ARTICLE

Continuous Renal Replacement Therapy in the

Initial Management of Neonatal Hyperammonemia
Due to Urea Cycle Defects
Kevin V. Lemley, MD, PhD,* Susan R. Hintz, MD,† and Gregory M. Enns, MB, ChB‡
pathic state of the patient. The
OBJECTIVES patient’s coagulopathy necessitated
After completing this article, readers should be able to: multiple infusions of cryoprecipitate
and fresh frozen plasma over the
1. Describe the metabolic acidosis that may be seen in urea cycle defects. first few hospital days. The dialysate
2. Delineate the most important factor in determining neurologic out- flow rate was increased over the
come in urea cycle defects. following 4 days to a maximum of
3. Explain the factors that affect the blood ammonia concentration in 700 mL/h. CVVHD was discontin-
continuous renal replacement therapy (CRRT).
ued on the seventh hospital day.
4. Delineate the most difficult issue in pursuing CRRT in neonates.
5. Describe the morbidities associated with CRRT. Hemodialysis rapidly, but transiently
decreased the blood ammonia level
to less than 200 mcmol/L (280 mcg/
dL). With the initiation of CVVHD,
Case Study 0.06 mmol/L. Results of liver func- the blood ammonia levels stabilized
MP was born at 39 weeks’ esti- tion tests were abnormal, and the in the range of 150 to 200 mcmol/L
mated gestational age by vaginal infant had a prothrombin time of (210 to 280 mcg/dL) (Fig. 1). When
delivery to a 35-year-old gravida 3 35.9 seconds, a partial thromboplas- the blood ammonia level fell to less
para 2 woman who had an uncom- tin time of 54.3 seconds, and a than 200 mcmol/L (280 mcg/dL),
plicated pregnancy. The 3- and fibrinogen concentration of 1.75 g/L the patient began to show increased
6-year-old female siblings of the (175 mg/dL). Genetic and nephrol- activity and responsiveness. On the
patient were healthy. Apgar scores ogy consultations were requested sixth hospital day, her blood ammo-
were 8 at 1 minute and 9 at 5 min- immediately. Additional metabolic nia levels fell abruptly and dramati-
utes. The newborn was discharged studies were obtained, including cally and remained within the nor-
to home after a 2-day stay in the measurement of plasma amino acids; mal range of 9 to 33 mcmol/L
well baby nursery during which time acylcarnitine profile; total, free, and (12.6 to 46.2 mcg/dL), even after
she appeared to be alert and was esterified carnitine levels; plasma CVVHD was discontinued.
breastfeeding appropriately. She pre- free fatty acid levels; and urine The patient’s presentation and
sented to the emergency department organic and orotic acid levels. initial laboratory results suggested a
less than 1 day later after her par- Hemodialysis was initiated after urea cycle defect. Therefore, contin-
ents noted increasing lethargy and placement of an 8F Medcomp dialy- uous intravenous infusions of
very poor feeding at home. She was sis catheter in the right internal jug- sodium benzoate, sodium phenyl-
admitted to the neonatal intensive ular vein. The patient suffered a car-
care unit (NICU). Results of a com- diac arrest immediately after
plete blood count with differential initiating the first session of hemodi- ABBREVIATIONS
count and C-reactive protein evalua- alysis, probably due to hypocalcemia ACT: activated clotting time
tion were unremarkable, but the induced by the priming blood. BFR: blood flow rate
patient progressed to worsening leth- A subsequent hemodialysis session CAVH: continuous arteriovenous
argy, respiratory failure, and abdom- that day was successful using an hemofiltration
inal distension requiring intubation HG100 filter and a blood flow rate CAVHD: continuous arteriovenous
within hours of admission. The ante- (BFR) of 50 to 75 mL/min. After a hemodiafiltration
rior fontanelle was soft on admis- second uneventful hemodialysis ses- CRRT: continuous renal
sion physical examination. Further replacement therapy
sion on the second hospital day, CVVH: continuous venovenous
testing revealed a base deficit of 6.1 continuous venovenous hemodiafil- hemofiltration
on arterial blood gas, serum ammo- tration (CVVHD) was started using CVVHD: continuous venovenous
nia level of 810 mcmol/L a HF400 filter. Filter replacement hemodiafiltration
(1,134 mcg/dL), serum lactate level fluid was infused to allow a filtra- DL: double lumen
of 5.6 mmol/L (5.6 mEq/L), and tion rate of 150 mL/h without net ET: exchange transfusion
serum pyruvate level of fluid removal, and the initial dialy- FRF: filter replacement fluid
sate flow rate was 200 mL/h. Hemo- HD: hemodialysis
*Division of Nephrology. dialysis and CVVHD were inter- OTC: ornithine transcarbamylase
†
Division of Neonatology. rrupted almost daily because of PD: peritoneal dialysis
‡
Division of Genetics, Department of
clotting of the circuit, despite acti- SL: single lumen
Pediatrics, Stanford University School of vated clotting times (ACTs) within UF: ultrafiltration
Medicine, Stanford, CA. the target range and the coagulo-

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 NEPHROLOGY
Continuous Renal Replacement Therapy

acetate, and arginine hydrochloride

were initiated on the day of admis-
sion after correction of the acidosis.
The rate of the arginine infusion
was increased on the fourth hospital
day. Intravenous carnitine therapy
also was started. Evaluation of urine
organic acids revealed elevated
orotic acid and hydroxy-fatty acid
levels. The acylcarnitine profile doc-
umented markedly elevated long-
chain species, including 3-hydroxy
species, which were considered to
be due to liver dysfunction. Exami-
nation of plasma amino acids
showed elevated citrulline concen-
trations, suggestive of citrullinemia.
The diagnosis of citrullinemia was
confirmed later by skin fibroblast
assay of argininosuccinic acid syn-
thase activity.
The patient received hyperalimen-
FIGURE 1. Graph of blood ammonia concentrations as a function of time in patient
MP. Hemodialysis sessions are marked with arrows. Note that blood ammonia levels
tation, including 0.5 g/kg per day of
began to fall before the first hemodialysis session. CVVHD is shown by a horizontal amino acids, starting on the third
line (breaks in the line indicate interruption of CVVHD). Arginine, benzoate, and hospital day and increasing to
phenylacetate infusions are indicated by the horizontal line at the top of the chart. 1.0 g/kg per day by the next day.
The rate of arginine infusion was increased at about hour 87. She was extubated to room air
9 days after admission. There was
initial concern about possible gastro-
esophageal reflux, but a pH probe
study was negative. Oral feedings
were not started until hospital day 8
due to the question of reflux and the
critical condition of the patient.
A low-protein formula and human
milk mixture was advanced slowly
to supply 2 g/kg protein per day,
and serial plasma ammonia and
amino acid levels were followed
closely. The patient was changed to
oral medications of arginine hydro-
chloride and phenylbutyrate after her
feedings were advanced success-
fully. She had no seizure activity
during her hospitalization, although
electroencephalography performed
early in her course was abnormal for
bursts of sharp wave activity consis-
tent with the hyperammonemia at
the time of the study. The hepatol-
ogy/gastroenterology service was
consulted because of mildly but con-
sistently abnormal liver function
tests and the possible need for liver
transplantation in the future. She
was discharged to home after
FIGURE 2. Algorithm for the evaluation of the probable etiology in neonatal 37 days in the NICU with normal
hyperammonemia. OTC⫽ornithine transcarbamylase, CPS⫽carbamyl phosphate findings on neurologic examination
synthetase, ASA ⫽ argininosuccinic acid, AL ⫽ argininosuccinase, AS ⫽ and close follow-up with multiple
argininosuccinic acid synthetase medical services.

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Introduction
Hyperammonemia is caused by spe-
cific defects in the urea cycle or
related pathways that result in
impaired disposal of excess amino
nitrogen produced by metabolism
(Fig. 2). The condition is an unusual
but important disorder in the neo-
nate, with a frequency of about 1 in
30,000 live births. Most of the 30%
to 50% of infants who present with
hyperammonemic coma due to an
inborn error of metabolism and who
survive the neonatal period will
develop significant neurologic defi-
cits (seizures, cortical atrophy, spas-
tic quadriparesis). Because the inher-
itance of most inborn disorders of
metabolism leading to hyperam-
monemia is autosomal recessive, a
prior history of unexplained perina-
tal death in siblings may be signifi-
cant. Important exceptions include
ornithine transcarbamylase (OTC)
deficiency, which is inherited as an
X-linked trait (with about 20% of
female heterozygotes being symp-
tomatic), and the hyperinsulinism-
hyperammonemia syndrome, an
autosomal dominant condition
caused by glutamate dehydrogenase
gene mutations.
The presenting symptoms of
hyperammonemia due to urea cycle
defects such as OTC deficiency are
stereotypical but nonspecific. Leth-
argy, vomiting, grunting, tachypnea,
and hypothermia often are inter-
preted initially as representing sep-
sis. A bulging fontanelle reflects
cerebral edema. Untreated, the con-
dition progresses to seizures, coma,
and eventually death. Although most
cases of neonatal hyperammonemia
are due to defects in enzymes of the
urea cycle, a wide variety of other
metabolic defects can lead to sec-
ondary hyperammonemia (eg,
organic acidurias, fatty acid oxida-
tion defects, dibasic amino acid
transport defects, primary lactic aci-
dosis, fulminant liver failure). Urea
cycle defects are suggested by a
presentation at more than 24 hours
of age in the absence of acidosis or
ketosis. If acidosis is present in a
urea cycle defect, it usually repre-
sents lactic acidosis due to poor
peripheral perfusion in a critically ill
infant.
Transient hyperammonemia of
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NEPHROLOGY
Continuous Renal Replacement Therapy
the newborn is a condition of unde-
termined etiology that typically
occurs earlier than the “genetic”
syndromes (usually within the first
48 h) in preterm neonates of low
birthweight. Although it can lead to
plasma ammonia concentrations
greater than 2,000 mcmol/L
(2,801 mcg/dL) and significant mor-
bidity or death, some studies have
suggested a good neurologic out-
come in patients who survive the
neonatal period, with little risk of
recurrent hyperammonemia.
Normal values of blood ammonia
nitrogen in neonates in our institu-
tion range from 7 to 33 mcmol/L
(9.7 to 46.2 mcg/dL), although lev-
els between 50 and 90 mcmol/L
(70 and 126 mcg/dL) appear to be
relatively common in the first
2 weeks of life in otherwise normal
neonates.
Management
The initial management of neonatal
hyperammonemia consists of mea-
sures to decrease protein catabolism
(provision of adequate calories and
elimination of exogenous protein
intake), continuous intravenous infu-
sion of the nitrogen “scavengers”
sodium benzoate and sodium
phenylacetate, and administration of
arginine hydrochloride to “prime”
the urea cycle. In very sick neonates
who have anuria or severely reduced
renal function, the utility of scaven-
gers such as sodium benzoate, which
depend on renal elimination, is
limited.
If plasma ammonia concentra-
tions are dangerously elevated (eg,
⬎400 to 500 mcmol/L [560 to
700 mcg/dL]) or accompanied by
coma, they must be reduced imme-
diately to prevent permanent neuro-
logic damage. This usually is
accomplished by dialysis, although
exchange transfusion (ET) also has
been used when immediate access to
dialysis was not possible. Blood
ammonia concentrations greater than
approximately three times the upper
limit of normal are cytotoxic. It is
the duration of hyperammonemic
coma, however, rather than the peak
blood ammonia level that determines
neurologic outcome. Enhanced
removal of ammonia by dialysis
often is a temporizing measure that
is pursued until a definite diagnosis
can be made or until metabolic
interventions can take effect.
Peritoneal dialysis (PD) also can
enhance ammonia clearance. Very
rapid equilibration of blood ammo-
nia with the dialysate has led to the
use of very short exchange cycles of
approximately every 30 to 60 min-
utes. Although each ET removes
more ammonia than the single cycle
of PD, only a limited number of
ETs can be undertaken in the course
of a day. Accordingly, PD can
remove more total ammonia than ET
(15 to 20 mg/d for PD compared
with 1.2 to 3.6 mg per double-
volume ET). Hemodialysis (HD) is
very effective for rapid lowering of
blood ammonia levels, although the
risks of morbidity and mortality in
sick neonates are significant, as
illustrated by the patient in the case
study.
A number of studies have com-
pared the relative efficiencies of
ammonia removal by ET, PD, HD
and continuous arteriovenous hemo-
(dia)filtration (CAVH, CAVHD). In
a male neonate who had OTC defi-
ciency, Donn and colleagues docu-
mented an ammonia removal rate of
12.6 mg/h with HD, 3.4 mg/h with
ET, and 1.4 mg/h with PD. Siegel
and Brown reported a rate of
approximately 2 mg/h by rapid-cycle
PD in a small neonate who had
OTC deficiency. Blood ammonia
levels were not lowered substan-
tially, however, probably because of
a very high rate of ammonia produc-
tion. Pérez Rodrı́guez and coworkers
found that double-volume ET could
lower blood ammonia levels by
approximately 214 mcmol/L
(300 mcg/dL) per hour compared
with approximately 21 mcmol/L
(30 mcg/dL) per hour with PD and
about 93 mcmol/L (130 mcg/dL) per
hour with HD. The rates of reduc-
tion varied and were proportional to
the initial blood ammonia concentra-
tion. Recently, Wong and colleagues
showed that CAVH/D cleared
ammonia at about five times the rate
of PD, similar to the relative rates of
HD and PD.
The apparent effectiveness of any
form of adjunctive ammonia
removal is a function of both its
characteristic clearance and the rate
of ammonia production. Thus, it
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 NEPHROLOGY
Continuous Renal Replacement Therapy
may be difficult to ascribe a specific
quantitative efficacy to any single
component (eg, dialysis, medica-
tions) of the overall management
strategy. For example, in a report of
Rutledge and colleagues, a neonate
who had argininosuccinate syn-
thetase deficiency had a blood
ammonia concentration of
931 mcmol/L (1,304 mcg/dL) sev-
eral hours after the initiation of infu-
sions of sodium benzoate, phenyl-
acetate, and arginine. The level
subsequently fell to 280 mcmol/L
(392 mcg/dL) after 1.5 hours of HD,
but rose to 411 mcmol/L (576 mcg/
dL) about 6 hours later. Even
though a second HD treatment could
not be administered, ammonia levels
fell to 331 mcmol/L (464 mcg/dL)
and after 11 hours of PD, to
50 mcmol/L (70 mcg/dL). This
lower level more likely was due
principally to decreased ammonia
production (due to metabolic stabili-
zation) and benzoate/phenylacetate/
arginine infusions than to removal
of ammonia by PD.
Our Current Protocol
The current immediate management
of hyperammonemic coma in neo-
nates at the Lucile S. Packard Chil-
dren’s Hospital at Stanford involves
several steps (Table). The first step
is to obtain appropriate diagnostic
studies that include measurement of
the blood ammonia level and com-
prehensive chemistries. Central vas-
cular access is established both for
infusion of high-concentration dex-
trose solutions and medications and
for continuous renal replacement
therapy (CRRT). Intravenous infu-
sion of glucose to a goal of
12 mg/kg per minute is designed to
prevent tissue catabolism. If such
high-dose glucose infusion leads to
hyperglycemia (greater than the tar-
get blood glucose range of 8.33 to
11.1 mmol/L [150 to 200 mg/dL]),
an insulin drip (eg, 0.1 U/kg per
hour) may be started. We discon-
tinue exogenous protein intake for
24 to 48 hours and correct hypovo-
lemia, anemia, and acidosis, espe-
cially prior to initiation of arginine
hydrochloride therapy. A urinary
catheter is placed to monitor urine
output.
The goal of mechanical ventila-
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TABLE. Initial
Management of
Hyperammonemia in
Neonates
● Laboratory studies:
comprehensive chemistries,
including anion gap, blood
lactate and pyruvate, arterial
blood gas, quantitative serum
and urine amino acids, routine
urinalysis, urine organic acids
(eg, quantitative urine orotic
acid), carnitine levels, and
acylcarnitine profile
● Central vascular access for
high-concentration dextrose
infusion (possibly for CRRT)
● Protein-free nutritional support
(IV glucose at 12 mg/kg per
minute) to prevent catabolism
● Correction of hypovolemia,
anemia, and acidosis
● Intubation and ventilation with
target PaCO2 of 30 to 35 mm Hg
● Urinary catheter to monitor
urine output
● Sodium benzoate and sodium
phenylacetate (load and
continuous infusions)
● Arginine hydrochloride (load
and continuous infusion)—
check arterial blood gases
before and after loading dose
● Neomycin (⬎2 d of age) and/
or lactulose as needed
tion is to produce a mild respiratory
alkalosis (Paco2 of 30 to 35 mm
Hg), and paralysis may be induced
as needed.
Specific medications are started
immediately only if the hyperam-
monemia is considered likely to be
due to urea cycle defect. These
agents include sodium benzoate and
sodium phenylacetate (each as
250 mg/kg loading doses over 1.5 h
followed by continuous infusions in
25 mL/kg D10W at 250 mg/kg per
day) and arginine hydrochloride
10% (load with 2 mL/kg⫽0.2 g/kg
in D10W over 1.5 h, followed by
2 mL/kg per day by continuous
infusion). The arterial blood gas
should be examined after adminis-
tration of the loading doses because
NeoReviews
acidosis may occur and should be
corrected. Neomycin 50 mg/kg per
day PR every 6 hours (only in neo-
nates ⬎2 d of age for 48 h) or lac-
tulose (2.5 mL NG/PO tid prn) also
may be used for a few days to
decrease intestinal production of
ammonia.
“Nitrogen scavengers” enhance
nonurea excretion of waste nitrogen
from the body. Sodium benzoate
combines with the amino acid gly-
cine (which contains a single nitro-
gen) to produce hippurate, which is
cleared almost completely from the
blood in a single passage through
the kidney (ie, approximately four
times faster than the glomerular fil-
tration rate). Sodium phenylacetate
conjugates to glutamine (with two
nitrogens) and also is cleared effi-
ciently by the kidney.
Continuous Renal
Replacement Therapy
In addition to the previously
described maneuvers, the initial
management in severe cases of
hyperammonemia includes the use
of CRRTs such as continuous veno-
venous hemofiltration (CVVH) or
CVVHD to enhance the removal of
ammonia. For more details about
CRRT, see the accompanying article
in this issue by Yorgin and
colleagues.
CAVH, CVVH, and CVVHD
have several similarities to HD. In
CAVH, the force moving blood
through the extracorporeal circuit is
the patient’s arteriovenous pressure
gradient; in CVVH and CVVHD,
blood is pumped through the circuit
by a peristaltic pump. In all of these
forms of CRRT, fluid crosses the
artificial kidney membrane (hemofil-
ter) under the influence of a hydro-
static pressure gradient. Solutes are
removed from the blood at a rate
equal to their blood concentration
times the fluid filtration rate. The
filtration rate is regulated by adjust-
ing the outflow rate from the filter
by an infusion pump through which
the effluent flows. The addition of
counterflowing dialysate fluid (in
the filter housing holding the bundle
of filter fibers) allows for additional
solute removal by diffusion down a
chemical concentration gradient
(dialysis). Dialysis is much more
Vol. 1 No. 9 September 2000

efficient at removing small solutes
such as ammonia than filtration
alone.
MODALITY
PD generally is considered inade-
quate to remove ammonia in severe
cases of hyperammonemia. Intermit-
tent HD removes ammonia about
5 to 10 times as fast as PD, but it
typically is used only for a few
hours per day, which can lead to a
lower net daily removal rate than
PD (as well as to intermittently high
blood ammonia levels). CVVH/
CAVH provide relatively rapid rates
of removal coupled with the advan-
tage of continuous operation. CAVH
has been used less often than CVVH
in recent years. In our opinion, the
optimal form of therapy for severe
neonatal hyperammonemia is the
initial use of HD to lower blood
ammonia levels rapidly, followed by
CVVH or CVVHD. If we start with
CVVH, counterflow dialysis
(CVVHD) may be added if ammo-
nia clearance is inadequate. Blood
ammonia equilibrates relatively rap-
idly, so the adequacy of ammonia
removal by CVVH/D can be
assessed within a reasonable period
of time.
ACCESS
Probably the most difficult issue in
neonatal CRRT is vascular access.
Because the required vascular cathe-
ters are large, access usually is
obtained via the external or internal
jugular vein, femoral artery/vein, or
umbilical artery/vein. Either one
double-lumen (DL) catheter or two
single-lumen (SL) catheters may be
used. For CVVH, both the “arterial”
catheter (taking blood to the extra-
corporeal circuit) and the “venous”
catheter (returning blood to the
body) are placed in veins. Use of
the relatively large catheters is nec-
essary to permit a sufficiently high
BFR to prevent clotting, but if a
catheter is too large for the vein, it
may cause vascular damage, increas-
ing the risk of later thrombosis, or it
can collapse the vein, halting blood
flow. Medcomp or Cook 7 Fr DL
hemodialysis catheters have been
used in children weighing as little as
2.3 kg. Other possible catheters
include Vas-Cath 6.5 Fr DL, 16 G
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NEPHROLOGY
Continuous Renal Replacement Therapy
Medcomp SL in the femoral or
umbilical vein, and 5 Fr Cook/Med-
comp in the umbilical artery with a
5 or 8.5 Fr catheter in the umbilical
vein. Small catheters, such as umbil-
ical artery catheters, are less likely
to support the BFR necessary for
adequate clearance of blood
ammonia.
In neonates and small infants,
recirculation (drawing already pro-
cessed effluent blood back into the
circuit via the adjacent arterial cath-
eter opening) is a particular prob-
lem. Apparent recirculation rates as
high as 40% to 80% have been
found, even when separate venous
catheters with tips in different parts
of the inferior vena cava and iliac
vein have been used. Excessive
recirculation can be reduced by
transdiaphragmatic placement of
venous catheters (eg, one in the
internal jugular vein and one in the
femoral vein). Soft catheters are
subject to external segment kinking
and require good stabilization. Regu-
lar (nonHD) soft silastic catheters
(eg, Hickman) tend to collapse with
negative pressures and are not suit-
able for CVVH.
THE EXTRACORPOREAL
CIRCUIT
To avoid hemodynamic instability, it
is necessary to use a blood prime if
the extracorporeal circuit volume is
more than 7% to 10% of estimated
blood volume (80 to 85 mL/kg in
neonates). For example, because
neonatal HD blood lines (used for
CVVH) have a volume of 32 mL
and a Minifilter Plus威 hemofilter has
a volume of 15 mL, any infant
weighing less than 5 kg is likely to
need a blood prime for this system.
It is advisable use fresh or washed
blood for large blood primes, espe-
cially in patients who have compro-
mised renal function, to avoid a
large potassium load. In addition,
large blood primes may induce sig-
nificant hypocalcemia, so serum ion-
ized calcium should be measured
before setting up the circuit and
monitored closely afterward.
Clearance of small solutes such
as ammonia is proportional to the
filter surface area (in the setting of
adequate BFR). Two filters often
used in neonates are the Amicon
Minifilter Plus威 (membrane area,
0.08 m2; filter volume, 15 mL) in
small neonates (2.5 kg) and the
Menntech HF400 (membrane area,
0.30 m2; filter volume, 28 mL). The
Minifilter Plus威 may need special
adapters to connect to a standard
HD tubing set. Although smaller
filters may suffice for treatment of
fluid overload in neonates, they may
be inadequate for solute clearance.
BLOOD FLOW RATE
A principle concern in CVVH is
assuring an adequate BFR to avoid
relative stasis and clotting of the
filter. Clearance of ammonia based
on ultrafiltration alone (CVVH) is
independent of BFR in contrast to
clearance in CVVH/D or HD, which
increases with BFR up to a BFR
about two thirds of the dialysate
flow rate. Initial BFRs usually are in
the range of 3 to 5 mL/kg per
minute and increase to 6 to
10 mL/kg per minute as necessary
to maximize ammonia clearance.
ANTICOAGULATION
There is a high risk of intracranial
hemorrhage in preterm (⬍35 wk
estimated gestational age) neonates,
which could be a contraindication to
anticoagulation. Routine anticoagula-
tion also is not necessary among
patients who have a significant
coagulopathy. Some studies have
suggested that regional anticoagula-
tion does not increase circuit life-
times under any circumstances.
Regional anticoagulation (anticoagu-
lation of the circuit only) may be
used in patients at particular risk of
bleeding. We have used citrate-
based regional anticoagulation suc-
cessfully in neonates. Heparin-based
anticoagulation is used most com-
monly in patients who can tolerate
some systemic anticoagulation. No
heparin loading dose is given to
neonates. The rate of infusion of
heparin (10 U/mL) into the post-
pump, prefilter port is adjusted to
give a postfilter circuit ACT of
150 to 200 seconds (usually requir-
ing doses of 5 to 20 U/kg per hour).
The coagulation status of the patient
(ie, the systemic blood) should be
monitored regularly via ACT and
partial thromboplastin time.
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 NEPHROLOGY
Continuous Renal Replacement Therapy
ULTRAFILTRATION AND
DIALYSATE FLOW RATES
In CVVH, clearance of ammonia is
proportional to the ultrafiltration
(UF) rate. A reasonable initial UF
rate for “pure” hemofiltration used
for fluid removal is 1 to 2 mL/kg
per hour. The ammonia clearance
with this low rate of UF is less than
1% of that which can be attained
even with PD and is likely to be
inadequate for removing ammonia in
more severe cases. The ammonia
clearance rate with CVVH may be
considerably enhanced simply by
increasing the rate of UF by a set
amount and compensating for the
increased fluid removal by infusing
the same amount of a physiologic
filter replacement fluid (FRF) into
the circuit “prepump” (so-called
predilution replacement). If
500 mL/h of predilution FRF is
infused and the total UF rate is cor-
respondingly increased to 500 mL/h,
the rate of ammonia removal would
be about twice that which is
achieved with PD and about one
third the rate of removal with HD
without any net fluid removal. At
such high rates of UF in neonates,
the actual UF rate must be verified
periodically by volumetric or weight
assessment of the CVVH effluent. It
may exceed by up to 10% the nomi-
nal pump setting, potentially leading
to unaccounted fluid losses (or
gains) of up to 50 mL/h! In
CVVHD, the small solute clearance
increases with greater dialysate flow
rates as long as BFR is adequate.
Initial countercurrent flow rates are
usually in the range 300 to
500 mL/h.
FILTER REPLACEMENT FLUID
AND DIALYSATE COMPOSITION
Dialysis fluid may be custom-made
by the hospital pharmacy or com-
mercial peritoneal dialysate (eg,
Baxter 1.5% dextrose Dianeal威) may
be used. When dialysate is made in
the hospital pharmacy, it is probably
advisable to check the sodium and
potassium concentrations before use.
FRF and dialysate must not contain
calcium in patients receiving citrate-
based anticoagulation. Instead, a
separate infusion of calcium directly
into the systemic circulation makes
up for CVVH-related losses. Both
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bicarbonate-based and lactate-based
solutions have been used as dialy-
sate and FRF. Use of the latter
depends on the ability of the liver to
metabolize lactate to bicarbonate.
Some centers add calcium to the
bicarbonate-based FRF; others use a
separate 10% calcium gluconate
infusion adjusted to maintain blood
ionized calcium concentrations
greater than 0.5 mmol/L
(1.0 mEq/L) and a calcium-free
FRF.
LABORATORY MONITORING
Frequent laboratory monitoring is
necessary to assess the efficacy of
ammonia removal and to monitor
for effects of CRRT on electrolytes
and acid-base status. Initially, blood
gases are obtained hourly, blood
ammonia is evaluated every 2 hours,
and other chemistries are checked
every 4 hours. The frequency of
monitoring decreases as stable blood
values are acheived.
Complications of CRRT
The use of CRRT for treatment of
neonatal hyperammonemia is very
effective, but very labor-intensive
and requires extensive involvement
of highly trained personnel. It also is
associated with substantial risks for
morbidity. Significant bleeding may
result from systemic anticoagulation
or from the presence of large vascu-
lar catheters. Daily head ultrasonog-
raphy during CRRT is indicated in
many patients to monitor for intra-
ventricular hemorrhage. Clotting of
the filter or vascular catheter may
lead to loss of the circuit. Several
studies have shown an average loss
rate of vascular access or CVVH/D
filter of about one per day.
Electrolyte imbalance is an ever-
present potential complication of
CVVH, including potentially life-
threatening hypocalcemia when initi-
ating CVVH in small infants. Other
electrolyte and acid-base distur-
bances may be due to the specific
medical therapies used (high sodium
load from sodium benzoate and
sodium phenylacetate, acid load
from arginine hydrochloride) or
from errors in the composition of
FRF or dialysate solutions when
NeoReviews
made in the hospital pharmacy with-
out adequate testing.
Excessive cooling of neonates
and small infants is prevented by
close attention to patient temperature
and the use of blood warmers in the
postfilter (venous) circuit.
Hemodynamic instability is prob-
ably the single most common com-
plication. It may be due to excessive
rates of fluid removal or other
mechanisms (metabolic distur-
bances) and may restrict the upper
limit of achievable BFR.
High-flux, aggressive CVVH and
CVVH/D are used in hyperammone-
mia because they efficiently remove
small molecules such as ammonia
from the blood. Other small mole-
cules removed by the processes
include amino acids, water-soluble
vitamins, and carnitine. Removal of
nutrients such as phosphate (the
blood concentrations of which are
measured easily) by CVVH can be
compensated for by providing addi-
tional amounts in hyperalimentation
or supplemental infusions. This is
more difficult to accomplish with
nutrients such as amino acids, carni-
tine, and vitamins, the blood levels
of which typically are not measured
by the routine clinical laboratory.
A recent study in critically ill chil-
dren documented amino acid losses
of about 12 g/d per 1.73 m2 in both
high-flux CVVH and CVVH/D. In
addition to leading to net negative
nitrogen balance, the removal of
significant amounts of amino acids
by CVVH makes it difficult to
determine net protein intake. It is
important to correct all known nutri-
ent deficiencies in these patients.
Phosphate depletion, for example,
may limit the activity of the urea
cycle enzyme carbamyl phosphate
synthetase. Some centers have found
it necessary to provide supplemental
intravenous infusions of amino acids
to neonates who have hyperam-
monemia and are undergoing CRRT.
Adjusting drug doses appropri-
ately for neonates treated with
CRRT can be complicated by the
difficulty in calculating the rate of
removal of any given medication by
CVVH. Most drugs are small mole-
cules that pass through the hemofil-
ter with little or no restriction unless
they are significantly protein-bound.
Although it is possible to estimate
Vol. 1 No. 9 September 2000

drug clearances as the sum of UF
rate and some fraction (probably
⬍80%) of dialysate flow rate plus
endogenous clearance, dosing should
be based on blood levels wherever
feasible.
Intermediate-term
Management
After initial stabilization, hyperali-
mentation that includes intralipid
should be started to provide 100 to
120 kcal/kg per day. To aid in pre-
venting catabolism, amino acids at
0.25 to 0.50 g/kg per day should be
started within 48 hours of admission
and increased as tolerated to approx-
imately 1.0 g/kg per day. Greater
amounts of amino acids may be nec-
essary in the setting of high-flux
CVVH/D. When the patient’s condi-
tion allows it, oral or nasogastric
nutrition should be initiated and
intravenous hyperalimentation
weaned. The level of protein intake
that eventually is tolerated (usually
0.7 to 1.6 g/kg per day) and the
rapidity of the increase in dietary
protein intake must be established
for each individual. It may be bene-
ficial to supply a portion of the
daily protein as essential amino
acids or cognate keto acids to
decrease the amino nitrogen load.
Intravenous sodium benzoate and
phenylacetate are switched to oral
phenylbutyrate as soon as possible.
The decision of when to remove
vascular access for CVVH is diffi-
cult. It may require a week or more
to arrive at a definitive diagnosis.
A patient who has been stabilized
adequately on a medical regimen
may experience a subsequent hyper-
ammonemic crisis if sepsis or
another condition compromises
nutrition. The decision to remove
vascular access should be made
jointly (and cautiously!) by repre-
sentatives of the neonatal, nephrol-
ogy, genetics, and pediatric surgery
teams. It is important to remember
that discontinuation of CVVH will
lead to a net gain in protein/amino
acids available for catabolism.
Outcomes
Neonatal hyperammonemia is a rare
occurrence, even in large tertiary
NeoReviews Vol. 1 No. 9 September 2000
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NEPHROLOGY
Continuous Renal Replacement Therapy
care neonatal units. This fact com-
bined with the substantial heteroge-
neity of disease severity makes it
very difficult to judge the relative
merits of competing treatment
options.
SUGGESTED READING
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Bunchman TE, Maxvold NJ, Kershaw DB,
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venous hemodiafiltration in infants and
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NEOREVIEWS QUIZ
3. You are examining a 2-day-old
term infant who is lethargic,
obtunded, and hypothermic. He has
respiratory distress, a bulging
fontanelle, and poor perfusion.
Diagnostic tests reveal hyperam-
monemia due to a defect in urea
cycle metabolism. You decide to
initiate continuous venovenous
hemofiltration. Of the following,
the most unfavorable site for
venous cannulation for hemofiltra-
tion is the:
A. External jugular vein.
B. Femoral vein.
C. Internal jugular vein.
D. Subclavian vein.
E. Umbilical vein.
4. Hyperammonemia is caused by
specific defects in the urea cycle
and related pathways of metabo-
lism. Of the following, the most
accurate statement regarding hyper-
ammonemia in neonates is that:
A. Hyperammonemia is often tran-
sient in term neonates.
B. Initial treatment should involve
nitrogen scavengers.
C. Peak blood ammonia level
influences neurologic outcome.
D. The most common metabolic
complication is ketosis.
E. The most common mode of
inheritance is X-linked.
e179
Continuous Renal Replacement Therapy in the Initial Management of Neonatal
Hyperammonemia Due to Urea Cycle Defects
Kevin V. Lemley, Susan R. Hintz and Gregory M. Enns
NeoReviews 2000;1;e173
DOI: 10.1542/neo.1-9-e173

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Continuous Renal Replacement Therapy in the Initial Management of Neonatal
Hyperammonemia Due to Urea Cycle Defects
Kevin V. Lemley, Susan R. Hintz and Gregory M. Enns
NeoReviews 2000;1;e173
DOI: 10.1542/neo.1-9-e173

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/1/9/e173

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