA) and several auto-mated immunoassays (ADVIA CentaurBNP Assay, Bayer Healthcare, Tarrytown,NY; AxSYM BNP Test, Abbott Laborato-ries, Abbott Park, IL; Elecsys proBNP As-say, Roche Diagnostics, Indianapolis, IN)are now available for clinical use. Inhead-to-head comparisons, BNP and NT-proBNP measurements have similar ac-curacy for detecting systolic left ventric-ular dysfunction, although NT-proBNPmay have an advantage for early ventric-ular dysfunction (65, 66). Other differ-ences between commercially available as-say systems that measure BNP and NT-proBNP are summarized in Table 3.

TREATMENT OF HEARTFAILURE WITH NATRIURETICHORMONE INFUSIONS

The endogenous biological activity ofthe natriuretic hormone system may beinadequate in patients with severe CHF,which provides some rationale for theexogenous administration of natriuretichormones. The biological activity of thenatriuretic hormone system may be esti-mated by determining the molar ratio ofplasma cGMP levels to natriuretic hor-mone levels (32, 6770). cGMP plasmaconcentrations increase in proportion toANP levels in mild heart failure, butcGMP levels plateau despite a further risein ANP in severe heart failure, perhaps

related to down-regulation of natriureticpeptide receptors (32, 67).

In adults with CHF, ANP and BNPinfusions decrease mean pulmonary ar-tery pressure, pulmonary artery occlu-sion pressure, and systemic vascular re-sistance, leading to a secondary increasein cardiac output (Fig. 3) (4, 7173). Thelusitropic properties of ANP and BNP in-fusions may be beneficial for patientswith diastolic dysfunction (71, 7476). Ithas been suggested that the pharmaco-logic responsiveness to ANP infusions areblunted in adult CHF patients (72, 77),although no direct comparisons withBNP infusions have been made in thispatient population.

Nesiritide (Natrecor, Scios, Fre-mont, CA), a recombinant form of hu-man B-type natriuretic peptide that wasapproved by the U.S. Food and DrugAdministration in 2001 for the treat-ment of acutely decompensated CHF inadults, is well tolerated and results inimproved hemodynamics and patientsymptoms (78). Several studies suggestthat nesiritide is advantageous whencompared with other inotropic or vaso-active infusions that are commonlyused to treat adults with decompen-sated CHF. When compared with nitro-glycerine, nesiritide has equal or supe-rior effects on hemodynamics andpatient symptoms and a lower inci-dence of headache (79). When com-pared with dobutamine, nesiritide useis associated with a significantly lowerincidence of serious ventricular ar-rhythmias and cardiac arrest and maybe associated with lower 6-month read-mission and mortality rates (8082).An analysis of observational data fromthe Acute Decompensated Heart Failure

National Registry for 15,230 adults withdecompensated CHF requiring hospi-talization and intravenous vasoactivemedications found that the risk factor-and propensity score-adjusted odds ra-tios for in-hospital mortality were sig-nificantly lower in patients receivingnitroglycerine or nesiritide comparedwith those receiving dobutamine ormilrinone (83). Dobutamine and milri-none increase intracellular cyclic aden-osine monophosphate, leading to in-creased myocardial contractility andoxygen consumption, whereas nesirit-ide has no intrinsic inotropic proper-ties. In patients with decompensatedheart failure, the myocardium isstressed by altered hemodynamics andfurther activation of neurohormones,cytokines, and oxygen free radicals (84).Inotropic stimulation during these pe-riods of myocardial energy depletionmay induce subclinical myocardialischemia or apoptosis due to sympa-thetic stimulation and intramyocardialcalcium accumulation (85).

Recent studies have questionedwhether the beneficial effects of nesiritideinfusions on renal function in healthyhumans are present in those with CHF.In a meta-analysis of five randomizedstudies (involving 1269 total adult de-compensated CHF patients) that com-pared nesiritide with either placebo oractive control, nesiritide use was associ-ated with an increased risk of worseningrenal function (defined as an increase inserum creatinine0.5 mg/dL at any timeduring the hospitalization) when com-pared with controls (21% vs. 15%; riskratio, 1.54; 95% confidence interval,1.201.99; p .001) (86). In this study,no difference was found in the need fordialysis. These findings of this meta-analysis generated concern, as worseningrenal function is associated with worseoutcomes in adult heart failure patients.However, further analysis of data fromthese five studies suggested that the in-crease in creatinine was of clinical impor-tance only in the patients who did notreceive nesiritide. Controls who had anincrease in serum creatinine 0.5 mg/dLfrom baseline had a statistically signifi-cant 3.4-fold increase in the risk of dyingwithin 30 days of hospitalization com-pared with control patients without anincrease in serum creatinine (p .005).Among patients treated with nesiritide,however, those with elevated serum cre-atinine levels had a nonsignificant 1.1-fold increase in 30-day mortality risk

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) withpermission from Blackwell Publishing.


compared with those without elevated se-rum creatinine levels (p .722), sug-gesting a protective effect of the drug(87).

Although theoretically attractive foruse in patients with decompensated CHFand renal dysfunction, in a recent double-blind placebo-controlled, crossover studyof 15 hospitalized adults with decompen-sated CHF, fluid overload, and mild renalinsufficiency that was worse than base-line, a 24-hr nesiritide infusion did notimprove glomerular filtration rate, effec-tive renal plasma flow, urine output, or

sodium excretion (88). However, thesmall sample size, timing of patient en-rollment, and lack of a washout periodbetween study drug infusions all must beconsidered when interpreting these find-ings (89).

The effect of nesiritide use on mortal-ity in adult heart failure patients is un-known and the subject of ongoing con-troversy (9092). A recently publishedpooled analysis of three randomized trialsinvolving 862 total adult decompensatedCHF patients found that, when comparedwith patients receiving non-inotrope-

based control therapies, those given ne-siritide tended to have a higher incidenceof death within 30 days (7.2% vs. 4%; riskratio, 1.74; 95% confidence interval,0.973.12; p .059) (93). In contrast, asubsequent risk-adjusted analysis of allavailable nesiritide trials with 30-day and6-month mortality data found no differ-ence in mortality rates between patientsreceiving nesiritide and controls (94).

Given these concerns about the effectof nesiritide use on renal function andmortality, an expert panel of adult cardi-ology experts was convened to reviewavailable safety and efficacy data, issuerecommendations for the use of nesirit-ide, and provide guidance for furtherclinical development of this drug (95). Alarge randomized clinical trial designedto assess the impact of nesiritide on mor-tality in adults with acute decompensatedheart failure will begin enrolling patientsin Europe in early 2006 (96).

In several small, uncontrolled case se-ries, investigators have reported that ne-siritide infusions in children with decom-pensated CHF are well tolerated, decreasecentral venous pressure, and improveurine output, appetite, and functionalstatus (9799). Many of the patients inthese reports were concurrently receivingconventional inotropic and diureticagents. Clinical trials designed to assessthe pharmacokinetics, safety, and efficacyof nesiritide infusions in children areneeded before this drug can be recom-mended for routine use. Until such stud-ies are completed, it seems reasonable toconsider a trial of nesiritide in carefullyselected children with decompensatedCHF when conventional therapies are in-effective.

The recommended adult dosing regi-men for nesiritide is a bolus of 2 g/kg

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

Assay

NT-proBNP BNP BNP BNP

Elecsys NT-proBNPE170 (Roche)

Triage BNP Test(Biosite)

AxSYM BNP Assay(Abbott)

ADVIA CentaurBNP assay (Bayer)

Range of detection (pg/mL) 535,000 55,000 24,000 25,000Total coefficient of variation (%) 3.65.8 9.912.2 6.59.4 2.34.7Point-of-care testing No Yes No NoInteraction with nesiritide No Yes Yes YesHalf-life of peptide (minutes) 120 20 20 20Peptide stable at room

temperature 4 hoursYes No No No

Specimen Plasma or serum Whole blood orplasma

Whole blood orplasma

Plasma

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

Figure 3. Effects of nesiritide on pulmonary artery occlusion pressure (in mmHg), cardiac index (inL/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 TheAmerican 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.


followed by a continuous infusion of 0.01g/kg/min. After 3 hrs, if clinically indi-cated, a repeat bolus of 1 g/kg may beadministered and the infusion increasedby increments of 0.005 g/kg/min up to amaximum dose of 0.03 g/kg/min. Dose-related hypotension, azotemia, and bra-dycardia have been reported in adults. Aswith any vasodilator, ventricular preloadshould be optimized before the initiationof nesiritide, and it should not be used ifovert cardiogenic shock exists. Althoughthe half-life of nesiritide is relativelyshort (18 mins), its hemodynamic effectsmay last for several hours. Natriuretichormone infusions do not require doseadjustment in the setting of hepatic orrenal insufficiency. Currently, nesiritideis the only natriuretic hormone infusionavailable for clinical use in the UnitedStates. Alpha-human ANP (carperitide,HANP Injection 1000, Daiichi SuntoryPharma Company, Tokyo, Japan) hasbeen approved for clinical use for decom-pensated CHF in Japan since 1995 (100),and phase II trials are ongoing in theUnited States. Enrollment was recentlycompleted in Europe for a phase II clin-ical trial of urodilatin (Ularitide, Cardio-Pep Pharma GmbH, Hanover, Germany)in adults with decompensated CHF.

THE NATRIURETIC HORMONESYSTEM ANDCARDIOPULMONARY BYPASS

Following CPB, systemic and pulmo-nary vascular resistances are typically in-creased, related in part to the release of

catecholamines, vasopressin, endothelin,and activation of the renin-angiotensin-aldosterone system (101107). This neu-rohumoral response, along with inflam-mation, endothelial dysfunction, andhemodilution, also leads to generalizedfluid retention. As disturbances in neuro-humoral and endothelial regulation ofvascular tone and fluid balance followingCPB are somewhat similar to those seenwith CHF, it is intuitively attractive toinvestigate the natriuretic hormone sys-tem in the postoperative period.

Predictable changes in natriuretichormone levels occur during and follow-ing CPB in infants, children, and adults.Natriuretic hormone levels fall duringCPB due to underfilling of the atria, hy-pothermia, dilution, and exclusion of theheart from the circulation (69, 108). Op-erations that result in increased atrialstretch are associated with an immediatepostoperative rise in ANP levels, such asthe atriopulmonary Fontan operation(102, 109). In contrast, ANP levels alsofall, at least transiently, after extracardiactotal cavopulmonary connection Fontancompletion, in which the atria are ex-cluded from the systemic venous circula-tion (110, 111). In patients with completeatrioventricular canal or large ventricularseptal defects and CHF, we and othershave shown that ANP levels are elevatedpreoperatively but decline significantly by24 hrs following surgery (68, 69). A sim-ilar decline in ANP levels has been re-ported within 24 hrs of mitral valve sur-gery in adults, which is likely related tolower left atrial pressure (112).

In the early postoperative period, BNPlevels rise following CPB in adults, andthe extent of rise is inversely related toindices of ventricular function (113, 114).BNP levels increase, at least transiently,in children following repair of tetralogyof Fallot and the total cavopulmonaryconnection Fontan operation (110). Wehave documented an early postoperativerise in BNP levels following repair of in-tracardiac left to right shunts in five in-fants (69). In a subsequent study of 25infants and children undergoing a varietyof cardiac surgical procedures, BNP levelsincreased in the early postoperative pe-riod (Fig. 4), and the extent of rise in BNPlevels correlated with longer CPB time(rs .4, p .043) (70). The utility of BNPlevels for predicting morbidity and mor-tality following congenital heart surgeryrequires investigation in a larger numberof patients undergoing similar proce-dures.

Emerging evidence suggests that thebiological activity of the natriuretic hor-mone system is inadequate followingCPB, as has been reported in advancedCHF. In adults undergoing mitral valvesurgery, the molar ratio of cGMP to ANPis inversely associated with the durationof CPB, postoperative atrial filling pres-sure, and pulmonary vascular resistance(115). In pediatric patients, Seghaye et al.(68) reported that a longer CPB time wasassociated with lower molar ratio ofcGMP/ANP. We suggest that inclusion ofmultiple natriuretic peptide levels in thecalculation of biological activity may bemore appropriate, as they all activate na-triuretic peptide receptors to increaseproduction of cGMP. In our initial inves-tigation of five infants following CPB, themolar ratio of cGMP/(ANP BNP DNP) significantly decreased within thefirst 24 hrs after surgery (69). In a sub-sequent larger study, we also observed atransient decrease in the biological activ-ity of the natriuretic hormone system(Fig. 5) (70). The underlying mechanismfor decreased biological activity followingCPB is unknown, but potential contrib-uting factors include receptor down-regulation, alterations in signal transduc-tion, increased phosphodiesteraseactivity, and hypothermia (67, 116118).

As cGMP also serves as the secondmessenger for nitric oxide, the use ofplasma cGMP levels in the assessment ofnatriuretic hormone system biologicalactivity warrants discussion. In smoothmuscle cells, both natriuretic hormonesand nitric oxide increase intracellular

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 (*significantchange vs. preoperative). Reproduced from Costello et al. (70) with permission from the AmericanAcademy for Thoracic Surgery. Baseline, following induction of anesthesia and before CPB; all othertime points are post-CPB. ICU, intensive care unit; POD, postoperative day.


cGMP concentrations. However, some in-vestigations suggest that plasma levels ofcGMP are predominantly determined bynatriuretic hormone activity on endothe-lial cells (119). Plasma levels of nitritesand nitrates, markers of endogenous ni-tric oxide production, do not correlatewith plasma cGMP levels following pedi-atric CPB (68), and exogenous infusion ofthe nitric oxide donor sodium nitroprus-side does not raise plasma cGMP levels(119). Administration of inhaled nitricoxide, however, increases plasma cGMPlevels (107). Although the relative influ-ence of natriuretic hormones and nitricoxide on plasma cGMP levels requiresfurther investigation, the aforementionedstudies support the notion that, in theabsence of the use of inhaled nitric oxide,plasma levels of cGMP may be used as amarker of natriuretic hormone systemactivity.

Preliminary studies in humans suggestthat provision of exogenous natriuretic hor-mones may improve hemodynamics and endorgan function following CPB. Comparedwith controls, adult coronary artery bypassgraft patients receiving a 24-hr continuousinfusion of ANP had improved loading condi-tions and cardiac index, improved respiratoryand renal function, and suppression of therenin-angiotensin-aldosterone axis (120). Inadults undergoing elective open heart sur-gery, a 72-hr infusion of ANP, when com-pared with placebo, was associated with im-proved postoperative hemodynamics,suppression of renin and aldosterone levels,and lower fluid, diuretic, and potassium sup-plementation requirements (121). Following

the atriopulmonary Fontan operation in chil-dren, a 1-hr infusion of ANP was well toler-ated and improved cardiac loading condi-tions, cardiac index, and urine output; thesevariables returned to baseline once the infu-sion was discontinued (109). Small, uncon-trolled case series in adults suggest that ne-siritide provides hemodynamic and renalbenefit for selected patients (122125). Insmall, uncontrolled pediatric case series,postoperative nesiritide use was reportedlywell tolerated (126) and associated with lowercentral venous pressure and improved urineoutput (99, 127). As is the case with pediatricheart failure patients, the perioperative use ofnesiritide requires prospective investigationin children. These studies should determinewhether nesiritide or other natriuretic hor-mone infusions alter the neurohumoral re-sponse to CPB as well as the need for conven-tional inotropic, vasoactive, and diureticagents. In isolated heart and whole animalmodels of myocardial ischemia-reperfusion,and in adults undergoing percutaneous cor-onary reperfusion for acute myocardial in-farction, provision of exogenous natriuretichormones limits myocardial ischemia reper-fusion injury (128132). It is not knownwhether the administration of natriuretichormones before removal of the aortic cross-clamp during pediatric cardiac surgery willminimize ischemia reperfusion injury. Natri-uretic peptide infusions have beneficial effectson pulmonary function and gas exchange inanimal models and adult patients with acutelung injury (133, 134), and these propertiesshould be investigated following cardiopul-monary bypass.

THE NATRIURETIC HORMONESYSTEM AND RENAL FAILURE

Natriuretic hormone levels are elevated inthe plasma of patients with renal failure,likely related to salt and water retention andleft ventricular hypertrophy (135, 136). Al-though preliminary studies in animal modelsand adult humans with ischemic or nephro-toxic acute renal failure found that ANP orurodilitin infusions improved creatinineclearance and decreased the need for hemo-dialysis (3, 137), no benefit was found in sub-sequent large, randomized, double-blind, pla-cebo-controlled trials in adults with acutetubular necrosis (138140). ANP also was notbeneficial for preventing radio-contrast-induced nephropathy in adults with stablechronic renal failure (141). BNP infusionshave not been formally evaluated in patientswith acute renal failure. The preliminary dataappear somewhat more promising for renalinsufficiency following cardiac surgery, per-haps related to the controlled nature of theinsult. In animal models of renal ischemia-reperfusion injury, infusions of ANP pre-served glomerular filtration rate and mini-mized histologic injury when compared withplacebo (142, 143). Small, uncontrolled stud-ies in adults with acute renal impairmentfollowing CPB suggest that both ANP andBNP infusions improved renal function (124,144, 145). Given the current concerns aboutnesiritide use and renal function in adults,and in the absence of randomized studiesdemonstrating clinical benefit (3), the use ofnatriuretic hormone infusions cannot be rec-ommended for the prevention or treatmentof renal failure in critically ill children.

THE NATRIURETIC HORMONESYSTEM, ACUTE LUNG INJURY,AND ASTHMA

ANP and BNP levels are elevated in pa-tients with acute lung injury, likely relatedto myocardial dysfunction and abnormalcardiac loading conditions (51, 146, 147).When compared with furosemide and pla-cebo in animal models of acute lung injury,ANP infusions result in improved gas ex-change, reduced pulmonary artery pres-sure, and better diuresis (133, 148), per-haps due to cGMP-mediated reduction inendothelial permeability leading to a reduc-tion of extravascular lung water (133). In arandomized study of 40 adults with acutelung injury, ANP infusion, when comparedwith placebo, resulted in improved oxygen-ation, lung compliance, lung injury score,and urine output (134). Enrollment hasrecently been completed in a multiple-

Figure 5. The biological activity of the natriuretic hormone system transiently decreases in infants andchildren following cardiopulmonary bypass (CPB) (*significant change vs. preoperative). Reproducedfrom 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, intensivecare unit; POD, postoperative day.


center phase II study evaluating the use ofcarperitide in adults with respiratory dis-tress syndrome.

In asthmatics, the ability of natriureticpeptides to promote bronchial smoothmuscle relaxation by increasing intracel-lular levels of cGMP has been investi-gated. In a randomized, double-blind,placebo-controlled clinical trial in stableasthmatic adults, indexes of pulmonaryfunction improved to a similar extentwith intravenous infusion of urodilatinand inhaled albuterol (149). Further-more, combination therapy with albu-terol and urodilatin provided maximal ef-ficacy when compared with separateadministration of the two drugs (149). Nodata are currently available regarding theuse of natriuretic hormones as broncho-dilators in adults or children with statusasthmaticus.

THE NATRIURETIC HORMONESYSTEM AND PULMONARYHYPERTENSION

ANP and BNP levels are elevated inadults with primary and secondary pulmo-nary hypertension and correlate with theextent of elevation of mean pulmonary ar-tery pressure and pulmonary vascular re-sistance (150152). BNP levels are predic-tive of mortality in adults with pulmonaryhypertension (151, 153). ANP levels are el-evated in premature infants with broncho-pulmonary dysplasia, and BNP levels areelevated in term infants with persistent pul-monary hypertension (55, 154). Pediatricexperience using natriuretic hormones in-fusions for treatment of pulmonary hyper-tension is limited. Ivy et al. (155) found thatonly three of eight patients with repairedcongenital heart disease had a significantreduction in mean pulmonary artery pres-sure and pulmonary vascular resistancewith an infusion of ANP, whereas five ofeight patients responded to inhaled nitricoxide. These investigators concluded thatalthough some children responded to ANP,inhaled nitric oxide might be the preferredagent in this setting because of its efficacyand selective pulmonary vasodilation (155).

CONCLUSIONS

The natriuretic hormone system, animportant regulator of fluid balance andvascular tone, is activated in a predictablefashion in infants and children with sig-nificant structural or myopathic heartdisease. Additional studies are needed todetermine the diagnostic and prognostic

value of routine measurement of natri-uretic hormone levels in critically ill chil-dren. The biological activity of the systemis disturbed following CPB, and carefullydesigned clinical trials are needed to de-termine whether the use of natriuretichormone infusions will provide meaning-ful benefit in children undergoing cardiacsurgery or treatment for decompensatedCHF or other critical illnesses.

ACKNOWLEDGMENTS

Emily Flynn-McIntosh and Emily Har-ris from the Department of Cardiology atChildrens Hospital Boston assisted withthe figures used in this manuscript.

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