Pediatric Cardiac Intensive Care Society 2014
Consensus Statement: Pharmacotherapies in
Cardiac Critical Care Fluid Management
Amy N. McCammond, MD1; David M. Axelrod, MD2; David K. Bailly, DO3;
E. Zachary Ramsey, PharmD4; John M. Costello, MD, MPH5
Objective: In this Consensus Statement, we review the etiology
and pathophysiology of fluid disturbances in critically ill children
with cardiac disease. Clinical tools used to recognize pathologic
fluid states are summarized, as are the mechanisms of action of
many drugs aimed at optimal fluid management.
Data Sources: The expertise of the authors and a review of the
medical literature were used as data sources.
Data Synthesis: The authors synthesized the data in the literature
in order to present clinical tools used to recognize pathologic fluid
states. For each drug, the physiologic rationale, mechanism of
action, and pharmacokinetics are synthesized, and the evidence
in the literature to support the therapy is discussed.
Conclusions: Fluid management is challenging in critically ill
pediatric cardiac patients. A myriad of causes may be contribu-
tory, including intrinsic myocardial dysfunction with its associated
neuroendocrine response, renal dysfunction with oliguria, and
systemic inflammation with resulting endothelial dysfunction. The
development of fluid overload has been associated with adverse
outcomes, including acute kidney injury, prolonged mechani-
cal ventilation, increased vasoactive support, prolonged hospital
length of stay, and mortality. An in-depth understanding of the many
1
Department of Pediatrics, Doernbecher Children’s Hospital, Oregon
Health and Science University, Portland, OR.
2
Division of Pediatric Cardiology, Department of Pediatrics, Lucile Packard
Children’s Hospital, Stanford University Medical Center, Palo Alto, CA.
3
Division of Pediatric Critical Care, Department of Pediatrics, Primary
­Children’s Hospital, University of Utah, Salt Lake City, UT.
4
Department of Pharmacy, the Children’s Hospital of Philadelphia,
­Philadelphia, PA.
5
Division of Cardiology, Department of Pediatrics, Ann and Robert H. Lurie
Children’s Hospital of Chicago, Northwestern University Feinberg School
of Medicine, Chicago, IL.
Dr. Costello’s effort for this article was supported in part by a generous gift
from Mr. and Mrs. Warren and Eloise L. Batts (Chicago, IL). Dr. Costello’s
institution received funding from Mr. and Mrs. Warren and Eloise L. Batts
(Chicago, IL). The remaining authors have disclosed that they do not have
any potential conflicts of interest.
For information regarding this article, E-mail: jmcostello@luriechildrens.org
Copyright © 2016 by the Society of Critical Care Medicine and the World
Federation of Pediatric Intensive and Critical Care Societies
DOI: 10.1097/PCC.0000000000000633
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Copyright © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
factors that influence volume status is necessary to guide optimal
management. (Pediatr Crit Care Med 2016; 17:S35–S48)
Key Words: acute kidney injury; congenital heart disease; diuretics;
fenoldopam; fluid; nesiritide
F
luid management is challenging in critically ill pediatric
cardiac patients. Patients with passive pulmonary blood
flow, restrictive right or left ventricular physiology, paral-
lel circulations, intracardiac shunting, and marginal coronary
reserve all warrant meticulous fluid management. Common
reasons for disturbances in intravascular and total body fluid
status include intrinsic myocardial dysfunction with its associ-
ated neuroendocrine response, renal dysfunction with oliguria,
and systemic inflammation with resulting endothelial dys-
function. Fluid overload is associated with adverse outcomes,
including acute kidney injury (AKI), prolonged mechanical
ventilation, increased vasoactive support, prolonged hospital
length of stay, and mortality (1, 2). An in-depth understanding
of the many factors that influence volume status is necessary to
guide optimal management. In this Consensus Statement, we
review the etiology and pathophysiology of fluid disturbances
in critically ill children with cardiac disease. Clinical tools used
to recognize pathologic fluid states are summarized. We then
performed an extensive literature search with regard to con-
temporary fluid management principles and strategies, focus-
ing on conventional and adjunctive pharmacologic agents. For
each drug, the physiologic rationale, mechanism of action,
and pharmacokinetics are summarized, and the evidence from
both the literature and the expertise of the authors is presented.
ETIOLOGY AND IMPACT OF FLUID
DISTURBANCES
The transcapillary exchange of fluid from the vascular space to
the interstitium is governed by the balance between hydrostatic
pressure and the opposing tissue protein osmotic pressure (3).
The net effect under normal conditions is the movement of
fluid into the interstitial space, where the lymphatic vessels
 McCammond et al
may then drain excess interstitial volume into the venous sys-
tem (4). Edema occurs when fluid accumulates in the inter-
stitium. Marked fluid overload is currently less of a problem
when compared with earlier eras because of advances in the
conduct of cardiopulmonary bypass (CPB) and the provision
of cardiac intensive care (5). However, varying degrees of gen-
eralized edema still develop in an important subset of neo-
nates and older children undergoing complex cardiac surgical
procedures.
In infants and children undergoing cardiac surgery, the
multiple etiologies of imbalances in fluid status may conve-
niently be classified into those existing in the preoperative,
intraoperative, and postoperative periods.
Preoperative
A number of factors may contribute to preoperative distur-
bances in fluid status. Neonates are commonly receiving pros-
taglandin E1, which may increase the risk of interstitial edema
(6). Excessive pulmonary blood flow will often develop, as
pulmonary vascular resistance falls, in neonates with ductal-
dependent systemic blood flow, which may lead to pulmonary
edema. Those who present in shock may receive substantial
amounts of volume during initial resuscitation. Decreased
cardiac output and diminished tissue oxygen delivery may
develop in patients with a number of pathophysiologic states,
including those with decreased systolic and diastolic function,
atrioventricular valve regurgitation, hypoxia, and large left to
right shunts. Neurohormonal compensatory mechanisms are
in turn activated to promote fluid retention, including the
renin-aldosterone-angiotensin system and increased release of
antidiuretic hormone (7–9). Contrast injections and nephro-
toxic medications also contribute to the risk of preoperative
AKI leading to fluid and salt retention (10, 11). Variability
exists between patients in preoperative plasma protein levels,
immune system, and capillary permeability, all of which may
influence the severity of perioperative edema and pleural or
pericardial effusions or ascites (5, 12–15).
Preoperative patients are also at risk of relative hypovole-
mia. Tachypnea and hypermetabolic profiles, such as high-out-
put failure or fevers, increase insensible losses. Children may
become dehydrated because of “nil per os” status before sur-
gery. Hypoproteinemia and diuretics may also induce a state of
relative intravascular volume depletion.
Intraoperative
The etiology of intraoperative fluid overload is multifactorial.
An increase in venous capacitance during anesthetic induction
may result in a relative hypovolemic state and inadequate pre-
load. Infants are particularly vulnerable to priming volumes
and the hemodilutional effects of CPB that result in reduced
plasma colloidal oncotic pressure leading to fluid extravasa-
tion (16–19). The inflammatory cascade induced by CPB
promotes interstitial edema by altering Starling forces. Resul-
tant changes include increased capillary hydrostatic pressure,
decreased plasma oncotic pressure, increased tissue osmotic
pressure, increased capillary permeability or filtration surface
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area, and decreased lymphatic drainage (20–22). Hypogam-
maglobulinemia occurs in 50% of infants following CPB and
is associated with increased proinflammatory cytokines and a
positive 24-hour fluid balance (20). Independent of inflam-
matory effects, the use of hypothermia during CPB is associ-
ated with a four-fold increase in net fluid extravasation (23,
24). The extravasation is likely related to hypothermia-induced
vasoconstriction and increased blood viscosity (25, 26). All of
the above conditions are often treated with fluid resuscitation,
which may cumulate in a fluid overloaded state.
Less commonly, patients may return from the operating
room with hypovolemia. Contributing factors may include the
use of ultrafiltration during or immediately following CPB,
diuretic administration in the operating room, and bleeding.
Postoperative
In patients recovering from complex cardiac surgery, the
immediate postoperative period may be characterized by the
need for ongoing volume replacement. Many factors may be
contributory, including the sequelae of CPB and myocardial
ischemia-reperfusion injury, side effects of sedatives and nar-
cotics, and residual cardiac lesions. In neonates and infants
enrolled in the Boston Circulatory Arrest Study between 1988
and 1992, Wernovsky et al (27) found an average fluid accu-
mulation of 664 mL (≈ 30% weight gain) following the arte-
rial switch operation. This extent of fluid accumulation is less
commonly seen in the current era but remains problematic for
some patients.
Capillary leak and low–cardiac output syndrome (LCOS)
following CPB are most pronounced during the first 6 to
18 hours after surgery (27, 28). During this period of endo-
thelial and myocardial dysfunction, interstitial edema may
develop. Diminished renal arterial perfusion pressure and a
commensurate increase in antidiuretic hormone secretion
serve to inhibit renal perfusion. Positive pressure ventilation
further increases plasma renin activity, plasma aldosterone
levels, and urinary antidiuretic hormone concentrations (29,
30). Adult and pediatric studies have found that the natriuretic
hormone system is dysfunctional early after CPB (31–33).
AKI may develop after CPB, which may exacerbate fluid
overload. Patients at greater risk include those with younger
age, lower gestational age, receiving preoperative ventilation,
longer bypass and hypothermic circulatory arrest times, and
greater surgical complexity (1, 34). Alternatively, fluid overload
may precede and exacerbate AKI (2, 35).
Less commonly, intravascular hypovolemia or frank dehy-
dration may develop in the postoperative period. Contributory
factors may include excessive diuretic administration and lack
of complete accounting for insensible or gastrointestinal losses.
Impact on Outcomes
A growing body of literature suggests that fluid overload in
the immediate postoperative period may contribute to poor
outcomes (36). In one study of 98 postoperative pediatric car-
diac patients after CPB, an early, modest fluid overload (5% on
postoperative day 1) was associated with prolonged duration

of mechanical ventilation, inotropic support, and length of
stay. In this cohort, fluid overload preceded the development
of AKI (35). Another retrospective study confirmed the asso-
ciation between fluid overload and prolonged duration of
mechanical ventilation and ICU length of stay (37). These
investigators also found that in cyanotic patients, fluid over-
load predicted worsening oxygenation index. The deleterious
nature of fluid overload may be more pronounced in younger
patients. A study of 49 infants less than 6 months old found
that fluid overload was associated with poor outcomes and
that AKI developed in 86% of patients (2).
RECOGNITION OF FLUID OVERLOAD
Consensus definitions for fluid overload do not exist (38, 39).
Fluid overload may be defined as a positive fluid balance of
at least 50–100 mL/kg on a given day. Percentage fluid over-
load is calculated as: ([volume fluid in (L) – volume fluid out
(L)]/[weight] × 100). Using this equation, 5% fluid overload is
equivalent to a positive fluid balance of 50 mL/kg. Attention to
both “early fluid overload” (e.g., first 24 postoperative hours)
and cumulative fluid overload (e.g., since admission) is impor-
tant to facilitate decision making and optimize outcomes.
Patient Risk Factors
Anticipation of patients at particular risk of fluid overload
may facilitate a proactive management strategy. Risk factors
of AKI and postbypass edema include younger age and gesta-
tional age, preoperative mechanical ventilation, type of repair,
and longer CPB and hypothermic circulatory arrest times
(1, 34, 35). Infants are especially prone to edema secondary to
decreased glomerular filtration rate, elevated total body water,
and increased capillary membrane permeability.
Inputs, Outputs, and Weights
Daily rounds should include a detailed review of the daily and
cumulative fluid intake and output (i.e., “ins and outs”) and
patient weight (37, 40). Insensible losses will cause discrep-
ancies between net fluid totals and expected patient weights.
Clinically relevant insensible losses include evaporative water
losses from the skin, respiratory tract, and open body cavities,
all of which may increase with fever.
Systems to tally net fluid balance multiple times during a
shift rather than the traditional once per shift may also lead
to earlier recognition of fluid disturbances and more timely
deployment of effective therapies. Large-volume medications
and blood products can be insidious contributors to fluid
overload. Trending urine output in a timely manner against
diuretic administration provides an early opportunity to
deploy combination therapies when monotherapy is failing or
to eliminate a drug that is not efficacious. Note that oliguria
may also be a marker of hypovolemia, which would warrant a
reduction in diuretics and possible volume repletion.
For most patients, the need for intermittent fluid boluses
beyond the first postoperative day suggests an evolving altera-
tion in myocardial mechanics, cardiopulmonary interactions,
or intravascular status and warrants investigation (e.g., occult
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Supplement
bleeding or oozing, residual lesions, or drug delivery through a
catheter that has migrated to an extravascular position).
Invasive Pressure Monitoring
Invasive pressure waveform monitoring provides real-time
analysis of intravascular volume status. Although fluid overload
elevates central venous pressures (CVPs), ventricular compli-
ance must be taken into account. In the setting of ventricu-
lar dysfunction or existing fluid overload, small boluses may
result in a large and rapid increase in CVP. Intracardiac filling
pressures trended against anesthesia records, filling pressure at
admission, and expected values may alert the clinician to the
subtle changes in intravascular volume. Bladder pressures can
be measured by transducing an indwelling catheter. Bladder
pressure is a reliable surrogate for intra-abdominal pressure,
which may be elevated in the setting of vascular leak and fluid
resuscitation. In contrast to the fluid overloaded state, patients
with hypovolemia may have low intracardiac filling pressures.
The presence of pulse pressure variation may be a marker of
intravascular volume depletion and preload recruitable stroke
volume (41, 42).
Biomarkers of Fluid Status
Clinical context is important when considering biomarkers
of fluid status. The most commonly accepted biomarkers of
fluid status are serum and urine concentrations of sodium
and creatinine. Azotemia may develop from a number of fac-
tors, including intravascular volume depletion, inadequate
renal perfusion pressure, or exposure to nephrotoxic agents.
The calculation of fractional excretion of sodium (FENa)
may be helpful in understanding prerenal volume status and
differentiating between intrinsic and extrinsic renal disease.
Note that FENa is not accurate in patients receiving diuret-
ics. An alternative is the fractional excretion of urea, which
is a reliable measure of prerenal status even in patients who
are receiving diuretics (43). Extracellular fluid overload may
yield “diluted” samples of creatinine and thus delay the recog-
nition of AKI (44, 45). Adjusting serum creatinine values to
reflect fluid overload and total body water can be done using
the formula proposed by Liu et al (44). The adjusted serum
creatinine = measured serum creatinine × (1 + [cumulative
net fluid balance/total body water]). Total body water is cal-
culated as 0.6 × weight in kilograms.
Cardiopulmonary Manifestations
Patients who are fluid overloaded may develop pulmonary
edema. Pulmonary edema manifests clinically with hypox-
emia and increased work of breathing. Infants with pulmonary
edema are particularly vulnerable to diaphragmatic fatigue
because of the decreased numbers of type I muscle fibers in
the diaphragm (46). Radiographic findings of pulmonary
edema include effusions and Kerley B lines. Chest wall edema
and pleural effusions may also be seen in patients with fluid
overload. In patients with fluid overload who are mechanically
ventilated, flattened pressure/volume loops may be present,
consistent with poor lung compliance (47). Airway pressures
 McCammond et al
in mechanically ventilated patients will progressively trend
upward when fluid accumulates in the chest or when abdomi-
nal competition exists from tense ascites (48). Increased
pulmonary dead space in the first 48 postoperative hours is
associated with longer duration of ventilation and hospital
length of stay (49).
Cardioplegic arrest may cause myocardial ischemia-reper-
fusion injury, which has been associated with systolic and
diastolic dysfunction (50–52). Myocardial edema manifests as
decreased contractility and stroke volume with elevated filling
pressures. Reduced stroke volume manifests as a narrow pulse
pressure with compensatory tachycardia. Aggressive volume
resuscitation can cause ventricular distention, atrioventricular
valve regurgitation, and unfavorable interventricular inter-
actions. The clinical consequences of elevated cardiac filling
pressures include pleural and peritoneal effusions, venous and
hepatic congestion, and ascites.
Patients with relative hypovolemia may present with sinus
tachycardia, hypotension, cool extremities, and oliguria. This
clinical scenario can be difficult to distinguish from LCOS
because of myocardial dysfunction in the early postoperative
period but is often ameliorated with judicious volume admin-
istration and restoring normovolemia.
FLUID MANAGEMENT PRINCIPLES
Physiologic Rationale
The physiologic rationale for IV fluid administration, although
based mostly on experiential data, is derived from the fact that
in certain circumstances, patients cannot independently regu-
late fluid intake. “Maintenance” fluid requirements for children
were first calculated by Holliday and Segar (53), as reported in
their landmark 1957 publication.
Special considerations are needed when managing fluid
status in children with cardiac disease. Maintenance IV fluids
cannot be indiscriminately given to infants and children with
cardiac disease given the important impact of loading condi-
tions of cardiac physiology. Adequate systemic venous preload
is particularly important to maintain sufficient pulmonary
blood flow in certain patients with congenital heart disease.
For example, infants with tetralogy of Fallot and those with
functional single ventricles who have undergone a superior
(i.e., bidirectional Glenn or hemi-Fontan) or total cavopul-
monary connection (i.e., Fontan) may be preload dependent.
Preoperative neonates with d-transposition of the great arter-
ies may benefit from augmented pulmonary venous volume to
facilitate adequate interatrial mixing.
Pediatric cardiac patients warrant meticulous attention to a
number of fluid management variables. Fluid intake must be
serially assessed, including volume of infusions, medications,
and blood products. Ongoing losses should also be tracked
closely, including those from urine, bleeding, insensible losses,
and capillary leak into the interstitium.
Specific guidelines for the composition and rate of IV fluid
administration for the pediatric cardiac patient do not exist.
Adequate organ perfusion requires appropriate circulating
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blood volume. Most centers initially provide the pediatric
cardiac patient with adequate fluid volume to support organ
perfusion and prevent the biochemical development of organ
dysfunction, while attempting to avoid fluid overload. Early
after surgery, provision of half to two thirds of the calculated
maintenance fluid requirement for a postoperative pediatric
cardiac patient is often adequate.
Maintenance of Renal Perfusion Pressure and
Function
Adequate renal perfusion is essential for prevention of post-
operative fluid overload and AKI. Renal perfusion pressure
is calculated as mean arterial pressure (MAP) minus CVP.
Widely accepted values for normal renal perfusion pressure
in the pediatric cardiac population have not been established.
A number of variables should be considered to determine
whether an individual patient has adequate renal perfusion
pressure, including patient age and the cardiac physiology (see
below).
The underlying cardiac physiology must be considered
when determining the adequacy of renal perfusion pressure.
Congenital heart lesions that feature a noncompliant right
ventricle (e.g., pulmonary atresia with intact ventricular sep-
tum; tetralogy of Fallot) may have elevated right atrial pressure
and systemic venous hypertension. Similarly, patients with a
functional single ventricle palliated with a total cavopulmo-
nary anastomosis (i.e., Fontan circulation) have a nonphasic,
elevated CVP. For both of these populations, a higher MAP
may be needed to achieve adequate renal perfusion. Inadequate
renal perfusion may exist in some patients because of a combi-
nation of elevation of systemic venous pressure and inadequate
arterial pressure because of pump failure. Pharmacologic mea-
sures to provide sedation and analgesia may result in systemic
arterial hypotension. Benzodiazepines, narcotics, and propo-
fol are frequently considered causative agents. Clinicians must
balance the requirement for adequate sedation and analgesia
with the maintenance of an adequate MAP to optimize renal
perfusion. Inotropic or vasopressor infusions may be useful to
establish and maintain adequate renal perfusion pressure in
selected patients.
Note that pressure alone may not correlate well with
regional organ perfusion and that quantification of flow to end
organs is often impractical at the bedside. However, urine out-
put is quite sensitive to renal perfusion pressure and should
be followed closely. Serum blood urea nitrogen, creatinine,
and creatinine clearance may assist in the assessment of renal
perfusion pressure and evolving renal dysfunction. The recent
published Kidney Disease: Improving Global Outcomes defi-
nitions may be used to provide a uniform approach to the
diagnosis of AKI (54). Near-infrared spectroscopy may be used
to measure renal tissue oxygenation (55). Finally, biomarkers,
such as neutrophil gelatinase–associated lipocalin (NGAL) and
cystatin C, are useful for early identification of AKI and may
become part of routine clinical care in the near future (56).
Up to 40% of all medications prescribed in the pediatric
cardiac ICU may adversely affect intrinsic renal function (57).

Our understanding of medication-induced renal dysfunc-
tion is limited by current reporting systems that underes-
timate AKI (58). However, close attention is warranted with
medications known to affect renal perfusion or glomerular
filtration. Mechanisms of renal injury include the alteration
of glomerular perfusion (e.g., nonsteroidal anti-inflammatory
drugs [NSAIDs] and angiotensin-converting enzyme [ACE]
inhibitors), direct glomerular injury (e.g., NSAIDs), tubular
epithelial damage (e.g., aminoglycosides and radiographic
contrast dye), and tubulointerstitial injury (e.g., cyclosporine
and penicillins). Consultation with a dedicated pediatric clini-
cal pharmacist and use of electronic medical record alerts can
assist the clinician in prescribing medications while limiting
nephrotoxicity.
Abdominal fluid accumulation may occur in critically ill car-
diac patients. Intra-abdominal hypertension may be defined as
an intra-abdominal pressure of greater than 20 mm Hg. Recent
consensus guidelines on the diagnosis and management of
intra-abdominal hypertension in critically ill children recom-
mend measuring intra-abdominal pressure when risk factors
are present, including a positive end-expiratory pressure of
greater than 10 cm of water, after massive fluid resuscitation,
or with significant positive fluid balance and a distended abdo-
men (59). In patients in whom intra-abdominal hypertension
develops, consideration for drainage of the peritoneal cavity is
warranted.
Studies suggest that peritoneal cavity drainage can be per-
formed safely and may improve outcomes by improving renal
perfusion. Retrospective studies in children recovering from
selected cardiac operations have found an association between
peritoneal drainage and shorter time to negative fluid balance
and extubation (48,60,61). Intraoperative or early postopera-
tive placement of a peritoneal drain may be more prudent than
awaiting the development of renal failure (62, 63). However, a
prospective trial of empiric peritoneal drainage placement in
patients after the Norwood palliation found no difference in
fluid balance or improvement in outcomes, yet a higher preva-
lence of complications (64). Enrollment is ongoing in another
randomized trial of early initiation of peritoneal dialysis in
infants recovering from cardiac surgery in whom AKI develops
(ClinicalTrials.gov Identifier, NCT10709227).
Normal Versus Hypotonic Fluid Administration
Considerable debate has surrounded the appropriate composi-
tion of IV fluids for hospitalized children. Since the seminal
publication by Holliday and Segar (53), hypotonic mainte-
nance fluids (e.g., 0.2 normal saline [NS] or 0.5NS) have been
commonly administered based on the calculation of electrolyte
needs for a newborn or child. However, hyponatremia com-
monly occurs with the administration of hypotonic fluids.
Pain, mechanical ventilation, surgery, and other factors com-
mon to pediatric cardiac patients may all contribute to non-
osmotic antidiuretic hormone release, which may be further
exacerbated by the administration of hypotonic fluids. In a sys-
tematic review and meta-analysis of 10 randomized controlled
studies, which included 893 hospitalized children, both mild
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and moderate hyponatremia occurred more frequently with
hypotonic fluid (pooled relative risks, 2.4 and 6.1, respectively)
(65). Multiple studies of pediatric postoperative patients have
corroborated these findings (66–70), and the cumulative evi-
dence indicates that the use of isotonic fluids is associated with
a lower prevalence of hyponatremia in hospitalized children
(71). No guidelines exist for maintenance fluid composition
for the postoperative pediatric cardiac patient, and some cli-
nicians continue to use hypotonic fluid for younger patients
(e.g., 0.5NS for children less than 3 months old).
Similar debate has surrounded the fluid choice for volume
expansion. Both crystalloid and colloid fluids are frequently
used to increase intravascular volume. Colloids include pooled
human proteins (albumin) and synthetic colloids, such as
hydroxyethyl starch (hetastarch) and dextran. In a systematic
Cochrane Database review of 78 clinical trials of crystalloid
versus colloid in critically ill patients, the pooled data did not
favor either IV solution (a possible increase in mortality with
hetastarch was found) (72). The authors concluded that col-
loids do not improve mortality, are more costly than crystal-
loid, and cannot be justified as volume expanders.
The use of various colloids in the pediatric CPB circuit
prime and early postoperative period has been investigated.
In preliminary randomized trials involving children under-
going cardiac surgery, hetastarch was found to be safe when
compared with albumin (73) and fresh frozen plasma (74),
although no consistent benefit to either fluid could be dem-
onstrated. Patients administered larger volumes of hetastarch
(compared to albumin) may develop coagulation abnormali-
ties (75). In a randomized trial of 86 infants and young children,
CPB prime of either 5% albumin versus crystalloid resulted in
net negative fluid balance only for those who received albumin.
However, the patients receiving albumin had lower hematocrit
and received more blood transfusions, and no significant dif-
ferences between groups were found 24 hours after CPB (76).
CONVENTIONAL DIURETICS
Diuretics may be used to optimize hemodynamics and
eliminate excess circulating volume. Key properties of the
conventional diuretic agents that remain ubiquitous in the
management of pediatric cardiac patients are summarized in
Table 1.
Loop Diuretics
Loop diuretics are the backbone of diuretic therapy in pedi-
atric cardiac patients because of a favorable safety profile
and extensive clinical experience. Loop diuretics induce both
diuresis and natriuresis through inhibition of sodium and
chloride reabsorption in the thick ascending limb of the loop
of Henle. Furosemide and bumetanide are the most commonly
used in this class of diuretic. Both agents are highly bound
to serum albumin and depend on excretion into the tubular
lumen to exert their effect on the Na+/K+/2Cl cotransporter.
Consequently, factors that impact tubular function, such as
glomerular filtration rate and postgestational maturity, signifi-
cantly impact the pharmacologic profile and diuretic effect of
 McCammond et al

Table 1. Dosing, Pharmacokinetic Data, and Common Adverse Effects of Conventional

Diuretic Agents
Classification Agent Typical Dose Pharmacokinetics Adverse Effects Other

Loop Furosemide Intermittent, enteral: initial: t½ (hr) = variable depending Ototoxicity Bioavailability
(78, 86, 88, 2 mg/kg per dose every on age: 1.53 (adult), Hypercalciuria of ≈ 60%
90, 159–161) 6 hr; maximum: 6 mg/kg 1.98 (infant), and Nephrocalcinosis
per dose every 6 hr 1.8–26.8 (neonate)
Onset = 30 min
Intermittent, IV: initial: Peak = 1–2 hr Hyponatremia
1 mg/kg per dose every V (L/kg) = variable Hypochloremic
d
6 hr; maximum: 3 mg/kg depending on age: 0.1 alkalosis
per dose every 6 hr (adult), 0.49 (infant), and Hypokalemia
0.17–0.83 (neonate)
Continuous, IV: Initial: PB = ≥ 95% Hypomagnesemia
0.05–0.2 mg/kg/hr; Hypocalcemia
maximum: 1 mg/kg/hr Hypotension
Bumetanide Intermittent, enteral or IV: t½ (hr) = variable Hypokalemia Bioavailability of
(77, 78, 94, initial: 0.005–0.1 mg/kg depending on age: 59–89%
95, 100, per dose every 6 to 24 hr; 1–1.5 (adults), 1.5–2.5 1 mg bumetanide =
160, 162) maximum: 10 mg/d (range, 0.73–5.27) for 40 mg furosemide
infants, and 6 to 15 hr
(neonate) Ototoxicity IV preparation
contains benzyl
alcohol
Continuous, IV: initial: Onset = NS Muscle cramps Lower doses (i.e.,
0.001–0.1 mg/kg/hr; Peak (hr) = 1–3 Hypotension 0.035–0.04 mg/kg)
maximum: 0.2 mg/kg/hr V (L/kg) = 0.18–0.43 achieve maximal
d diuretic response
(up to 1.6)
PB = 97%
Thiazide Chlorothiazide Intermittent, enteral or IV: t½ (hr) = ≈ 5 Hypercalcemia Limited bioavailability
(100, 104, infants < 6 mo: 10– Onset (hr) = 1 Hyperuricemia Some centers use
160, 163) 30 mg/kg/d divided once Peak (hr) = 2–6 Hyperglycemia lower IV doses
or twice daily and infants
≥ 6 mo, children, and Hyperlipidemia
adolescents: 10–20 mg/ Cholestasis
kg/d divided once or
twice daily; maximum daily
doses: infants and children
< 2 yr: 375 mg/d, children
2–12 yr: 1,000 mg/d, and
adolescents: 2 g/d
Thiazide-like Metolazone Intermittent, enteral: t½ (hr) = 5–6 (adult) Similar to Only available for
(101, 104) children and Onset (hr) = < 1 (adult) thiazides enteral
adolescents: PB = 90–95% administration
0.2–0.4 mg/kg/d
Potassium- Spironolactone Intermittent, enteral: t½ (hr) = 1.5 (adult) Hyperkalemia Only available
sparing (104, 164, preterm < 32 wk: Onset (hr) = 48–72 (adult) Nephrocalcinosis for enteral
165) 1 mg/kg once daily; Peak (hr) = 1–3 Gynecomastia administration
term neonate: Use caution with
1–2 mg/kg/d divided PB = 91–98%
concurrent potassium
every 12 hr; infants and supplements,
children: 1–3 mg/kg/d angiotensin-
divided every 6 to 12 hr; converting enzyme
maximum daily dose: inhibitors, angiotensin
3.3 mg/kg/d or II antagonists, and
100 mg/d nonsteroidal anti-
inflammatory drug
PB = protein binding, NS = not significant, Vd= volume of distribution.

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these agents. Prematurity is associated with a prolonged half-
life and delayed clearance of all loop diuretics and necessitates
decreased frequency of dosing (77).
Furosemide is the less potent of the two commonly used
loop diuretics. In pediatric cardiac patients, hemodynamic sta-
tus, renal function, and anticipated fluid shifts often dictate the
route of administration and dosing regimen (intermittent vs
continuous infusion, with or without a preceding bolus) (78).
In infants following congenital heart surgery, initial pediatric
studies comparing dosing regimens had mixed outcomes (79,
80). Luciani et al (81) demonstrated that a continuous infusion
of furosemide resulted in less total volume of urine output;
however, the infusion resulted in higher urine output per total
dose of diuretic. In addition, patients receiving a continuous
infusion had a more favorable negative fluid balance secondary
to a decreased requirement for fluid administration because
of hemodynamic instability and fluid shifts. In a recent meta-
analysis of randomized clinical trials, summary data from 15
adult studies suggest that an IV bolus followed by continuous
infusion of loop diuretic is associated with overall higher urine
output compared with intermittent dosing, whereas no differ-
ence in urine output was found between dosing regimens in
three trials that enrolled children recovering from cardiac sur-
gery (82). A meta-analysis of randomized controlled trials in
adults with decompensated heart failure found that the admin-
istration of a continuous infusion of a loop diuretic was associ-
ated with greater decrease in body weight but no advantage in
terms of total volume of urine output, prevalence of electrolyte
abnormalities, or overall mortality (83). A continuous infusion
has the additional advantage of decreasing the frequency of
central line access necessary for intermittent dosing in patients
without peripheral venous lines, as frequency of central line
access is an established risk factor of central line–associated
blood stream infections (84). Intermittent dosing also incurs
more expense by way of administration charges for each dose.
Pharmacokinetic modeling has demonstrated a strong cor-
relation between renal excretion of furosemide and effective
urine output. As such, in patients with impaired renal func-
tion and decreased renal excretion of furosemide, higher dos-
ing may be beneficial (85, 86). In patients receiving repeated
or chronic doses of furosemide, pharmacologic tolerance may
develop related to a compensatory increase in sodium reab-
sorption in the distal tubule. Several strategies, involving com-
bination diuretic therapy and adjunct agents, have evolved to
counteract this phenomenon (87).
The adverse side effects of furosemide are most notable
in neonates and premature infants. Both transient and per-
manent ototoxicity have been demonstrated in up to 1% of
patients in some reports. Hearing loss is most often bilateral
and clinically significant. Although the exact mechanism is not
well delineated, the ototoxicity seems to be related to effects on
the stria vascularis of the cochlear duct, impacting the endoco-
chlear potential. The occurrence of ototoxicity has been asso-
ciated with both the total dose of furosemide and peak serum
concentrations and duration of therapy (88). Peak serum lev-
els greater than 50 μg/mL have been associated with greater
Pediatric Critical Care Medicine www.pccmjournal.org S41
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Supplement
ototoxicity (89). Given these factors, some practitioners favor
continuous infusions over bolus dosing in neonates and pre-
term infants.
Hypercalciuria with resulting nephrocalcinosis is diagnosed
in up to 27% of preterm infants treated with furosemide. The
prevalence is strongly associated with lower birth weight and
total daily dose of diuretic, and severe cases of calcium deposits
requiring intervention have been reported (90).
Furosemide is associated with important pulmonary effects
independent of diuresis. Pulmonary vasodilation, enhanced
lung fluid absorption, and possibly an increased prevalence of
patent ductus arteriosus in preterm infants treated with furose-
mide are all effects that are proposed to be related to increased
prostaglandin production (91–93). These effects may be of
clinical importance in the pediatric cardiac patient, although
further prospective data are lacking.
Bumetanide has a similar mechanism of action as furose-
mide but is approximately 40 times more potent. Bumetanide
has a shorter half-life and the additional advantage of wider
compatibility when administered continuously with other IV
medications (77, 78). Although pediatric data for bumetanide
are limited and published dosing regimens vary, existing evi-
dence and wide clinical experience with this agent support
its role as a safe and effective loop diuretic, particularly in the
setting of evolving furosemide resistance. Like furosemide,
pharmacokinetic properties of bumetanide are dependent
on renal function, gestational maturity, and age, and there is
some evidence for delayed clearance in patients with cardiac
disease (94, 95). Of note, benzyl alcohol is used as an antimi-
crobial component in the preparation of bumetanide. Gasping
syndrome has been reported in neonates exposed to greater
than 99 mg/kg/d of benzyl alcohol. As such, the lowest dose of
bumetanide required to achieve desired diuretic effect is rec-
ommended (78).
Thiazide Diuretics
Thiazide diuretics inhibit reabsorption of sodium in the dis-
tal renal tubules, thus increasing urinary excretion of sodium,
water, potassium, and hydrogen ions. In adults with heart fail-
ure and hypertension, thiazides have been shown to reduce
morbidity and mortality (96). Although thiazides can be used
as monotherapy, they are frequently used in combination with
loop diuretics to enhance urine output in the setting of loop
diuretic resistance. This combination strategy is well estab-
lished in the adult heart failure population and has been shown
to significantly augment urine output, relieve volume over-
load, and improve clinical heart failure symptoms. Hypoten-
sion, worsening renal function, and electrolyte derangements
remain potential drawbacks of this combination approach
(97). In practice, many clinicians routinely administer thiazide
and loop diuretics in close temporal proximity to maximize
the desired synergistic diuretic effect.
The majority of pediatric data related to the use of thiazides
in children stem from investigations in preterm infants with
bronchopulmonary dysplasia (98). In addition, given the effect
of thiazide diuretics in enhancing calcium reabsorption, these
 McCammond et al
diuretics are used frequently in the setting of inherited forms of
hypercalciuria in children (99). Rigorous studies investigating
the effectiveness of thiazide diuretics alone or in combination
in the pediatric cardiac population do not exist, yet anecdotal
experience indicates efficacy in the acute setting. In addition to
electrolyte derangements, long-term therapy with thiazides in
children is associated with hyperglycemia and hyperlipidemia
(100).
Metolazone
Metolazone is a potent thiazide-like diuretic, which acts by
blocking sodium reabsorption in both proximal and distal
regions of the renal tubule. Available only by enteral admin-
istration and with a notably long duration of action ranging
from 12 to 24 hours, this medication is often employed as a
second- or third-line agent in combination with standard loop
and thiazide diuretics for refractory volume overload. Limited
pediatric data suggest that metolazone is effective in achieving
diuresis (101, 102). The enteral route of administration, vari-
able absorption, limited dosage preparations, and associated
electrolyte abnormalities when administered in combination
with other agents warrant careful patient selection (103).
Spironolactone
Spironolactone is a synthetic steroid, which acts as a competi-
tive antagonist at the aldosterone receptor in the distal renal
tubule. Aldosterone is secreted by the adrenal gland with the
purpose of preserving intravascular volume. Aldosterone acts
by increasing the reabsorption of sodium in exchange for
potassium and hydrogen ions. Inhibition of this activity by spi-
ronolactone permits excretion of sodium and spares the loss
of potassium (87, 104). Given that it is a relatively weak inde-
pendent diuretic, in the intensive care setting, spironolactone
is a frequent adjunct to diuretic regimens to prevent or treat
hypokalemia and thus reduce the need for potassium replace-
ments. However, data to support the efficacy of this practice
are lacking.
Spironolactone has a central role in the chronic manage-
ment of adult and pediatric heart failure. Large adult trials
have demonstrated improved survival in heart failure patients
and those with ventricular dysfunction following myocardial
infarction (105, 106). Selective aldosterone blockade is thought
to have beneficial effects in preventing myocardial fibrosis, and
spironolactone is proposed to have additional beneficial effects
on endothelial function via nitric oxide–mediated pathways
(107, 108). Aldosterone also seems to play a key role in mediat-
ing endothelial cell dysfunction and fibrosis in patients with
pulmonary hypertension. Spironolactone has demonstrated a
promising effect in improving exercise tolerance and clinical
symptoms in this patient population (109, 110). This interac-
tion with endothelial cell function has been suggested as a pos-
sible mechanistic explanation for spironolactone’s occasional
efficacy in treating single-ventricle patients following Fontan
procedure with protein losing enteropathy (111–113).
Although frequently used for its potassium-sparing effects,
hyperkalemia remains a potential and life-threatening adverse
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effect of spironolactone, which requires close laboratory moni-
toring. Patients with impaired renal function and those receiv-
ing potassium chloride supplementation, ACE inhibitors, or
NSAIDs are at higher risk. Less commonly, gynecomastia has
been associated with long-term spironolactone therapy, which
is often reversible with discontinuation of the medication
(104).
Diuretic-Induced Metabolic Derangements
Electrolyte derangements are common in critically ill cardiac
patients who are receiving diuretics. They should be antici-
pated and thus safely managed. Loop diuretics commonly
result in hypokalemia and hypochloremia with resultant
metabolic alkalosis. Hypocalcemia, hypomagnesemia, and
hyponatremia may also occur. Thiazide diuretics share a simi-
lar electrolyte-wasting profile, although do not contribute to
important calcium wasting (104). The prevalence of diuretic-
related electrolyte derangements in pediatric cardiac patients is
poorly described in the literature, and the clinical significance
varies substantially. In the majority of patients, the need for
diuresis and resolution of volume overload takes priority over
potential electrolyte depletion. Clinicians must weigh the need
for fluid removal with the risk of arrhythmias.
In practice, most electrolyte derangements can be man-
aged with a combination of serial laboratory monitoring and
electrolyte replacement. Both enteral and IV potassium reple-
tion have comparable and reproducible efficacy in increasing
serum potassium in the pediatric cardiac population (114,
115). Potassium chloride is designated as a “high-alert” medi-
cation given the potential of iatrogenic hyperkalemia (116).
IV potassium supplementation may cause acute hyperkalemia
if administered too rapidly. Although the enteral administra-
tion of potassium is generally perceived to be relatively safe,
anecdotal experience suggests that the variable and potentially
rapid absorption of large doses of liquid potassium supple-
ments may be problematic.
Metabolic alkalosis resulting from aggressive diuresis occurs
most often in the setting of hypochloremia. Metabolic alkalosis
can alter respiratory drive, hinder the weaning of respiratory
support, and has been associated with increased morbidity
and mortality in some studies (117, 118). Chloride and volume
depletion seem to be central to the development of metabolic
alkalosis in the ICU setting, with an estimated prevalence near
50% in infants undergoing congenital heart surgery. Younger
age, exposure to CPB, and preoperative ductal dependence
have been identified as independent risk factors (119, 120).
Metabolic alkalosis can frequently be ameliorated via volume
repletion or weaning of diuretic therapy. Chloride repletion
seems to be critical in the renal tubules ability to correct the
elevation of bicarbonate, and can be achieved by using potas-
sium chloride, sodium chloride, or arginine hydrochloride,
the choice of which will depend on the coexisting electrolyte
derangements (121).
Acetazolamide, an inhibitor of carbonic anhydrase in the
proximal renal tubule, promotes excretion of both sodium
and bicarbonate in the urine. Acetazolamide may be used to

treat metabolic alkalosis in patients in whom further volume
or chloride administration is undesirable (104). In pediatric
cardiac patients, retrospective data suggest that acetazolamide
may be used safely and effectively to correct serum bicarbonate
levels and normalize pH (122, 123).
ALTERNATIVE AGENTS
Diuretic resistance presents a challenging clinical scenario in
patients with volume overload. In pediatric cardiac patients,
impaired renal function, compromised systemic cardiac out-
put, and elevated systemic venous pressure may contribute to
unsatisfactory diuretic response and ineffective fluid removal.
Several alternative strategies have been used to address diuretic
resistance, although strong pediatric evidence for these
approaches is lacking.
Albumin
Both furosemide and bumetanide are highly bound to serum
albumin. When bound to albumin, these drugs are delivered
to the renal tubules and secreted in active free form into the
tubular lumen. As such, the administration of albumin in com-
bination with loop diuretics, particularly in hypoalbuminemic
patients, may be used with the goal of increasing urine output
in diuretic resistant patients. Mechanistically, albumin may
increase intravascular oncotic pressure to assist in mobilizing
third spaced fluid, as well as optimizing the delivery of pro-
tein-bound diuretic to the renal tubules. Published data sup-
porting this practice in children are limited to patients with
hypoalbuminemia resulting from nephrotic syndrome. Exist-
ing studies in this population demonstrate some beneficial
effects of albumin administration in augmenting urine output,
although the impact on overall fluid balance is often transient
(124, 125). Kitsios et al (126) recently performed a meta-analy-
sis of 10 ­randomized control trials in adults comparing furose-
mide versus coadministration of albumin and furosemide. The
authors concluded that there is a transient yet modest increase
in urine output in diuretic resistant patients who receive albu-
min, but the benefit was short lived and of questionable clinical
significance. The role of albumin administration specifically
related to fluid management in critically ill pediatric cardiac
patients has not been investigated.
Dopamine
Dopamine is widely employed in the pediatric cardiac ICU.
Dopamine produces a variety of dose-dependent effects by
activating dopamine receptors, as well as α- and β-adrenergic
receptors. Through its action on renal dopaminergic receptors,
dopamine is proposed to impact renal perfusion and urine pro-
duction independent of its global hemodynamic effects. At lower
doses (3–5 μg/kg/min), dopamine has been shown in healthy
adults to promote renal afferent arterial vasodilation, increase
glomerular filtration rate, augment sodium excretion, and
increase urine volume (127, 128). However, the use of low-dose
dopamine to augment renal perfusion, preserve renal function,
and promote urine output in critically ill adult and pediatric
patients remains controversial. In critically ill adult patients,
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existing literature fails to support low-dose dopamine as an
adjunct for fluid management. The first large, randomized, pla-
cebo-controlled trial in critically ill adults with oliguria showed
no benefit in terms of renal function or total volume of urine
output (129). More recently, the Renal Optimization Strategies
Evaluation Acute Heart Failure Randomized Trial investigated
the utility of low-dose dopamine compared with both placebo
and low-dose nesiritide in patients with acute decompensated
heart failure and renal dysfunction. This multicenter, random-
ized control trial also failed to demonstrate any benefit of low-
dose dopamine on renal function or fluid balance (130).
Pediatric data for low-dose dopamine remain limited in
scope and generalizability. Prins et al (128) reviewed seven
clinical studies, primarily in the neonatal population. Although
some studies demonstrated modest benefit with low-dose
dopamine in terms of urine volume and creatinine clearance,
variability in study design and dosing, along with small sample
sizes limited the ability to make strong recommendations in
favor of low-dose dopamine for optimization of urine output
and renal function. More recently, Crouchley et al (131) inves-
tigated the effects of low-dose dopamine on urine output in
65 very low birthweight premature infants, demonstrating a
significant increase in urine output in 64% of patients, con-
trolling for fluid intake, diuretic use, and concomitant treat-
ment with hydrocortisone. Strong evidence for the routine use
of renal dose dopamine to augment urine output in pediatric
cardiac patients is lacking.
Fenoldopam
Fenoldopam mesylate is a selective agonist of D1 type dopa-
mine receptors. Fenoldopam promotes vasodilation in renal,
mesenteric, and coronary arteries. This drug has been shown
to increase renal sodium excretion and urine production in
adults (132). Fenoldopam is approved by the U.S. Food and
Drug Administration for the short-term treatment of hyper-
tension in both children and adults. Fenoldopam has been pro-
posed as a useful agent to promote urine output and preserve
renal function, particularly in patients with AKI, although
evidence of efficacy remains mixed. In a randomized pla-
cebo-controlled trial of 80 adults undergoing cardiac surgery,
Ranucci et al (133) reported that patients assigned to receive
fenoldopam had a significantly lower prevalence of AKI but
no augmentation of urine output. A recent meta-analysis of
six randomized control trials involving a total of 440 adult car-
diac surgery patients concluded that fenoldopam significantly
reduced the prevalence of AKI but had no impact on hospital
length of stay, need for renal replacement therapy, or mortal-
ity (134). However, in a large multicenter trial, in adults who
developed early AKI after cardiac surgery, fenoldopam did not
reduce either the need for renal replacement therapy or risk for
mortality and was associated with an increased prevalence of
hypotension (135).
Strong prospective evidence and widespread experience with
fenoldopam are lacking in the pediatric cardiac population. In
a retrospective, uncontrolled study of 25 neonates who were
recovering from cardiac surgery and failing to achieve negative
 McCammond et al
fluid balance on conventional diuretic therapy, the initiation of
fenoldopam was associated with improved urine output (136).
Similarly, Moffett et al (137) reported 13 critically ill pediatric
patients in whom the administration of a fenoldopam infu-
sion was associated with increased urine output without asso-
ciated hemodynamic compromise or elevation in creatinine.
Conversely, in a prospective controlled trial in which 40 neo-
nates undergoing cardiac surgery were enrolled, an empiric
fenoldopam infusion was not associated with increased urine
output or improved renal function (138). In a prospective,
randomized, double-blind, placebo-controlled trial in which
80 infants undergoing complex two-ventricular repairs were
enrolled, patients assigned to receive empiric fenoldopam had
decreased urinary biomarkers of kidney injury (NGAL and
cystatin C) and decreased need for vasodilators and diuretics.
A trend toward decreased prevalence of AKI was also demon-
strated in the active treatment group (139). Confirmation of
the results of this trial and further prospective data in other
pediatric cardiac populations are needed before its routine
clinical use can be recommended.
Nesiritide
Nesiritide is a recombinant B-type natriuretic peptide. Nesirit-
ide causes arterial and venous vasodilation, modulates the
renin-angiotensin-aldosterone system, and has modest diuretic
and natriuretic effects (140, 141). The U.S. Food and Drug
Administration approved the use of nesiritide for use in adults
with acutely decompensated heart failure in 2001 following
early studies that found improvement in cardiac filling pressures
and clinical symptoms in this patient population (142). Since
its approval, however, accumulating evidence raises significant
questions about the efficacy of nesiritide. A recent multicenter,
randomized, placebo-controlled trial in which over 7,000 adults
with decompensated heart failure were enrolled failed to dem-
onstrate a benefit from nesiritide with respect to clinical symp-
toms of dyspnea, prevalence of re-hospitalization, or mortality
(143). Although treatment with nesiritide seems to have neutral
impact on serum creatinine and renal function in adult heart
failure patients, further studies have also failed to demonstrate
augmentation of diuresis (144, 145). In a 2005 open letter to
healthcare providers, the manufacture of nesiritide reported the
findings of an expert panel that specifically recommended that
nesiritide should not be used to replace diuretics, improve renal
function, or enhance diuresis (146).
Several groups have investigated the use of nesiritide in
pediatric cardiac patients. Retrospective case series in pediat-
ric heart failure patients, including some patients recovering
from cardiac surgery, concluded that nesiritide was generally
well tolerated and had a favorable impact on diuresis, car-
diac filling pressures, and overall clinical status (147–150).
In an uncontrolled, prospective trial of 32 pediatric patients
with congestive heart failure, nesiritide was associated with
improved urine output, decreased CVP, and improved func-
tional status. Although the study population varied consider-
ably in terms of age and the etiology of congestive heart failure,
a favorable safety profile was observed (151). In a randomized,
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double-blind, placebo-controlled trial in which 106 children
undergoing the Fontan operation were enrolled, empiric treat-
ment with nesiritide failed to improve early clinical outcomes,
including length of hospitalization, urine output, duration of
chest tube drainage, or hemodynamic variables when com-
pared with either milrinone or placebo (152). Strong pro-
spective evidence to support the routine use of nesiritide in
the pediatric cardiac population is thus lacking. However, the
available data suggest that nesiritide can be used safely and
may provide some modest benefit in selected infants and chil-
dren with heart failure.
Aminophylline
Aminophylline, an adenosine receptor antagonist, inhibits
renal vasoconstriction. Aminophylline has been investigated as
a diuretic and renal protective agent in several patient popula-
tions. In a retrospective, single-center study of pediatric cardiac
patients with established AKI, aminophylline administration
was associated with improved renal function (153). A prospec-
tive, randomized trial designed to determine whether amino-
phylline can minimize the prevalence of AKI after pediatric
CPB is ongoing (ClinicalTrials.gov Identifier: NCT01245595).
Vaptans
Hyponatremia is a common complication in patients with
heart failure and has been associated with adverse outcomes.
The etiology is multifactorial and may include free water over-
load, elevated plasma arginine vasopressin levels, conventional
diuretic use, and renal dysfunction. The vaptans (tolvaptan
and conivaptan) are arginine vasopressin antagonists that
have been developed to increase free water output and serum
sodium levels in patients with euvolemic and hypervolemic
hyponatremia. Thus, vaptans have been named “aquaretics.”
Tolvaptan blocks the binding of arginine vasopressin at the
V2 receptors in the distal portions of the nephron, resulting
in excretion water without the depletion of electrolytes. Ran-
domized trials in adults have found that tolvaptan effectively
normalizes hyponatremia, improves symptoms of congestion,
and has modest beneficial hemodynamic effects but does not
reduce mortality or rehospitalization rates (154–157). Expe-
rience with vaptans is limited in children. In a single-center,
retrospective, uncontrolled study in 28 pediatric heart failure
patients hospitalized with heart failure, treatment with tolvap-
tan was associated with increased serum sodium levels and
greater urine output (158). More data are needed to determine
the safety and efficacy of vaptans in pediatric cardiac patients.
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