43  Diagnosis and Treatment of Acute Kidney Injury in Children and Adolescents

the 1980s; this system relied on the arteriovenous
pressure gradient to drive circuit flow. The advent
of continuous venovenous hemofiltration adapted
for children in the 1990s, as well as improvements to filter and circuit design, allowed longer
circuit survival and precise ultrafiltration. These
advancements effectively replaced historical
CAVH systems and ushered the way forward for
the safe use of CRRT in children [85]. Several
different commercially available machines may
be used to deliver CRRT (not covered here).
Ultrafiltration (removal of fluid from the
patient) is driven by hydrostatic pressure generated across the semipermeable membrane
of the hemofilter. Clearance of solutes may be
accomplished by convection (continuous venovenous hemofiltration, CVVH), diffusion (continuous venovenous hemodialysis, CVVHD), or
both (continuous venovenous hemodiafiltration,
CVVHDF) (Fig. 43.3) [72]. In CVVHD, as with
IHD, solute clearance is achieved by diffusion,
with dialysis fluid being run countercurrent to
blood flow across the semipermeable membrane
of the hemofilter. In CVVH, convective solute
clearance is achieved by infusing high volumes
of sterile replacement fluid solution into the circuit, in order to allow for simultaneous removal
of large amounts of fluid across the hemofilter to
drive convective clearance. With CVVHDF, both
dialysis fluid and replacement fluid are used. It is
theorized that CVVH or CVVHDF, which provides convective (middle molecule) clearance,
may provide additional benefit over CVVHD
due to clearance of inflammatory molecules
(e.g., with sepsis). To date, there is little strong

evidence to support this [86], and center practice
variation dictates decisions on use of convective
clearance in patients with severe inflammatory or
infectious conditions.
Small solute clearance is achievable using
either CVVHD or CVVH (or CVVHDF). CVVH
and CVVHDF additionally provide middle molecule clearance (via convection). Replacement
fluid in CVVH and CVVHDF can be delivered
pre-filter (via a port located within the circuit,
before the hemofilter) or post-filter. The advantage of pre-filter delivery of replacement fluid is a
reduced risk of filter clotting (as the replacement

847

fluid “dilutes” the blood entering the hemofilter)
compared to post-filter replacement where the
blood delivered to the filter is more viscous. The
risk of circuit clotting with post-filter replacement in CVVH (as well as with CVVHD, where
no replacement fluid is used) is increased when
the filtration fraction rises above 25%. Filtration
fraction is the ratio of ultrafiltration rate to
plasma flow rate: filtration fraction  =  QUF/[Qb
(1 − Hct) + Qr], where QUF represents ultrafiltrate
flow rate, Qb represents blood flow rate, Hct represents hematocrit, and Qr represents pre-­dilution
replacement flow rate (include where applicable).
However, post-filter replacement provides higher
solute clearance, as solute concentration in the
blood pre-hemofilter is not affected by infused
replacement fluid.


 emofilter and Blood Prime
H
CRRT hemofilters contain hollow fibers that
are permeable to non-protein-bound solutes
with a molecular weight below approximately
40,000 Daltons. Filters are selected according
to patient weight. Biocompatible filters are the
standard for CRRT and include acrylonitrile
(AN69)-based and polysulfone-based filters.
AN69 membranes come with a risk of bradykinin release syndrome, which is worsened by the
use of angiotensin-­
converting enzyme inhibitors and blood prime. The risk of this reaction
is also pH dependent. In order to prevent this
complication, the blood prime can be administered post-filter, and bicarbonate (infusion with
bolus) is administered to maintain a neutral pH
[87]. Another method utilized to minimize the
bradykinin release syndrome with AN69 membranes and metabolic complications of performing blood prime is to perform a “pre-dialysis”
procedure on the blood prime solution, whereby
the blood is circulated through the CRRT
machine against dialysis solution for 5–10 min
(before connecting the patient to the circuit) to
normalize pH, calcium, and potassium content
of the blood prime solution [88]. Bradykinin
release syndrome is not a complication of nonAN69 polysulfone membranes and is much less
common and severe with newer protein-coated
AN69 membranes. The size of the hemofilter


E. H. Ulrich et al.


848

should be selected based on patient size, when
possible, to avoid the need for a blood prime.
Children for whom the extracorporeal circuit volume exceeds ~10% of estimated blood
volume will generally require a blood prime;
most children <10–11 kg need a blood prime for
CRRT initiation. Packed red blood cells (reconstituted to hematocrit ~30% to prevent circuit
clotting and avoid excessive unwanted rise in
patient hemoglobin) may be used to prime the
CRRT circuit. In patients with borderline circuit
extracorporeal volume and who are hemodynamically stable, 5% albumin solutions may be used
for circuit priming.

Solutions (Table 43.9)
Typically, the same solution is used for dialysis fluid of CVVHD and replacement fluid of
CVVH. Most centers use commercially prepared
solutions with a bicarbonate buffer (and low concentrations of lactate) and a variable amount of
sodium, potassium, calcium, phosphorus, magnesium, and glucose. Solutions bags are hung
onto the CRRT machine for use (Fig.  43.3).
Solutions used when performing citrate anticoagulation should be calcium-free. Table  43.9
outlines CRRT solutions commonly used at our
centers. Sodium concentration of solutions may
be modified (by adding water to reduce sodium
concentration or adding sodium to increase

sodium concentration) in patients with severe
hyponatremia or hypernatremia to avoid rapid
sodium shifts [89]. Potassium and phosphate
concentrations of solutions are also commonly

modified by addition of potassium chloride or
sodium phosphate, due to the very common problem of severe hypokalemia and hypophosphatemia development during CRRT therapy. At some
centers, modification of electrolyte concentrations of solutions is performed by pharmacy and
in others, by the bedside CRRT nurses. Great care
must be taken to attempt to remove any sources
of errors when modifying CRRT solutions. In
rare cases of specific conditions (e.g., Wilson’s
disease, to remove copper; certain protein-bound
drug intoxications), 25% albumin may be added
to the dialysis solution (to achieve ~5% albumin
dialysis solution) to perform what is referred to
as “single-­pass albumin dialysis” and promote
removal of protein-bound substances [90, 91].

 RRT Prescription: Blood Flow
C
(Table 43.10)
Unlike IHD, the blood flow rate does not significantly impact solute clearance in CRRT but
greatly impacts circuit survival. Blood flow rate
is determined by patient size, hemofilter, and
vascular access. Blood flow rates range from 2
to 10  mL/kg/min. At our centers, the minimum
suggested blood flow rates are 50  mL/min for

Table 43.9  Commercially prepared CRRT solutions and citrate solutions (for anticoagulation)
Analyte
(mmol/L)
Sodium
Potassium
Chloride

Bicarbonate
Lactate
Calcium
Phosphate
Magnesium
Glucose
Trisodium
citrate
Citric acid

Dialysis/replacement solutions
Prism0Cal® Prism0Cal®
Prismasol®
B22
0
140
140
140
–
4
–
106
120.5
109.5
32
22
32
3
3
3

–
–
1.75
–
–
–
0.5
0.75
0.5
–
6.1
6.1
–
–
–

Prismasol®
4
140
4
113.5
32
3
1.75
–
0.5
6.1
–

Citrate solutions

Phoxilium®a ACD-A
Sodium citrate
solution
4%
140
224
408
4
–
–
116
–
–
30
–
–
–
–
–
1.25
–
–
1.2
–
–
0.6
–
–
–
139

–
–
74.8
136

–

–

–

–

–

38.1

Not
specified


43  Diagnosis and Treatment of Acute Kidney Injury in Children and Adolescents

849

Table 43.10  Sample of some aspects of CRRT prescription
Vascular access
Hemofilter

Blood prime

Modality

Blood flow rate

Dialysis flow rate
Solution
Anticoagulation

Table 43.7
Weight <10 kg
10–30 kg
>30 kg
<10 kg
CVVH
CVVHD
CVVHDF
HF20
ST60
HF1000
2 L/1.73 m2/h
Table 43.9
Citrate
Heparin

HF20 (polysulfone filter)
ST60 (AN69 filter)
HF1000 (polysulfone filter)
Use blood prime; otherwise 0.9% NaCl solution

50 mL/min (minimum 40 mL/min)

~50–100 mL/min
100 mL/min (minimum 80 mL/min)
Consider higher rate for neonates admitted with hyperammonemia
Use citrate if heparin-induced thrombocytopenia

CRRT prescription items taken from Hospital for Sick Children, Toronto, Canada

a

patients <11  kg (though blood flows as low as
30 mL/min have been used) and range from 50 to
150 mL/min (>11 kg) (Table 43.10). At our centers, we use the hemofilter (which is affected by
patient size) to guide blood flow; at other centers,
blood flow may be based specifically on patient
size. Because of the need for minimum blood
flows of 30–50  mL/min, neonates are subjected
to high relative blood flow rates (per unit weight);
this is especially relevant when using citrate anticoagulation because as described below, citrate
prescription rate is based on blood flow. Reasons
to change blood flow during CRRT may include
access problems (e.g., blood flow reduced to
address rising access pressures), rising hemofilter transmembrane pressures or clot formations (increasing blood flow may help reduce
clot formation), or need to reduce citrate delivery (decreasing blood flow leads to lower citrate
infusion requirements).

 RRT Prescription: Solute Clearance
C
(Table 43.10)
With CRRT, solute clearance or “dialysis dose”
is determined by the dialysis and/or replacement

fluid flow rates, which affect the degree of diffusive and/or convective clearance of small solutes
(i.e., urea). In adult studies and clinical practice,
solute clearance rate (or delivered dialysis dose)
is expressed in terms of dialysis and/or replace-

ment fluid rate in mL/kg/h. A minimum dose of
20–25  mL/kg/h is generally recommended, and
flow rates higher than this have not shown significant impacts on patient outcome [72, 92, 93].
In children, solute clearance dose is prescribed based on body surface area; a standard
dose is 2–2.5 L/h/1.73 m2. So if CVVHD is being
performed in a patient with body surface area of
0.7  m2, then the dialysis solution rate is run at
~2 L/1.73 m2/h or ~800 mL/h. If CVVH is used
for this patient, the replacement solution is run at
~800 mL/h. If CVVHDF is used, the combined
rate of dialysis fluid and replacement fluid should
total ~800 mL/h (e.g., 400 mL/h of dialysis fluid
+ 400 mL/h of replacement fluid). Some CRRT
machines require a minimum post-filter replacement fluid rate to prevent clotting in the circuit;
this replacement fluid should be included in the
total solute clearance dose.
This level of solute clearance will be adequate
for most patients treated with CRRT.  However
in some AKI patients, higher clearance may be
desired. For example, in patients with hyperammonemia with AKI, much higher clearance rate
(e.g., 4–8 L/1.73 m2/h) may be desired to rapidly
reduce ammonia levels; or patients with life-­
threatening serum potassium level may require
higher than standard solute clearance to prevent
arrhythmia and death. When prescribing high

clearance rates, it is crucial to be mindful of


850

the effects. For example, if there is concern for
dialysis disequilibrium syndrome and rapid urea
reduction, administering intravenous mannitol
may be helpful. Other solutes (e.g., potassium,
phosphate), antibiotics, nutrition (especially
amino acids), and citrate (for citrate anticoagulation) will also be cleared quickly, and infusion/
medication adjustments should be made accordingly, ideally in conjunction with a pharmacist.
Regarding high clearance CRRT during citrate
anticoagulation, very close monitoring of circuit and patient ionized calcium levels is crucial
(citrate will be cleared at a higher rate) as adjustments to citrate and calcium infusion rates will
definitely be required to prevent low patient ionized calcium concentrations (citrate anticoagulation discussed below).

 RRT Prescription: Ultrafiltration
C
(Table 43.10)
Fluid removal is often a primary goal for initiating CRRT.  In critically ill patients, a careful
balance between achieving fluid removal goals
and patient safety/tolerance may be challenging
to achieve and must be reassessed frequently.
Ultrafiltration rate (and desired daily and hourly
negative patient balance) should be determined
collaboratively between ICU and nephrology
teams to meet safe targets for the patient. The
prescribed ultrafiltration rate does not need to
consider any fluids which are being administered

by the machine (e.g., replacement fluid). In order
to keep the patient in neutral hourly balance, the
prescribed ultrafiltration rate (mL/h) should equal
to the hourly rate of all fluids administered to the
patient (e.g., medications, nutrition). Because
ultrafiltration rate can be continuously increased
to account for fluid intake, there is little reason
to delay initiation of appropriate nutrition (parenteral or enteral) for patients receiving CRRT. If
there is significant urine output or other outputs
(e.g., high-output chest tube), these hourly volumes should be subtracted from the prescribed
ultrafiltration rate. In order to achieve a negative
hourly balance, the prescribed ultrafiltration rate
is increased to achieve this negative balance.
Decisions on rate of negative balance (mL/h)
in critically ill patients should consider hemo-

E. H. Ulrich et al.

dynamic stability (and likelihood of tolerating a
negative balance) and urgency of need for fluid
removal (e.g., severe pulmonary edema with
reduced oxygenation). Overly aggressive negative fluid balance attainment can cause severe
hemodynamic instability and be detrimental,
especially in small patients, and potentially cause
further kidney injury. Two rules of thumb on
maximal negative balance in unstable patients
receiving CRRT include avoiding daily negative balance >3–5% of body weight (e.g., 10 kg
child, not exceeding >300–500 mL/day negative
balance) and to aim for ≤1–2 mL/kg/h negative
balance (e.g., 10  kg child, ≤20  mL/h negative

balance). When achieving negative balance is
urgent (e.g., need to stop ECMO as soon as possible), temporary slightly more aggressive negative
balance goals may be carefully used. Increasing
vasopressor support may be required for patients
to tolerate fluid removal. It is not recommended
to keep unstable patients in positive fluid balance
by reducing the ultrafiltration; rather, additional
fluid or inotropic support should be used to maintain blood pressure.

Anticoagulation
Although there are several options for anticoagulation, CRRT is generally performed using
either regional citrate anticoagulation or systemic
unfractionated heparin anticoagulation. CRRT
may be successfully performed with no anticoagulation (with or without flushing of the circuit
pre-filter with normal saline); however, circuit
life will likely be much lower (high incidence of
clotting).
As in IHD, systemic heparin anticoagulation is
performed by infusing heparin pre-filter and monitoring partial thromboplastin time (PTT) and/or
activated clotting time (ACT) for target PTT 1.5
times normal and/or ACT 180–220 s (with higher
blood flows or bleeding risk concerns, target ACT
may be lower). Patients with severe bleeding risk,
active bleeding, or heparin-induced thrombocytopenia should not receive heparin. Increasingly,
pediatric centers are using regional citrate anticoagulation for CRRT.  Studies in adults and children support that though there is no difference in
mortality, circuit life is likely to be longer when


43  Diagnosis and Treatment of Acute Kidney Injury in Children and Adolescents


using citrate anticoagulation, and bleeding events
tend to be higher when using heparin anticoagulation [94, 95].
Regional citrate anticoagulation is achieved
by infusing a commercially prepared citrate solution pre-filter (Table  43.9). Citrate chelates free
ionized calcium, which is required for clotting.
Citrate may be infused at the access port of the
catheter (using an intravenous pump separate
from the CRRT machine) or, for some machines,
may be administered as a pre-filter replacement
solution, incorporated within the machine. The
goal is to target an ionized calcium concentration of ~0.3–0.4 mmol/L in the blood within the
extracorporeal circuit (“circuit ionized calcium”)
to prevent clotting. Although calcium citrate
complexes are cleared at the hemofilter, a substantial amount of citrate in the circuit blood will
be returned to the patient, placing them at risk
for hypocalcemia. Thus, patients must receive a
continuous intravenous calcium infusion to prevent systemic hypocalcemia. Calcium is ideally
infused through a separate central line; however,
it may be infused at the end of the circuit, at the
return port of the vascular access, or near to the
patient’s skin (acknowledging that there is a theoretical risk of access clotting; single-center data
has not shown this to be the case) [96]. Systemic
citrate is metabolized predominantly by the liver
(and to a lesser extent by the skeletal muscle and
kidney) with one molecule of citrate yielding
three molecules of bicarbonate; calcium which
is complexed to citrate is released when citrate
is metabolized. Patient ionized calcium levels
must be closely monitored and kept within normal range. Several delivery and monitoring protocols for regional citrate anticoagulation exist.
Table  43.11 shows a sample citrate protocol.

Typically, citrate is administered at a rate proportional to the blood flow (to ensure adequate
anticoagulation). Circuit and serum ionized calcium levels are monitored serially (an hour after
any citrate or calcium infusion change and every
4–6 h when stable) with citrate and calcium infusion adjustments accordingly. As mentioned,
closer circuit and patient calcium monitoring is
needed when using high clearance rates (e.g.,
when treating hyperammonemia, current citrate

851

and calcium administration protocols were based
on targeting a clearance rate of ~2 L/1.73 m/h or
in patients with severe liver disease since systemic citrate may accumulate due to decreased
liver metabolism). Some citrate protocols incorporate a priori modified (lower) citrate rates in
patients with severe liver disease.
Common complications of citrate anticoagulation include hypocalcemia and metabolic alkalosis. Hypocalcemia occurs due to
inadequate patient calcium delivery or excess
systemic citrate binding free ionized calcium.
Hypercalcemia may occur if the circuit clots and
CRRT is stopped suddenly. In the setting of elevated systemic citrate, as citrate is metabolized
to bicarbonate, previously complexed calcium is
released into the bloodstream with limited means
of excretion in a patient with severe renal dysfunction. Metabolic alkalosis is due to excess
bicarbonate generation by citrate metabolism;
metabolic alkalosis may also be contributed to by
the high bicarbonate load in most commercially
prepared solutions. Citrate use also contributes
to hypomagnesemia, commonly seen in patients
receiving CRRT, due to magnesium binding. Less
commonly, hypernatremia (more commonly with

sodium citrate solutions, Table  43.9), hyperglycemia, and metabolic acidosis can occur.
The occurrence of excess systemic citrate
accumulation must be monitored, to avoid the
situation commonly referred to in the literature
as “citrate lock” or evidence of complications of
citrate accumulation described above (i.e., hypocalcemia/increasing calcium infusion needs). To
monitor for citrate accumulation, total patient
calcium is measured at least every 12–24 h; with
significant systemic citrate accumulation, total
calcium rises (includes citrate complex and free
calcium), and systemic ionized calcium will tend
to be low. A ratio of total to ionized calcium
>2.5–2.8 is a surrogate marker of significant systemic citrate accumulation (or a surrogate marker
of high citrate concentration). Risk factors for
significant citrate accumulation (or total/ionized
calcium >2.5–2.8) include young age (due to the
relatively high blood flows required and subsequently high citrate delivery), severe liver failure, and lactic acidosis. Citrate accumulation is


E. H. Ulrich et al.

852
Table 43.11  Sample CRRT citrate anticoagulation protocol: key items
Vascular access
Dialysis solution
Citrate flow rate

Calcium flow rate
Serum investigations


Target calcium
concentration

Citrate anticoagulation
management

Circuit change

Hemodialysis central line, ideally second central line for calcium infusion
Prism0Calđ
Table 43.9
1.5ì blood flow rate For example, if blood flow 50 mL/min, citrate flow
(mL/h)
rate = 75 mL/h
At Hospital for Sick Children, blood flow rate maximum of
100 mL/min to avoid excessive citrate delivery
0.4× citrate flow rate For example, if citrate flow rate is 75 mL/h, calcium flow
(mL/h)
rate = 30 mL/h
Initial
iCab, total calcium
Electrolytes (sodium, potassium, chloride, bicarbonate,
glucose, magnesium, phosphate)
Lactate
Creatinine, urea, albumin, ALT (assess for liver disease)
Complete blood count, PTT, INR
Every 2 h
iCa
Every 4 h
Total calcium

Electrolytes (sodium, potassium, chloride, bicarbonate,
glucose, magnesium, phosphate)
Every 12 h
Lactate
PTT, INR
Every 24 h
Creatinine, urea, albumin, ALT
Complete blood count
Circuit iCa
0.25–0.4 mmol/L
Call MD if <0.2 or >0.4 mmol/L
Patient iCa
1.1–1.3 mmol/L
Call MD if <1 or >1.5 mmol/L
Circuit iCa
<20 kg
Decrease citrate by
<0.25 mmol/L
5 mL/h
>20 kg
Decrease citrate by
10 mL/h
Circuit iCa
<20 kg
Increase citrate by
>0.4 mmol/L
5 mL/h
>20 kg
Increase citrate by
10 mL/h

Patient iCa
<20 kg
Increase calcium
<1 mmol/L
by 5 mL/h
>20 kg
Increase calcium
by 10 mL/h
Patient iCa >1.3
<20 kg
Decrease calcium
mmo/L
by 5 mL/h
>20 kg
Decrease calcium
by 10 mL/h
Every 72 h

Some items taken from CRRT citrate anticoagulation protocol used at the Hospital for Sick Children, Toronto, Canada
Ionized calcium
ALT alanine aminotransferase, INR international normalized ratio, PTT partial thromboplastin time
a

b

treated by increasing citrate removal or reducing
delivery. To increase removal, CRRT clearance
may be increased (i.e., increasing dialysis fluid
rate to increase removal of calcium citrate complexes; being mindful to adjust medication doses
and monitor for effects of higher clearance), or

blood flow decreased (to reduce citrate needs to

maintain anticoagulation). To decrease citrate
delivery, the citrate infusion may be decreased or
temporarily stopped (e.g., 3–6  h). If the citrate
infusion is held, it may be restarted at a lower rate
(e.g., ~70%). When there is no evidence of citrate
accumulation but there is clinically significant
metabolic alkalosis, reducing citrate delivery