Download Effects of Fluid and Electrolyte Management on

Effects of Fluid and Electrolyte Management on Amphotericin B-Induced
Nephrotoxicity Among Extremely Low Birth Weight Infants
Bernd Holler, MD*‡; Said A. Omar, MD*‡; Maged D. Farid, MD*‡; and Maria Jevitz Patterson, MD, PhD*§㛳
ABSTRACT. Objective. Greater use of invasive procedures and aggressive antimicrobial therapy predispose
extremely low birth weight (ELBW) infants to systemic
fungal sepsis. Despite its adverse effects (including renal
and electrolyte disturbances), amphotericin B (amphoB)
remains the preferred drug for fungal therapy. Multiple
studies have indicated that sodium loading may prevent
renal toxicity among animals and human adults. The
effects of fluid and electrolyte management on amphoBinduced nephrotoxicity among ELBW infants have not
been evaluated extensively. The purpose of this study
was to examine the effects of fluid and electrolyte management on amphoB-induced nephrotoxicity among
ELBW infants.
Design/Methods. The medical records were reviewed
for all ELBW infants (birth weights of <1250 g) who
developed systemic fungal sepsis, requiring amphoB
therapy, between January 1992 and December 2000. Demographic, clinical, and laboratory data were collected
from the medical records for each patient.
Results. Fungal sepsis requiring amphoB treatment
developed for 4.4% of ELBW infants (25 of 573 infants),
with a gestational age of 25 ⴞ 1 weeks and a birth weight
of 738 ⴞ 37 g, at a postnatal age of 16 ⴞ 2 days. Renal
compromise, as manifested by low urine output and high
creatinine levels, occurred for 44% of those infants (11 of
25 infants). There was no difference between the infants
who developed renal compromise (renal compromise
group [RCG], n ⴝ 11) and those who did not (no–renalcompromise group [NCG], n ⴝ 14) with respect to birth
weight, gestational age, and risk factors predisposing the
infants to fungal sepsis. The RCG demonstrated a decrease in urine output by 3.4 ⴞ 2 days and an increase in
serum creatinine levels by 3.9 ⴞ 2 days after the initiation
of amphoB therapy. Infants in the RCG had a significantly higher incidence of hyponatremia, compared with
infants in the NCG (7 of 11 infants vs 0 of 14 infants),
with no significant difference in the incidences of hypokalemia (2 of 11 infants vs 0 of 14 infants). Infants in the
RCG, compared with infants in the NCG, had significantly lower mean daily sodium intakes in the 4 days
before the initiation of amphoB therapy (2.6 –2.9 mEq/kg
per day vs 4.2– 4.7 mEq/kg per day) and in the first 4 days
From the *Department of Pediatrics and Human Development, College of
Human Medicine, and §Departments of Microbiology and Molecular Genetics and 㛳Pediatrics, College of Osteopathic Medicine, Michigan State
University, East Lansing, Michigan; and ‡Division of Neonatology, Sparrow
Regional Children’s Center, Lansing, Michigan.
Received for publication May 28, 2003; accepted Jan 28, 2004.
This work was presented in part at the 2002 Pediatric Academic Societies’
Meeting; May 4 –7, 2002; Baltimore, Maryland.
Reprint requests to (S.A.O.) Division of Neonatology, Department of Pediatrics, Sparrow Health System, 1215 E Michigan Ave, Lansing, MI 48912.
E-mail: [email protected]
PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Academy of Pediatrics.
e608
of amphoB treatment (2.7–3.1 mEq/kg per day vs 4.5–5.6
mEq/kg per day). Mean daily sodium intakes were not
statistically significantly different between the 2 groups
between day 5 and day 10 of amphoB therapy. Infants in
the RCG tended to have lower mean daily potassium
intakes in the 4 days before the initiation of amphoB
therapy and during the first 4 days of amphoB therapy.
Subsequently, the mean daily potassium intakes remained not statistically significantly different between
the groups. Mean daily fluid intakes were not different
between the groups.
Conclusions. Conventional amphoB combined with
adequate hydration and higher sodium intakes of >4
mEq/kg per day may provide effective protection
against amphoB-induced nephrotoxicity among ELBW
infants. Our data confirm the published results of animal and human adult studies and suggest that higher
sodium intakes may prevent renal compromise during
amphoB therapy among ELBW infants. Pediatrics 2004;
113:e608 –e616. URL: http://www.pediatrics.org/cgi/
content/full/113/6/e608; amphotericin B, nephrotoxicity,
ELBW infants.
ABBREVIATIONS. RCG, renal compromise group; NCG, no–renal-compromise group; ELBW, extremely low birth weight; amphoB, amphotericin B.
T
he advances in neonatal intensive care have led
to increases in the survival rates for extremely
low birth weight (ELBW) infants.1 The invasive
treatment modalities required by ELBW infants increase their risk for nosocomial infections, which are
associated with significant rates of death and morbidity, including ophthalmologic, visceral, and cardiac abnormalities and meningitis.2–4
Candida species have been identified as the third
most common organisms for late-onset sepsis among
very low birth weight infants.4 Moreover, Kossoff et
al5 reported that the rate of candidemia in their neonatal intensive care unit increased 11-fold between
1981 and 1995. Because systemic fungal infections are
associated with mortality rates of 15% to 60% in
reported cases, early initiation of therapy is warranted.6–10 Rapid diagnosis and treatment of such infections are hindered by the high incidence of fungus
that is undetectable in cultures and the long periods
needed for fungal growth.11
With a questionnaire sent to United States-based
pediatric infectious disease specialists and neonatologists, Rowen et al12 found that 88% of respondents
considered amphotericin B (amphoB) the therapy of
choice for fungal sepsis. AmphoB has been favored
because of its fungicidal effects.12 Unfortunately, am-
PEDIATRICS Vol. 113 No. 6 June 2004
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phoB therapy is associated with adverse effects, including infusion reactions with hemodynamic and
temperature instability, thrombocytopenia, and
nephrotoxicity with electrolyte disturbances.13 Concern regarding these adverse reactions has contributed to hesitation in beginning empiric treatment
before positive culture findings are obtained.6,10,11
Efforts to reduce these side effects have led to the
development of amphotericin-lipid formulations and
research on the effects of salt supplementation before
amphoB therapy. Conventional amphoB is preferred
over the liposomal preparations because it achieves
higher concentrations in renal tissue, which is an
important consideration because 20% to 40% of infants demonstrate renal involvement.14
Multiple studies have indicated that adequate
fluid and electrolyte balances before amphoB administration may prevent renal toxicity.15–23 Studies of
animals and human adults have demonstrated that
salt loading before amphoB therapy ameliorates the
nephrotoxicity.22,23 The effects of fluid and electrolyte management on amphoB-induced nephrotoxicity among ELBW infants have not been extensively
evaluated. The purpose of this study was to assess
the effects of fluid and electrolyte (including sodium
and potassium) management on amphoB-induced
renal compromise among ELBW infants with birth
weights of ⱕ1250 g.
DESIGN/METHODS
Medical records were reviewed for all ELBW infants with birth weights of ⱕ1250 g who developed
systemic fungal infections that required amphoB
therapy between January 1992 and December 2000.
The infants were admitted to the neonatal intensive
care unit at Sparrow Hospital (Lansing, MI). The
institutional review board of the hospital approved
the study.
Demographic, clinical, and laboratory information
was collected from the medical records of each patient. Demographic data included gestational age,
birth weight, gender, race, and Apgar scores. The
charts were reviewed for clinical data such as symptoms and signs of infection and laboratory data including culture results. Infants with fungal sepsis
presented with at least 2 of the following clinical
manifestations: increased ventilatory support, increased apnea and bradycardia, hyperglycemia, hypotension, acidosis, leukopenia, leukocytosis, or
thrombocytopenia.9
For all infants with fungal sepsis, blood, urine,
cerebrospinal fluid, and endotracheal aspirate cultures were obtained. If the cultures for any of those
sites yielded positive results, then repeat cultures
were performed every 1 to 2 days until the cultures
yielded negative results. In addition, all infants with
fungal sepsis underwent fundal examinations performed by a pediatric ophthalmologist, as well as
renal ultrasonographic and echocardiographic evaluations. Infants were treated with antifungal drugs
for a minimum of 7 days after the first persistent
negative culture.
The following data were collected to assess the risk
factors for developing systemic fungal infections:
number of ventilator days, number of central line
days, postnatal corticosteroid use, number of transfusions, amount of intralipid administered, and use
of antibiotics before the diagnosis of fungal infection.
The following data regarding fungal sepsis were recorded: age of infant at time of diagnosis, Candida
species, infection site, number of positive cultures,
and time to achieve negative cultures. During the
study period, our protocol was to initiate amphoB
therapy with a test dose of 0.1 mg/kg. If the patient
tolerated the test dose, then the amphoB dose was
gradually increased by 0.1 mg/kg per day to a maximal dose of 0.5 to 1 mg/kg per day for the duration
of treatment. The length of amphoB therapy, the time
to reach 0.5 mg/kg per day, the dose of amphoB
used until renal compromised occurred, and the total
dose were recorded. We also examined the use of
nephrotoxic drugs (gentamicin, tobramycin, vancomycin, and indomethacin) before and during amphoB therapy.
The effects of fluid and electrolyte management on
amphoB-induced nephrotoxicity were examined by
collecting data on serum creatinine, sodium, and
potassium concentrations. Daily fluid intake and
urine output, as well as sodium and potassium supplementation, were also recorded. Fluid and electrolyte data were collected for 4 days before the initiation of amphoB therapy. These data were used as the
baseline values for the study infants. Serum electrolyte and creatinine concentrations for evaluation of
potential nephrotoxicity were obtained at the initiation of therapy, every other day for the first 2 weeks,
and twice weekly thereafter. Fluid and electrolyte
management was at the discretion of the attending
physician.
The patients were then divided into 2 groups, depending on the presence of renal compromise, ie, the
renal compromise group (RCG) and the no–renalcompromise group (NCG). Renal compromise was
defined as an increase in serum creatinine levels of
⬎1 mg/dL or ⬎50%, oliguria of ⬍1 mL/kg per hour,
or a decrease in urine output of 50%. Hyponatremia
was diagnosed when the serum sodium concentration was ⬍130 mEq/dL; hypokalemia was diagnosed when the serum potassium concentration was
⬍3 mEq/dL.
Fluid and electrolyte data were analyzed for 3 time
periods, ie, 4 days before amphoB therapy, 4 days
after the initiation of amphoB therapy, and days 5 to
10 after the initiation of amphoB therapy. These periods were selected on the basis of the development
of renal compromise in the RCG by a mean of 4 days
and its resolution by a mean of 9 days after the
initiation of amphoB therapy.
The demographic and clinical data for the 2 groups
were examined and reported as mean ⫾ SD. The
continuous data with normal distribution were compared by using Student’s t test. The Mann-Whitney
rank sum test was used if the normality test failed.
The ordinal data were compared by using Fisher’s
exact test. Significance was accepted at P ⬍ .05.
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RESULTS
A total of 573 infants with birth weights of ⱕ1250
g were admitted during the study period. Candida
species were isolated from blood, urine, or tracheal
aspirates for 26 patients. All cerebrospinal fluid cultures yielded negative results. One patient was
treated with liposomal amphoB and was excluded.
The remaining 25 infants were treated with conventional amphoB and were included in the study. None
of those infants exhibited congenital anomalies.
Two infants in the RCG expired. One expired on
day 7 of amphoB treatment, as a result of overwhelming sepsis and acute renal failure. The death of
the second infant occurred after amphoB therapy
had been completed and was unrelated to fungal
infection. The data for both infants were included.
The demographic data for both groups are presented in Table 1. The characteristics of all infants in
the study were appropriate for gestational age. There
was no significant difference in gestational age, birth
weight, gender, or postnatal age at the time of fungal
sepsis diagnosis.
There was no significant difference in the clinical
presentation of the study infants at the time of fungal
sepsis diagnosis, as summarized in Table 1. None of
the patients exhibited necrotizing enterocolitis near
the time of diagnosis of fungal sepsis, and the incidences of thrush and diaper rash were not significantly different between the 2 groups. There was no
statistically significant difference between the 2
groups with respect to the risk factors for developing
systemic fungal sepsis, including the number of ventilator days, the number of central line days, postnatal corticosteroid use, the number of transfusions,
and the amount of intralipid administered before
amphoB therapy, as summarized in Table 2. There
was no difference in the concomitant use of amphoB
and antibiotics between the 2 groups. The interval
from the last administration of antibiotics to the diagnosis of fungal sepsis tended to be shorter in the
RCG. None of the study infants received indomethacin within 7 days before amphoB therapy.
Candida albicans was the most common organism
in both groups (10 of 11 cases vs 7 of 14 cases, P ⫽
.08). Other fungal species included Candida parapsilosis, Candida tropicalis, Candida lambica, Malassezia, and
1 unidentified Candida species. Table 3 summarizes
the fungal infection sites. There was no significant
difference between the 2 groups in the numbers of
infants for whom fungus was isolated from multiple
sites (8 of 11 infants vs 4 of 14 infants, P ⫽ not
significant). There was also no difference between
the 2 groups in the numbers of renal fungal infections (6 of 11 infants vs 7 of 14 infants, P ⫽ not
significant). For 1 patient in each group, fungal balls
were identified with renal ultrasonography. One patient in the RCG exhibited both renal and ophthalmic
evidence of fungus. None of the patients demonstrated cardiac vegetation. There was no significant
difference between the groups in the mean postnatal
age at the time of fungal sepsis diagnosis (15 vs 16
days, P ⫽ not significant), the mean length of therapy
(15 vs 18 days, P ⫽ not significant), the mean cumulative amphoB dose at the time of renal compromise
(2 vs 2.8 mg/kg, P ⫽ not significant), or the mean
total dose of amphoB (14.5 vs 17 mg/kg, P ⫽ not
significant).
The dose and frequency of amphoB treatment
were not changed for any of the infants with amphoB-induced nephrotoxicity. There was no difference in the incidences of renal dysfunction with elevated serum creatinine levels of ⬎1 mg/dL before
the initiation of amphoB treatment between the
groups (4 of 11 infants vs 3 of 14 infants, P ⫽ not
significant). The serum creatinine concentrations
normalized for 2 of the 4 RCG patients before the
initiation of amphoB treatment. However, after the
initiation of amphoB treatment, serum creatinine levels increased by ⬎50% for all 4 patients. The renal
dysfunction in the 3 NCG infants resolved before the
initiation of amphoB therapy. Mean daily serum creatinine levels tended to be higher in the RCG than in
the NCG, and the difference achieved statistical significance between days 4 and 6 of amphoB therapy
(Fig 1). The increase in serum creatinine levels in the
RCG occurred at 3.9 ⫾ 2 days and was preceded by
a decrease in urine output at 3.4 ⫾ 2 days after the
initiation of amphoB therapy. Increases in serum
TABLE 1.
Demographic Data and Clinical Characteristics of Study Infants at the Time of Fungal
Sepsis Diagnosis
Gestation age, wk
Median (range), wk
Birth weight, g
Median (range), g
Gender (male/female), no.
Survival, no.
Increase ventilatory support, no.
Increased apnea and bradycardia, no.
Hypotension, no.
Metabolic acidosis, no.
Hyperglycemia, no.
Thrombocytopenia, no.
Leukocytosis, no.
Leukopenia, no.
Diaper rash/thrush, no.
RCG (n ⫽ 11)
NCG (n ⫽ 14)
P Value
25 ⫾ 1.8
25 (23–28)
740 ⫾ 211
665 (716–1250)
9/5
9/11
6
2
3
3
4
7
7
3
9
25.3 ⫾ 1.7
25 (23–29)
729 ⫾ 150
702 (535–1035)
5/6
14/14
8
4
5
2
6
7
9
2
10
.6
.88
.4
1.0
1
.7
1
.6
1
.6
.1
.6
.7
Values represent mean ⫾ SD or number of cases. The 2 groups were compared with Student’s t test
or the Mann-Whitney rank sum test. Ordinal data were compared with Fisher’s exact test.
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TABLE 2.
Treatment Data for Study Infants
Age at fungal sepsis diagnosis, d
Median (range), d
No. of positive fungal cultures*
Median (range)
Time until initiation of amphoB therapy, d†
Median (range), d
Time to negative fungal culture, d‡
Median (range), d
Length of therapy after negative culture, d
Median (range), d
Total length of therapy, d
Median (range) (d)
AmphoB dose at renal compromise, mg/kg§
Median (range), mg/kg
Total cumulative amphoB dose, mg/kg
Median (range), mg/kg
Ventilation days
Median (range)
Central line days
Median (range)
Lipids before diagnosis, g/kg
Median (range), g/kg
No. of blood transfusions
Median (range)
Postnatal steroid days
Median (range)
Concomitant antibiotics
Concomitant nephrotoxic drugs
Days since last dose of antibiotic
Median (range)
RCG
(n ⫽ 11)
NCG
(n ⫽ 14)
P Value
15 ⫾ 11
10 (1–35)
5⫾3
5 (1–12)
4.5 ⫾ 4.4
3 (0–16)
10.8 ⫾ 9
7 (2–33)
11.2 ⫾ 4.6
11 (7–21)
17 ⫾ 10
14 (7–41)
2 ⫾ 1.3
2.1 (0.6–5.5)
14.5 ⫾ 10.1
10.3 (3.6–33.5)
15 ⫾ 11
10 (1–35)
14.3 ⫾ 12
9 (1–13)
16.1 ⫾ 17.5
6.8 (0–55.2)
10.9 ⫾ 6.2
13 (0–19)
0.9 ⫾ 2.2
0 (0–7)
9/11
7/11
2.7 ⫾ 2.3
3 (0–7)
16 ⫾ 7
16.5 (1–29)
4⫾3
3.5 (1–10)
4.1 ⫾ 3.8
2 (0–11)
7.8 ⫾ 5
8 (3–16)
13.7 ⫾ 6.4
11 (7–25)
19 ⫾ 9
16 (8–30)
2.8 ⫾ 1.7
2.5 (0.2–5.5)
17 ⫾ 11
15.4 (2.75–38)
16 ⫾ 8
16.5 (0–29)
13.4 ⫾ 6.2
13 (7–30)
23 ⫾ 15.3
25.4 (1.8–52)
8.9 ⫾ 6.7
8.5 (1–23)
2.7 ⫾ 3.9
0 (0–10)
10/14
9/14
5.9 ⫾ 5.6
4 (0–19)
.8
.32
.85
.31
.29
.58
.23
.6
.83
.81
.31
.44
.35
1.0
1.0
.09
Values represent mean ⫾ SD. The 2 groups were compared with Student’s t test or the Mann-Whitney rank sum test. Ordinal data were
compared with Fisher’s exact test. P ⬍ .05 indicates significance.
* This represents the total number of positive cultures. Some of these could have been obtained on the same day or different days or from
different sites.
† This represents the time from obtaining the culture to the initiation of amphoB therapy. Some positive cultures were thought to be
contaminated and amphoB treatment was started after repeated cultures became positive.
‡ This represents the time from the drawing of the first positive culture to the first persistent negative culture.
§ This represents the cumulative amphoB dose at the time of renal compromise. Each infant in the RCG was matched by 1 infant in the
NCG.
TABLE 3.
Fungal Infection Sites
No. of Cases
Blood
Urine
Tracheal aspirate
Blood/urine
Blood/tracheal aspirate
Urine/tracheal aspirate
Eyes, blood, and urine
RCG
(n ⫽ 11)
NCG
(n ⫽ 14)
1
1
1
3
3
1
1
4
3
3
2
0
2
0
creatinine concentrations of ⬎50% occurred for 8 of
11 infants, and decreases in urine output of ⬎50%
occurred for 9 of 11 infants. Renal compromise lasted
for a period of 5.5 ⫾ 4.7 days and resolved on day 8.8
⫾ 5.4 of amphoB therapy.
Serum sodium concentrations and daily sodium
supplementation are summarized in Fig 2. In the 4
days before the initiation of amphoB treatment, none
of the patients in either group demonstrated hyponatremia. RCG infants exhibited a significantly
higher incidence of hyponatremia, compared with
NCG infants (7 of 11 infants vs 0 of 14 infants, P ⬍
.04), during the first 10 days of treatment. Hyponatremia was not associated with excessive weight gain
(Fig 3). The mean daily sodium intake in the 4 days
before amphoB therapy was statistically significantly
lower in the RCG than in the NCG (2.6 –2.9 mEq/kg
per day vs 4.2– 4.7 mEq/kg per day, P ⬍ .005) (Fig 2).
In addition, the mean daily sodium intake during the
first 4 days of treatment was significantly lower in
the RCG (2.7–3.1 mEq/kg per day vs 4.5–5.6 mEq/kg
per day, P ⬍ .04). During the first 4 days of amphoB
therapy, the mean daily sodium intake was ⬍3
mEq/kg per day for 6 of 11 infants in the RCG and
no infants in the NCG (P ⬍ .001). None of the infants
in the RCG and 9 of 14 infants in the NCG (P ⬍ .001)
demonstrated a mean daily sodium intake of ⬎4
mEq/kg per day (Table 4). The difference in the
mean daily sodium intake values between the
groups was not statistically significant between day 5
and day 10 of amphoB therapy (3.8 – 4.6 mEq/kg per
day vs 4.3–5.6 mEq/kg per day, P ⫽ not significant).
Even when we examined the mean daily sodium
intake before the development of renal compromise,
the RCG infants exhibited a statistically significantly
lower sodium intake, compared with the NCG infants (1.1–3.9 mEq/kg per day vs 3–10.3 mEq/kg per
day, P ⫽ .003) (Table 5). We also evaluated the mean
daily sodium intake for each individual infant in the
RCG and found that those infants demonstrated sta-
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Fig 1. Mean serum creatinine concentrations during the study period.
Fig 2. Serum sodium concentrations and daily mean sodium intake 4 days before and 10 days after the initiation of amphoB therapy.
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Fig 3. Fluid intake, urine output, and daily weight changes for 4 days before amphoB therapy and during the study period.
tistically significantly lower mean daily sodium intakes before the development of renal compromise,
compared with those after renal compromise (1.1–3.9
mEq/kg per day vs 3.3– 6.4 mEq/kg per day, P ⫽
.006) (Table 5).
RCG infants tended to have lower mean daily
potassium intakes in the 4 days before the initiation
of amphoB therapy (1.8 –2.2 mEq/kg per day vs 2.1–
2.6 mEq/kg per day, P ⫽ not significant) and in the
first 4 days of amphoB therapy (1.6 –1.9 mEq/kg per
day vs 2.2–2.6 mEq/kg per day, P ⫽ not significant)
(Fig 4). In the subsequent days of treatment, the 2
groups did not differ with respect to mean daily
potassium intakes. The incidences of hypokalemia
were not significantly different between the groups
(2 of 11 infants vs 0 of 14 infants, P ⫽ not significant).
There was no significant difference in the mean daily
potassium intakes for each individual infant in the
RCG before and after renal compromise (Table 5).
Although the mean daily fluid intake tended to be
lower in the 4 days before the initiation of amphoB
therapy, there was no statistically significant difference between the groups (Fig 3). Furthermore, there
was no statistically significant difference between the
2 groups in the mean daily urine output before the
development of renal compromise (3.4 ⫾ 1.5 mL/kg
per day vs 3.4 ⫾ 0.9 mL/kg per day, P ⫽ not significant) or in the mean daily weight gain during the
study period (Fig 3).
DISCUSSION
ELBW infants are at high risk of developing systemic fungal infections. Host factors such as immaturity of the immune system and prolonged use of
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TABLE 4.
Mean Daily Sodium Intake
No. of Infants
Before AmphoB
⬍3 mEq/kg per d
3–4 mEq/kg per d
⬎4 mEq/kg per d
First 4 d of AmphoB
Days 5–10 of AmphoB
RCG
NCG
P Value
RCG
NCG
P Value
RCG
NCG
P Value
5
6
0
0
6
8
.009
NS
.003
6
5
0
0
5
9
.003
NS
.001
3
2
6
0
6
8
.072
NS
NS
Summary of the numbers of infants in each group who had different sodium intakes before and during amphoB therapy. Data were
compared with Fisher’s exact test. NS indicates not significant.
TABLE 5.
Electrolyte Intake During AmphoB Therapy (Before and After Development of Renal Compromise)
Before RC
Sodium intake, mEq/kg per d
Median (range)
Potassium intake, mEq/kg per d
Median (range)
After Development of RC
RCG
NCG
P Value
RCG
NCG
P Value
2.7 ⫾ 0.9
2.9 (1.1–3.9)
1.5 ⫾ 0.6
1.5 (0–2.1)
4.7 ⫾ 1.9
4.3 (3–10.3)
2.4 ⫾ 0.5
2.4 (1.6–3.2)
.003*
4.4 ⫾ 1.2†
4 (3.3–6.4)
1.5 ⫾ 0.3
1.5 (1–2)
4.9 ⫾ 2.8
4.3 (3–12.8)
2.7 ⫾ 0.9
2.7 (1.5–4)
NS
NS
NS
Numbers represent mean ⫾ SD. These data summarize the sodium and potassium intakes for the study infants before and after the
development of renal compromise (RC). Each infant in the RCG was matched by 1 infant in the NCG. NS indicates not significant.
* P ⫽ .003 vs RCG (before renal compromise).
† P ⫽ .006 vs RCG (before renal compromise).
antibiotics make such infants more vulnerable.11 Systemic fungal infections among ELBW infants have
become a problem of increasing magnitude. Our incidence of 4.5% is within the range reported in the
literature.8,9,11 AmphoB remains the drug of choice
for treating systemic candidiasis.12 Concomitant antibiotic and nephrotoxic drug use or previous antibiotic treatment did not influence the incidence of amphoB nephrotoxicity in our study. Other risk factors,
such as the number of central line catheter days, the
number of ventilation days, the number of transfusions, postnatal corticosteroid use, and intralipid use
did not seem to influence the incidence of amphoB
nephrotoxicity in this study.
AmphoB belongs to the class of polyene antibiotics, which are characterized by lipophilic and hydrophilic regions. Free amphoB acts by binding to sterols in cell membranes, especially ergosterol in
fungal membrane and to a lesser degree cholesterol
in mammalian cells. Because renal tubular cells are
high in cholesterol, nephrotoxicity is an undesirable
side effect of amphoB therapy.24
Two strategies have been demonstrated to ameliorate renal toxicity, ie, incorporation into a liposomal
amphotericin system25–30 and salt loading before amphoB administration.14–21,24,31 Although some clinical trials have demonstrated decreased amphoB-induced nephrotoxicity with the use of liposomal
amphoB, other controlled clinical trials have failed to
demonstrate improved outcomes or decreased mortality rates, compared with conventional amphoB.32–35 Furthermore, liposomal preparations are
more costly.
Salt loading before amphoB administration can
reduce nephrotoxicity effectively, as demonstrated in
animal and human adult studies, and is inexpensive.14–21,24,31 The exact mechanism by which sodium
reduces the incidence and severity of amphoB-induced nephrotoxicity has not been clearly delineated. The 2 nonexclusive postulated mechanisms of
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nephrotoxicity suggested in the literature include
changes in membrane permeability and drug-induced preglomerular vasoconstriction.14 Animal
studies have suggested that enhancement of tubuloglomerular feedback is a mechanism for amphoBinduced nephrotoxicity. It was demonstrated that
tubuloglomerular feedback could be blocked by salt
loading.36 Sawaya et al37 demonstrated that systemic
and afferent arteriolar vasoconstriction was a second
mechanism of amphoB-induced nephrotoxicity in a
single-nephron model.
Reports on human adults have included mainly
case reports and retrospective studies. Llanos et al20
reported the only prospective, double-blind, placebo-controlled trial. They treated 20 adult male patients with amphoB (50 mg per dose) 3 times per
week for 10 weeks. In that study, 10 patients received
1 L of 0.9% saline solution, whereas the other 10
patients received 1 L of 5% dextrose solution. The
serum creatinine levels increased and the creatinine
clearance values decreased in the dextrose-treated
group; the parameters were not affected in the salinetreated group.20
Most of the published studies investigated the effect of sodium loading in decreasing amphoB-induced nephrotoxicity, whereas our study examined
the effect of total sodium intake in ameliorating amphoB-induced nephrotoxicity. Studies of human
adults have used 85 to 600 mEq/day of sodium
before amphoB administration.15,18,20,21 The exact
amount of sodium required to prevent nephrotoxicity among neonates is not known. The results of our
study indicated that normal sodium intakes of 3 to 4
mEq/kg per day had some beneficial effects in preventing renal compromise, whereas sodium intakes
of ⬎4 mEq/kg per day prevented renal compromise.
In the 4 days before and 4 days after the initiation of
amphoB treatment, none of the infants in the RCG
received ⬎4 mEq/kg per day, compared with 8 infants in the NCG. There is no clear explanation for
SODIUM INTAKE AND amphoB NEPHROTOXICITY AMONG ELBW INFANTS
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Fig 4. Serum potassium concentrations and daily mean potassium intake 4 days before and 10 days after the initiation of amphoB
therapy.
the discrepancy of the sodium intakes between the 2
groups, because electrolyte management was at the
discretion of the attending neonatologist. Interestingly, the increase in sodium intake in the RCG was
associated with amelioration of renal compromise
within 3 to 16 days of higher sodium intake. Heideman et al38 described this phenomenon for 5 adults
who developed amphoB-induced nephrotoxicity
early in the course of treatment. All patients were
sodium-depleted because of underlying illnesses.
Within 4 to 12 days after liberalization of dietary
sodium intake (150 –300 mEq/day) and discontinuation of diuretic therapy, renal function improved for
all patients.38
Other electrolytes, such as potassium, have been
implicated in nephrotoxicity.22,39 A potassium-deficient diet was shown to enhance nephrotoxicity after
gentamicin administration in an animal model.39 Potassium loading decreased functional and histologic
evidence of gentamicin-induced nephrotoxicity.39
Bernado et al22 reported that potassium depletion
potentiated amphoB-induced toxicity to the renal tubules in a rat model. The study showed that potassium depletion did enhance urinary sodium excretion and potentiated the development of renal
tubular toxicity. Our data showed that potassium
intake tended to be lower in the RCG before the
initiation of amphoB treatment and was not significantly lower in the first 4 days of amphoB therapy. In
addition, in an evaluation of RCG infants, there was
no difference in the mean daily potassium intakes
before and after renal compromise. Among adults,
salt loading resulted in increased urinary potassium
loss. In our study, higher sodium intakes were not
associated with decreases in serum potassium levels
(Figs 2 and 4). It is unclear whether the modest
increase in sodium intake was insufficient to trigger
a change in serum potassium levels or whether the
finding was attributable to differences in tubular
function among ELBW infants. However, the effects
of higher sodium intake on potassium homeostasis
were difficult to evaluate, because urine electrolyte
levels were not measured for these infants.
Clinical data for adults and animals have indicated
that adequate hydration is important for the prevention of amphoB-induced nephrotoxicity.23 We found
that fluid intakes before the initiation of amphoB
therapy tended to be lower in the RCG but intakes
became comparable during the first 4 days of amphoB therapy. Furthermore, urine outputs and mean
daily weight gains were comparable in the 2 groups.
Therefore, it is unlikely that fluid depletion played a
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e615
role in predisposing these ELBW infants to renal
compromise.
CONCLUSIONS
Our data confirm the findings of animal and human adult studies, indicating that higher sodium
intakes among ELBW infants were associated with
reductions in amphoB-induced nephrotoxicity. In
times of limited resources, cost-effective treatment
options are pivotal in improving the outcomes of
ELBW infants. We propose that conventional amphoB combined with adequate hydration and sodium intakes of ⬎4 mEq/kg per day may provide
effective protection against amphoB-induced nephrotoxicity among ELBW infants. A prospective study
to evaluate the effect of sodium loading on the prevention of amphoB-induced nephrotoxicity among
ELBW infants with proven fungal sepsis is warranted.
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Effects of Fluid and Electrolyte Management on Amphotericin B-Induced
Nephrotoxicity Among Extremely Low Birth Weight Infants
Bernd Holler, Said A. Omar, Maged D. Farid and Maria Jevitz Patterson
Pediatrics 2004;113;e608
DOI: 10.1542/peds.113.6.e608
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2004 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from by guest on August 1, 2017
Effects of Fluid and Electrolyte Management on Amphotericin B-Induced
Nephrotoxicity Among Extremely Low Birth Weight Infants
Bernd Holler, Said A. Omar, Maged D. Farid and Maria Jevitz Patterson
Pediatrics 2004;113;e608
DOI: 10.1542/peds.113.6.e608
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/113/6/e608.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2004 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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