Authors are listed in alphabetic order. *Denotes group facilitator.
Acute Dialysis Quality Initiative Fifth International Consensus Conference
Workgroup 2
Fluids for Prevention and Management of Acute Kidney Injury
Jorge Cerda
Lewis J. Kaplan
John A. Kellum*
Mitra K. Nadim
Paul M. Palevsky
Introduction
Fluids are the only known method of attenuating renal injury. Furthermore, fluid prescriptions whether for
hydration, resuscitation or renal replacement therapy, must be tailored to the fluid and electrolyte,
cardiovascular status and residual renal function of the patient. Different fluids have significantly different
effects both on volume expansion as well as electrolyte and acid-base balance. While controversial,
different fluids may even influence renal function differently. This ADQI workgroup has focused on fluids
for prevention and management of acute kidney injury. We have reviewed the evidence and have made
recommendations for clinical practice and future studies.
Fluids for Prevention of AKI
Prevention of AKI has significantly relied on fluid administration with or without an identified effective
circulating volume deficit in concert with avoidance of nephrotoxic medications. Fluid administration
serves to expand plasma volume, increase renal blood flow, and presumably glomerular filtration rate.
Increased renal blood flow augments renal parenchymal oxygen delivery to support cellular metabolism
while enhanced tubular filtration flushes potentially toxic elements out from the renal tubules. While these
benefits of fluid administration should reduce or ameliorate AKI, some components of commonly used
fluids may initiate or worsen existing AKI. This section will explore fluid prescription benefits and risks
with regard to AKI, including those derived from crystalloids, colloids, and hemoglobin-based oxygen
carriers.
ADQI
2
Do different crystalloid solutions pose a risk of AKI?
i. Anion composition
Hyperchloremic vs. Balanced lactated solutions. Large volume crystalloid resuscitation can result in
significant alterations in electrolyte and acid-base balance in patients. While perhaps of limited concern in
healthy subjects, these effects may create life- threatening abnormalities in the critically ill and injured. An
intra-operative comparison of 0.9% saline (NS) and lactated ringer’s solution (LR) for abdominal aortic
reconstruction demonstrated hyperchloremic metabolic acidosis (HCMA) occurred with NS much more
often than with LR, and NS resuscitated patients required greater amounts of blood component therapy.[1]
However, no differences in renal function were identified. In another small, related study, patients
undergoing renal transplantation were randomized to receive either NS (n=26) or LR solution (n=25) in a
double-blind fashion with a primary outcome measure of creatinine at day 3 post-transplant.[2]
Unexpectedly, the authors found a markedly increased incidence of hyperkalemia (> 6 meq/L) in 5 of the
NS group but it none of the LR group. Significant metabolic acidosis was noted only in the NS treated
patients, 8 of whom received some form of therapy to raise the pH. Due to these significant differences
between the groups, the trial was halted early for safety reasons.
Although hyperchloremia has been associated with impaired organ perfusion and function, including
diminished renal blood flow and longer time to diuresis in comparison to lactated Ringer’s solution [3, 4],
no significant differences in clinical outcomes have been reported. Acidosis has also been demonstrated to
impair coagulation. Importantly, the effect of acidosis on coagulation parallels that of hypothermia.[5] Of
note, both LR and NS have been identified as potent triggers of immune cell activation, although the
significance of these observations remains uncertain.[6]
Hyperchloremic vs. Balanced solutions with non-lactate buffer. Despite the availability of bicarbonate and
acetate buffered crystalloid solutions for renal replacement therapy. These agents have not been used for
maintenance fluids or resuscitation in any controlled trials.
Summary: There is no evidence that anion composition of currently available crystalloids increase the risk
of AKI in humans. Large volume administration of saline leads to HCMA. Some animal data suggesting
that HCMA can alter renal blood flow (RBF) but no data are available in humans. Compared to LR,
delayed diuresis has been observed with NS. Recommendations for clinical practice: Other than the need to
be aware of potential side effects seen with large volume crystalloid resuscitation, no recommendations can
be given concerning choice of crystalloids at this time. Recommendations for future research: Adequately
powered randomized trials will be needed to assess differences in risk for AKI form various fluids. Given
that these trials will need to be very large, the likelihood that they will be conducted seems low. As an
alternative to randomized trials, large observational studies might provide important information on the
risks, if any, of various crystalloids. These studies should include assessment of clinical consequences
related to volume requirements, metabolic acidosis, electrolyte abnormalities, and infectious complications
in addition to risk of AKI.
3
ii. Tonicity (Saline, Mannitol)
Hypertonic Saline. Hypertonic saline (HTS) has been evaluated as a possible fluid for resuscitation in
injury and sepsis, because of its purported hemodynamic, endothelial and immunomodulatory effects.[7, 8]
Data are available that support potential benefits of hypertonic saline infusion in various aspects of the
pathophysiology of sepsis, including tissue hypoperfusion, decreased oxygen consumption, endothelial
dysfunction, cardiac depression, and the presence of a broad array of proinflammatory cytokines and
various oxidant species as well as in the pathophysiology of traumatic brain injury associated increases in
cerebral parenchymal volume.[8] Despite the purported advantages of HTS in ex-vivo studies, no durable
outcome benefit has been identified with HTS use as a plasma volume expander even in a large multi-
institutional prehospital trial specifically addressing traumatic brain injury.[9] HTS solutions are commonly
utilized to correct abnormalities of water balance. However, due to the hypertonic nature of these solutions,
they may also serve as plasma volume expanders with the added benefit of drawing fluid into the vascular
compartment on the basis of water movement along a concentration gradient. HTS is also commonly
coupled with dextran to support plasma volume expansion. Accordingly, HTS-dextran has been utilized for
plasma volume expansion during surgery. One such study compared a single 250 cc intra-operative dose of
7.5% NS/6% dextran-70 versus 250 cc of a hydroxyethylstarch (HES) in NS in patients undergoing aortic
aneurysm surgery.[10] Both groups were resuscitated with NS as the concomitant crystalloid solution. The
authors identified no difference in acid-base balance between the two groups due to the large amounts of
NS and relative small volumes of test agents given. Importantly, no differences in renal function were
noted with either regimen for 24 hours post-operatively. A small study in burn patients compared those
resuscitated with HTS (1991-1993) to patients resuscitated with LR in an earlier time frame (1986-1988
versus a later time frame (1993-1994). The authors found a four-fold increase in renal failure and a
doubling of mortality with HTS compared to LR resuscitated patients.[11]
A recent meta analysis (Cochrane review) from 2002 comparing isotonic crystalloids with hypertonic
solutions included 5 studies in trauma patients and demonstrated no benefit of HTS on outcome.[12] A
2004 Cochrane review of the issue[13] did not generate enough data to establish whether hypertonic
crystalloid is better than isotonic and near-isotonic crystalloid for the resuscitation of patients with trauma,
burns, or those undergoing surgery. However, the confidence intervals were wide and did not exclude
clinically significant differences. Further trials which clearly state the type and amount of fluid used and
that are large enough to detect a clinically important difference are needed. Small volumes of HTS do not
appear to cause, or increase the risk, of AKI with isolated or sporadic use, but detailed studies and reporting
are lacking. By contrast, HTS as a primary resuscitation fluid for burns appears to result in increased risk of
AKI.
Hypertonic mannitol solutions. HT-mannitol may be harmful because of the potential to induce rapid
intravascular volume expansion, leading to pulmonary edema and resulting in hyperoncotic kidney injury
in those without a severe plasma volume deficit.[14-16] Moreover, mannitol-based volume expansion may
induce AKI due to excessive osmotic diuresis in patients with hypovolemia.
4
Summary: HTS as sole resuscitation fluid is associated with ARF and excess mortality in burns. Small
volume HTS appears safe with isolated or sporadic use and was not associated with AKI in available
studies–detailed studies and reporting are lacking. HT-mannitol may induce AKI with excessive osmotic
diuresis and untoward hyperoncotic. Recommendations for clinical practice: HTS should be used with
caution in patients at risk for AKI and should be avoided in patients with burns. HTS is indicated for
treatment of severe hyponatremia in appropriate clinical settings. Use of HTS for plasma volume expansion
is not recommended. HT-mannitol is not recommended for fluid resuscitation. Recommendations for future
research: Given the immunomodulatory properties of HTS this agent should be specifically studied to
define a patient population who may benefit from HTS administration. Specifically, timing and dose should
be clearly defined and explored to clarify appropriate use. Pairing HTS with other fluids such as dextran,
starches, or HBOC’s should be explored as a means of maximizing potential benefits of both fluids in
specific circumstances.
Do different crystalloid solutions have different effects on mitigating the risk of AKI?
i. Anion composition (Chloride vs Bicarbonate)
Radiocontrast nephropathy (RCN). Reducing the concentration of chloride (e.g. use of bicarbonate) in
solutions for the prevention of RCN has been recently tried in a small (n=119 patients), single-centered,
randomized trial, in which plasma volume expansion with sodium bicarbonate based solutions was shown
to be superior to NS for prevention of RCN.[17] It is unclear if the putative benefit from bicarbonate-based
plasma volume expansion derives from amelioration or prevention of HCMA at the same time as contrast
administration, or an undescribed interaction of contrast material with the anion. A larger trial (n=326
consecutive patients) of medium to high risk patients compared three different fluid regimens for the
prevention of radiocontrast nephropathy: 1) saline + n-acetyl cysteine (NAC) (n=111), 2) sodium
bicarbonate + NAC (n=108), and 3) saline + NAC + ascorbic acid (n=107).[18] In this study, 1.9% of
bicarbonate + NAC treated patients sustained RCN (25% or greater creatinine increase at 48 hours post-
contrast exposure), while RCN was identified in 9.9% of those receiving NS + NAC and 10.3% of those
receiving NSS/+ NAC+ ascorbic acid. While the results of these two studies suggest that isotonic
bicarbonate may provide greater benefit than isotonic saline, either with or without NAC, neither study can
be considered to be conclusive. Thus, confirmation of these results in a large, multicenter RCT is needed.
Rhabdomyolysis. There is good evidence that rhabdomyolysis leads to AKI although the exact mechanisms
are still in dispute. In addition to hypovolemia that is present to some degree in all patients with
rhabdomyolysis (based on the antecedent cause), the myoglobin that is released into the circulation as a
result of muscle damage may also cause renal cellular damage via direct renal cytotoxicity, renal
vasoconstriction and renal tubular obstruction.[19, 20] Therefore, prevention of AKI in this setting involves
vigorous plasma volume expansion to maintain renal perfusion pressure and dilute myoglobin and other
toxins. Although there is limited evidence, clinical practice also commonly involves urinary alkalinization
with bicarbonate aimed at preventing tubular precipitation of myoglobin. Correction of hypovolemia is
5
essential to prevent AKI.[21] Plasma volume should be aggressively expanded to restore and maintain
effective circulating volume and to maintain a urine flow rate of 100 to 150 cc/hr.[22] While the
administration of sodium bicarbonate together with crystalloid plasma volume expansion is widely
recommended, the extent to which this interventions provides additional benefit to volume expansion with
crystalloid solution alone remains uncertain. If used, bicarbonate containing solutions should be isotonic
and care should be exercised to avoid metabolic alkalosis or electrolyte abnormalities (e.g. hypokalemia).
While randomized controlled trials are lacking, the available evidence suggests that bicarbonate have no
benefit over and above aggressive fluid resuscitation.[23-25] Knottenbelt has demonstrated that large-
volume infusion of crystalloid alone creates a solute diuresis sufficient to alkalinize the urine.[21]
Summary: The value of reducing chloride (i.e. using bicarbonate) in solutions for the prevention of RCN is
presently uncertain although risks are small in most patients. Bicarbonate solutions may be of value in
rhabdomyolysis but more evidence is necessary. Recommendations for clinical practice: The primary
recommendation for fluids to prevent AKI in the setting of radio-contrast exposure and rhabdomyolysis is
to ensure that they are given. Exact volumes or anion composition cannot be determined based on available
evidence, although bicarbonate appears safe in high risk groups. Consider isotonic bicarbonate in
preference to NS in patients without metabolic alkalosis. Recommendations for future research:
Randomized clinical trials to separate the effects of bicarbonate versus saline and other interventions
(NAC, tonicity of contrast) in preventing RCN in high risk patients with and without underlying kidney
disease. Randomized controlled trials are needed, to ascertain the value of bicarbonate vs. NS in the setting
of rhabdomyolysis, possibly with and without mannitol.
ii. Tonicity (Hypotonic vs isotonic, saline, mannitol)
Isotonic vs. hypotonic saline. A large, prospective, randomized, controlled trial in patients undergoing
cardiac catheterization found plasma volume expansion with NS to be superior to 0.45% saline.[26]
However, the incidence of RCN was lower than previously reported in comparable patient cohorts (0.7% in
NS and 2% in the 0.45% saline group).
Mannitol. Although studies in animals have shown mannitol to help protect the kidney against ischemic
injury, human studies fail to demonstrate the efficacy of mannitol in preventing AKI. Although
prophylactic mannitol has also been promoted in patients considered to be at high risk for AKI, such as
those undergoing vascular (aortic aneurysm) surgery, cardiac surgery, or patients developing obstructive
jaundice, several small RCTs have found no reduction in the incidence of AKI with mannitol
administration or over-hydration.[27-30] In small studies of patients undergoing kidney transplantation,
mannitol administration appears to have salutary effects with regard to AKI. In these studies, 250 ml of
20% mannitol given immediately before vessel unclamping reduced the incidence of AKI, as determined
by a decrease need for post-transplant dialysis.[31-38] However, no durable outcome difference at 3
months was found in comparison to patients who did not receive mannitol.[38]
6
Mannitol results in a higher incidence of radiocontrast-induced nephrotoxicity as compared with saline
plasma volume expansion alone in either diabetic or non-diabetic patients.[39, 40] Solomon et al found that
25 g of mannitol prior to contrast administration plus plasma volume expansion with saline was not
associated with any reduction in risk compared with saline alone; instead, there was a trend toward
harm.[39] A forced diuresis regimen which included intravenous crystalloid, mannitol, furosemide and
low-dose dopamine similarly exerted no effect on the overall incidence of contrast-induced nephropathy.
[40] The trial design allowed independent evaluation of the effects of mannitol and the results demonstrated
no additive benefit. In patients with both diabetes and chronic kidney disease receiving radiocontrast agent,
mannitol increased the incidence of nephrotoxicity.[41, 42] Conversely, the use of mannitol has been
advocated in the setting of rhabdomyolysis to create an osmotic diuresis [43, 44], vasodilatation of renal
vasculature[45] and free-radical scavenging.[46, 47] However, available evidence suggests that mannitol
offers no benefit over and above aggressive fluid resuscitation.[23-25] Furthermore, mannitol can be
harmful if urine output cannot be maintained.
Summary: Isotonic fluids are superior to hypotonic fluids for plasma volume expansion prior to contrast
material with regard to AKI risk mitigation. Mannitol is of unproven benefit with rhabdomyolysis or renal
transplant to decrease AKI incidence, and should not be routinely utilized in clinical practice. Mannitol
may increase the risk of RCN associated AKI in diabetic patients, and should not be used in this patient
population. Recommendations for clinical practice: Use isotonic IV fluids to reduce the risk of AKI from
radiocontrast and rhabdomyolysis. Mannitol should be avoided in patients with AKI; its role in preventing
AKI in the setting of rhabdomyolysis is currently uncertain and it should be avoided in the setting of RCN.
Recommendations for future research: Further clarification regarding the duration and volume of isotonic
IV fluids before and after radiocontrast agent administration to guide clinical practice.
Do different colloid solutions pose a risk of AKI?
Albumin. Human albumin has been widely used as the colloid for the treatment of hypovolemia in critically
ill patients. The SAFE study which was a large multicenter RCT (n=6997) demonstrated no difference in
renal outcomes (including incidence of AKI, need for RRT or duration of RRT), mortality, LOS in the ICU,
or duration of mechanical ventilation between patients managed with 4% albumin or normal saline for fluid
resuscitation.[48] The authors concluded that albumin is a safe as NS for resuscitation of the critically ill.
Importantly the study used a preparation of albumin in NS and few patients in the SAFE trial received large
volumes fluid resuscitation. Whether specific subgroups of critically ill patients, including those with AKI,
fare better with albumin is unknown.
Starches. Some studies have shown that patients treated with certain HES solutions (High molecular weight
(HMW)-HES and HES with a high C2-C6 molar substitution ratio) may suffer from renal dysfunction.[49,
50] Histological studies have shown reversible tubular cell edema causing obstruction and medullary
ischemia.[51] Boldt recently reviewed the renal complications of HES use. Study limitations included a
lack of fixed endpoints for intravascular volume therapy, crude measures of kidney function, and lack of
7
control groups in those receiving crystalloid infusions.[52] Additionally, HES has been noted to accumulate
in renal tubular cells and is believed to be a cause of AKI.[52] However, appropriately controlled studies
are lacking. Use of HES has been associated with AKI in post-cadaveric renal transplant patients.[50, 53]
In an observational cohort study, Legendre reported an 80% rate of osmotic nephrosis-like lesions
(vacuolization of proximal tubular cells) in transplanted kidneys after administration of HES with a mid-
range MW (200kD) and high molar substitution ratio (0.62) to brain dead organ donors.[54] The lesions
had no negative effect on graft function or serum creatinine at 3 and 6 months post transplantation. Similar
lesions have been described with other substances including mannitol and dextran. Infusion of hyperoncotic
colloids likely induces hyperviscosity and stasis of tubular fluid, especially when HES concentration is high
(>10%). Large amounts (>2000 ml or > 20 cc/kg bw/day) of HES preparations with LMW or MMW (e.g.
HES 130/0.4 or HES 200/0.5) and a low MS (0.4, 0.5) have been used safely in humans as have HWM-
HES with high molar substitution (670/0.75).[55, 56]
Younes studied HES in NS compared to NS in trauma patients with hemorrhagic shock and documented
that less HES volume was required to achieve an identical blood pressure compared to the NS resuscitated
patients.[57] These data are consistent with that from Boldt who resuscitated 30 trauma and 30 septic
patients with a more concentrated starch (10%) of lower molecular weight (100kDa) and lower molar
substitution ratio (0.3) that that used in the US (6%, 670 kDa/0.75) versus albumin and found that the HES
group evidenced better splanchnic (septic patients only) and systemic hemodynamic indices (septic and
trauma patients).[58] Finally, intra-op evidence of improved microcirculation as judged by improved tissue
oxygenation was seen when comparing HES (130/0.4) to LR resuscitation during major surgery.[59] Thus,
starch resuscitation may have some benefits in restoring effective circulating volume and supporting
microcirculatory flow, but the data are difficult to interpret because of multiple different molecular weights
and molar substitution ratios, as well as different resuscitation targets and patient populations.
Worse serum creatinine was noted in septic patients resuscitated with HES compared to gelatin.[49] This
study used a low molecular weight starch with high molar substitution ratio (200 kDa/0.6-0.66) in NS, and
found that serum creatinine was higher on days 6 and 7 compared to gelatin. However, baseline serum
creatinine was also slightly higher in the HES group (NS) and differences between groups may not have
been clinically significant nor did they persist (values were identical at 14 days). Also, survival was
identical for both groups. By contrast, intra-operative infusion of 500 cc of 6% HES in a balanced
electrolyte solution containing lactate (Hextend) has been associated with improved urine output, systemic
perfusion, gut mucosal perfusion, and the absence of acidosis or hypocalcemia requiring correction in
elderly patients undergoing major surgery with an anticipated blood loss exceeding 500ml; no differences
in post-op renal function (or dysfunction) was identified.[60] This study compared Hextend to HES in NS
(Hespan). Similarly, the prospective (Hextend vs Hespan) Phase III US FDA registration trial for Hextend
utilized quite large volumes of Hextend (up to 5L) without identifying diminution in renal function.[61]
Interestingly, patients receiving Hextend demonstrated better clotting ability as interrogated by
thromboelastography that correlated with reduced intra-operative blood loss and component therapy.
8
Additionally, a retrospective comparison of cardiac surgery patients treated with a low molecular weight
(200 kDa) and degree of molar substitution (0.5) starch vs. gelatin, or both[62] found no differences in
post-operative serum creatinine. Thus, it may be that sepsis induces a sensitivity to starch resuscitation that
is not evident in other conditions like trauma, surgery, and cardiopulmonary bypass that are also
accompanied by a substantial inflammatory and cytokine response. In contrast, a rodent model of sepsis
demonstrated improved survival with Hextend resuscitation compared to 0.9% NS or LR despite identical
resuscitation endpoints.[63]
Gelatins. In contrast to the controversies that surround HES use, there is little negative data regarding
gelatin infusions. The Cochrane analysis did not identify a significant benefit for gelatin resuscitation but
neither did it identify a detrimental effect.[64] Gelatin resuscitation has been utilized to great effect in
trauma, surgery and burns. However, its utility is limited by its relatively short half-life and relative low
affect on colloid oncotic pressure. There is no data that gelatin infusion causes renal injury, or that its use
with AKI should be restricted. Although gelatin is widely used in the UK, Australia and parts of Europe, it
has never been approved for use in the US. Limited data are available comparing it to other colloids.
Colloids do contain “unmeasured anions” and thus will increase the anion (or strong ion) gap, although this
effect is of unknown significance.
Summary: Albumin in saline appears to be equivalent to 0.9% saline in terms of risk of AKI. The risks of
AKI associated with HES, if any, appear to vary depending on the size, concentration, molar substitution
and possibly the diluents’ composition used in these preparations. Current evidence is inconclusive to judge
the risk of AKI attributable to HES. Gelatin does not appear to result in a measurable risk of AKI; however
studies evaluating this endpoint have been limited. Recommendations for clinical practice: HES should be
used with caution in patients with sepsis and renal transplantation due to limited evidence suggesting risk
of AKI in these groups. However, current data do not preclude their use in these settings. HES appears safe
for trauma, burns, and large blood loss emergency and elective surgery. Neither albumin nor gelatin
appears to increase the risk of AKI. Insufficient evidence exists to recommend one colloid preparation over
another in terms of risk for AKI. Recommendations for future research: HES of different concentrations,
molecular weights, and degrees of molar substitution ratios in different diluents (based on chloride
concentration) should be studied; possibly in sepsis and non-septic models prior to conducting a
prospective randomized trial in humans in a multi-center fashion. Gelatin should be studied in a fashion
similar to starch, but with additional comparators to include different crystalloid solutions of different
chloride concentrations. Compound agents like hypertonic HES should have their investigation deferred
until the optimal HES construction has been defined with regard to concentration, molecular weight, and
degree of molar substitution ratio, and diluents’ electrolyte composition. HES administration with different
concentrations, molecular weights, and degrees of molar substitution ratios, in different diluents should be
specifically administered in an animal model to determine the incidence and prevalence of renal tubular
incorporation of starch with both hypovolemia and hypervolemia, hemorrhagic shock, and sepsis as well as
the incidence and prevalence of AKI in each of those settings.
9
Do different colloid solutions have different effects on mitigating the risk of AKI?
i. Cirrhosis
Albumin. Daily administration of albumin has been shown to be beneficial in reducing the risk of AKI in
patients with cirrhosis and spontaneous bacterial peritonitis, although the exact mechanism underlying this
effect remains opaque.[65] In a multicenter, randomized trial by Sort et al,[66] the addition of an
intravenous infusion of human serum albumin to standard antibiotic treatment in patients with spontaneous
bacterial peritonitis reduced the rates of renal impairment and mortality; whether the effect occurs
exclusively on the basis of expanded effective circulating volume alone is not known. Although large-
volume paracentesis (LVP) has been used in the treatment of ascites, the need for plasma volume expansion
after therapeutic paracentesis remains controversial. While hemodynamic studies in patients with ascites
have shown that a significant reduction in intravascular volume and renal impairment occurs more
commonly when ascitic fluid is totally mobilized without prior or concomitant plasma volume expansion,
[65, 67-69] other studies of LVP without the administration of any plasma volume expanders document no
increase in renal complications. [70-72] Based on the International Ascites Club guidelines, 6-8 grams of
albumin is recommended to be infused per liter of ascites fluid removed for paracentesis volumes greater
than 5-6 liters.[17]
Starch. In a pilot study comparing the use of albumin and HES (in normal saline) in patients with cirrhosis
and spontaneous bacterial peritonitis, renal outcome was similar between the two groups.[73] Although
albumin is the most frequently used plasma volume expander for LVP, other plasma volume expanders
including Dextran 70,[74] 5% synthetic polymerized gelatin (hemaccel),[75] HES (in NS),[76] have also
been shown to be as effective as albumin in the prevention of complications related to large-volume
paracentesis. In one study, Cabrera et al. removed a mean of 8 L of ascitic fluid from 14 patients, with
replacement only by intravenous normal saline solution.[70] None of the patients had any clinical
complications or alterations in kidney function tests.
ii. Renal Transplant
Albumin. Several observational studies in kidney transplant recipients suggest that volume expansion with
albumin reduces the onset and the extent of post-transplant oliguria, and AKI while improving 1-year graft
and patient survival. Unfortunately controlled clinical studies are still lacking.[77-79] In one study,
although higher intra-operative albumin dose (1.2-1.6 g/kg bodyweight) was associated with better
outcomes in comparison to those receiving lower albumin dose (0-0.4 g/kg), the possible effects of
concomitantly administered mannitol, furosemide and crystalloid plasma volume expansion on outcomes
cannot be ignored.[77]
Starch. Comparison of intra-operative albumin and dextran-40 in 17 renal transplant recipients from a
living related donor failed to show any difference between the two plasma volume expanding agents with
regard to renal function.[80]
10
Summary: Volume expansion appears to be useful in avoiding renal dysfunction following LVP and
possibly in the setting of bacterial peritonitis even with small volume removal. It is unknown whether
different colloid preparations are more or less effective for volume expansion in patients with cirrhosis.
Data are inconclusive comparing different colloids in renal transplant. Recommendations for clinical
practice: No recommendations can be made for selecting between colloid preparations for mitigating risk of
AKI following LVP or renal transplant. Recommendations for future research: Randomized controlled
trials comparing HES and albumin for LVP and most renal transplant are needed.
How potassium containing fluids should be used in patients with AKI?
Blood Products. Packed red blood cell (PRBC) transfusion will deliver a measurable amount of potassium
to the blood volume of a recipient. The amount of potassium transfused increases with the age of banked
blood, and is least with fresh whole blood transfusion, as sporadically occurs in military scenarios with type
specific “buddy” transfusion. As banked blood ages, the integrity of the red blood cell plasma membrane is
compromised leading to extracellular translocation of normally intracellular potassium. While the amount
of potassium infused is measurable, hyperkalemia requiring therapy is rare with normal plasma potassium,
and is virtually nonexistent with hypokalemic states. Patients at greatest risk for transfusion associated
hyperkalemia are those receiving component transfusion on a massive transfusion protocol for
exsanguinating hemorrhage from a variety of clinical conditions.[81] Despite this theoretic risk, the major
risk with massive transfusion is hyperkalemia and hypocalcemia, is readily identified with transfusion of
frozen PRBC.[82] A recent study of 131 penetrating trauma victims found that, by multivariable logistic
regression analysis, independent risk factors for hyperkalemia were an emergency-room plasma potassium
level of 4.0 mmol/L or higher (RR 3.40, 95% CI 1.17-9.84, p=0.024), and transfusion of 20 or more units
of cell- or plasma-based transfusion products (RR 14.66, 95% CI 4.68-45.97 p < 0.001).[83] Hyperkalemia
risk may also be ameliorated by preinfusion washing methods.[84] Some risk may be potentially
ameliorated by incorporating activated factor VII into massive transfusion protocols as a means of reducing
total transfused units of PRBC; there is no data at present to support this speculation. Since the potassium
load with components other than PRBC is minimal, transfusion associated hyperkalemia is not a clinically
relevant issue when transfusing fresh frozen plasma, platelets, or cryoprecipitate.
Lactated Ringer’s solution. Lactated Ringer’s solution is formulated with a small amount of potassium,
and, according to conventional wisdom, has been commonly avoided as a resuscitation fluid in patients
with AKI or CKD. Certainly, in patients with a normal of low plasma potassium, LR is safe with regard to
hyperkalemia induction. This condition is exceedingly rare in the trauma patient population for whom LR
is the predominant resuscitation fluid in the US. However, in the renal transplant patient population, large
quantity plasma volume expansion with NSS was compared to expansion using lactated Ringer’s.[2] In this
study, only NSS was associated with hyperkalemia (K+ > 6 mEq/L) and metabolic acidosis that required
therapy. Moreover, this study was terminated early due to safety concerns in the NSS arm. One may
11
speculate that this observation reflects diminutions in RBF and GFR that accompany hyperchloremic
metabolic acidosis, but the mechanism underpinning these observations has not been fully elucidated.
Summary: Transfusion associated hyperkalemia is rare, but should be assessed when treating a patient
using a massive transfusion protocol. Lactated Ringer’s is safe for plasma volume expansion in those at risk
for AKI. NSS should be used with caution in the renal transplant patient due to the risk of hyperkalemia.
Recommendations for clinical practice: No change in transfusion practice is recommended as transfusion
associated hyperkalemia is rare. LR does not carry a risk of hyperkalemia.
What is the risk of AKI associated with blood substitutes?
Hemoglobin-based oxygen carriers (HBOC). Over the last two decades animal and human trials have
explored the use of HBOC for both plasma volume expansion and restoration of oxygen carrying capacity
in malaria, orthopedic surgery, cardiac surgery, and hemorrhagic shock from injury. Since the HBOCs that
are currently under clinical investigation are formulated in a normal to low potassium concentration diluent,
there is little to no risk of infusion associated hyperkalemia. Due to the colloidal nature of the products, and
the known vasoactivity of the products, resuscitation with an HBOC utilizes less total volume compared to
crystalloids and therefore, delivers less potassium. HBOC vasoactivity appears to be related to the
tetrameric composition of the product, and is reduced with current products (< 3% tetrameric Hgb)
compared to the 1st generation progenitor product, Baxter’s ill-fated DCLHB (> 30% tetrameric Hgb).
Vasoactivity is principally related to nitric oxide scavenging, although not exclusively so and has been
chiefly explored in the systemic circulation (systolic and mean arterial pressures) as well as the
cardiopulmonary circuit (pulmonary artery pressures and cardiac output).[85]
There are two main US competitor products, neither of which has currently garnered FDA approval for
licensing: Nothfield’s Polyheme and Biopure’s Hemopure (HBOC-201). Both products have undergone
extensive preclinical testing in predominantly porcine models of hemorrhagic shock, a condition associated
with AKI.[86] HBOC-201 does not demonstrate increased rates of AKI compared to standard crystalloid
plasma volume expansion even in prolonged low-volume resuscitation conditions.[87] HBOC-201
controlled and uncontrolled hemorrhagic shock preclinical data also includes histopathologic and electron
microscopic analysis of renal parenchyma and tubules documenting the absence of renal injury in treated
pigs.[88] Similarly, both products have undergone clinical trials without an increased incidence of AKI
compared to crystalloid plasma volume expansion.[89-93] These trials included patients with sickle cell
disease, patients undergoing elective vascular surgery, and trauma patients. Each of these (except the sickle
cell disease trial) trials include patients in RIFLE classification R as well as many in the I category. There
is no evidence of increased AKI occurrence in these trials supporting the potential use of HBOC in plasma
deficit conditions from which patients are at risk of AKI. The reader should note that Northfield has
recently completed a pre-hospital and in-hospital hemorrhagic shock trial, the results of which are not yet
publicly available, but will shed additional information on the use of HBOC in at-risk patients for AKI.
12
Biopure also manufactures a veterinary product, Oxypure, whose use is unassociated with renal injury in a
variety of mammalian species.
Summary: No definitive data exists on the use of HBOCs and abrogation or induction of AKI at present.
Recommendations for clinical practice: No recommendation can be made with regard to HBOCs at present.
Recommendations for future research: Randomized controlled trials comparing HBOC plasma volume
expansion and oxygen carrying capacity to crystalloid and colloid plasma volume expansion in RIFLE “R”,
“I” and “F” patients in the pre-hospital and in-hospital setting.
Fluids for Renal Replacement Therapy (RRT)
This section will review and make recommendations on the use of fluids for RRT.
What should be the composition of replacement fluid and dialysate?
General considerations. Although Peritoneal Dialysis is still used in different areas of the world, it is not
the preferred modality of renal replacement therapy (RRT) in AKI. Therefore, the composition of PD
solutions will not be further discussed in this review. Given the technical differences between intermittent
Hemodialysis (IHD) and continuous renal replacement therapies (CRRT), different considerations apply to
fluid composition in each modality. Finally, although other extracorporeal techniques (MARS, Plasma
exchange) are used in AKI, given that they are generally not used as RRT, they will not be discussed in this
document.
Fluids for IHD and IHDF. Higher dialysate sodium concentrations are associated with increased
hemodynamic stability in IHD.[94-96] In IHDF, whether the replacement fluid is infused pre- or post-filter
has an impact on the relationship between sodium concentration and sodium balance. During dialysis, the
majority of sodium movement is due to ultrafiltration, Sodium can also potentially move by diffusion. As a
result of a variety of physicochemical factors, including the difference between plasma sodium
concentration and the true concentration of sodium in plasma water and the Gibbs-Donnan effect, plasma
sodium concentration generally must be at least 4 mMol/L greater than dialysate sodium in order to diffuse
down a concentration gradient.[97] During hemofiltration, sodium moves with plasma water across the
hemofilter membrane, but due to protein coating of the membrane retarding sodium movement, the amount
of sodium sieved is < 1.0. Thus, when the same sodium concentration is used in dialysate and replacement
solutions, convective therapies tend to result in a greater positive sodium balance than pure dialysis,[98, 99]
possibly accounting for the greater cardiovascular stability with convective techniques are compared with
pure dialytic techniques for the same net rate of ultrafiltration.[100] Commercially available hemofiltration
replacement fluids vary in sodium concentration from 138-155 mMol/l.[101] Studies have suggested that a
positive sodium balance occurs when plasma sodium is less than 8 mMol/l higher than the replacement
fluid.[98] During hemofiltration the overall sodium balance is also affected by the site of infusion of
replacement fluid, as post-dilution results in greater sodium retention than mid-dilution, and mid-dilution
13
greater sodium retention than predilution, due to changes in protein polarization and hematocrit as blood
flows through the hemofilter.
Requirements for chloride, potassium, magnesium are variable in different clinical situations. Maintenance
of normoglycemia in the critically ill patient has been associated with improved outcomes.[102-104]
Removal of glucose from the dialysate has been shown to create risk of severe hypoglycemia. Trace
elements, including water soluble metals, micronutrients, aminoacids and folate are lost during
dialysis.[105, 106]
Summary and Recommendations for clinical practice: In hemodynamically unstable patients, consider
using increased sodium (up to 150-155 mMol/L) dialysate concentration. When the same sodium
concentration is used in dialysate and replacement solutions, convective therapies tend to result in a greater
positive sodium balance than pure dialysis,[98, 99] possibly accounting for the greater cardiovascular
stability with convective techniques are compared with pure dialytic techniques for the same net rate of
ultrafiltration.[100] Chloride, Potassium, Magnesium and other anion needs must be adjusted to each
individual situation. Glucose. Utilize physiological glucose concentration in dialysis fluids. Replace trace
elements, aminoacids, micronutrients and vitamins as necessary.
Fluids for CRRT. Existing clinical practice based on available evidence and opinion demonstrates that
sodium is generally kept at an isonatric (physiologic) concentration except when special prescriptions are
used in combination with some citrate anticoagulation protocols. Chloride, potassium, magnesium and
anion needs are variable in different clinical situations. Hypophosphoremia due to increased clearance and
intracellular shifts due to “refeeding” are common in CRRT, and may place patients at risk of
complications including rhabdomyolysis.[107] Maintenance of normoglycemia has been shown to be
associated with lesser mortality in the critically ill patient.[102-104] Trace elements, including water
soluble metals, micronutrients, aminoacids and folate are lost during CRRT.[105, 106]
Summary and Recommendations for clinical practice: Physiologic concentrations of sodium should be used
except when using citrate anticoagulation. In the latter circumstances, adjustments may be necessary given
the variable contents of sodium in different citrate solutions. Chloride, potassium, magnesium anions
should be present in replacement fluid and or dialysate in concentrations tailored to patient need and
anticoagulation procedures. Calcium should be absent from the replacement fluid and dialysate when
citrate is used as an anticoagulant. To avoid hypophosphoremia, phosphate should be provided either as a
supplement in the CRRT fluids (replacement fluid or dialysate) or as a nutritional supplement.[107] To
avoid hyperglycemia, Glucose can be either absent or present at physiological concentration in dialysis
fluid. Loss of trace elements (water soluble metals, micronutrients, aminoacids, and folate) must be
appropriately replaced.
14
What metabolizable anion should be used and under what circumstances?
Both lactate and bicarbonate ions have been used in replacement fluid and dialysate for CRRT.
Historically, lactate has been preferentially used as a buffer due to the instability of bicarbonate-based
solutions when stored over prolonged periods of time. This problem has recently been overcome, allowing
commercial availability of bicarbonate-based fluids. Controlled (though not all randomized) trials have
suggested that lactate and bicarbonate buffered solutions have a similar efficacy for correction of metabolic
acidosis during CRRT.[96, 108-112] However, recent studies [113, 114] showed better control of metabolic
acidosis with bicarbonate as compared to lactate. Barenbrock [114] also showed better hemodynamic
tolerance of therapy with bicarbonate. Neither study showed a difference in mortality, but neither was
adequately powered. Blood levels of lactate are generally higher when lactate is used as a buffer and may
confuse the clinical interpretation of these measurements. Whether this hyperlactatemia is associated with
morbidity is not clear. Depending on tissue redox status and substrate availability, lactate is either
metabolized back to pyruvate and into the citric acid cycle, resulting in proton buffering, or into glucose by
gluconeogenesis. Potential concerns with excessive lactate accumulation are hemodynamic compromise
[111], increased urea generation [109, 115] and cerebral dysfunction.[115] Hyperlactatemia may develop in
situations of impaired lactate clearance including liver failure and tissue hypoperfusion. This
hyperlactatemia can be expected to be more pronounced if lactate-buffered solutions are used during high-
volume hemofiltration. Accumulation of the D-isomer of lactate may also be a concern as the D-isomer
constitutes 50% of the total lactate contents of racemic mixes. As D-lactate is non metabolizable by
humans, it may accumulate, contributing to severely elevated lactatemia and associated with neurologic
impairment.
In the IHD literature, acetate has been shown to be associated with impaired myocardial contractility and
decreased cardiac function. This anion has been rarely used as a buffer in CRRT. Citrate, used primarily for
its anticoagulant properties, serves as an effective buffer. Scant evidence is available on the use of citrate
exclusively as a buffer in CRRT. Importantly, citrate metabolism is often impaired in liver failure or
muscle hypoperfusion, both situations posing risk of hypercitratemia when citrate is utilized.
Hypercitratemia carries the risk of decreased ionized extracellular calcium concentration. Importantly,
blood products contain citrate as an anticoagulant; massive blood or plasma product transfusions are
associated with high citrate loads, which accumulate when citrate is simultaneously used as an
anticoagulant and/or a buffer. Low concentrations of citrate are present in some commercial dialysate
solutions for IHD. Complications of citrate toxicity have not been associated with these agents.
Summary: Both lactate and bicarbonate are able to correct metabolic acidosis in most CRRT patients;
however, correction of acidosis may not be as efficient with lactate as with equimolar bicarbonate.
Worsening hyperlactatemia has been noted when lactate was used in patients with lactic acidosis or liver
failure. The clinical relevance of this finding is unknown. Citrate used as an anticoagulant has also been
effectively used as a buffer in CRRT. Recommendations for clinical practice: There is consensus that
bicarbonate is the preferred dialysis buffer in IHD. For CRRT, bicarbonate is an effective buffer and is
15
currently the preferred organic buffer in commercially manufactured solutions. Lactate-buffered solutions
are safe and efficacious in the majority of patients, but these solutions may be hazardous whenever lactate
clearance is impaired, such as in liver failure patients or patients with severe tissue hypoperfusion. D-
lactate should be removed from lactate-containing solutions, which should consists almost exclusively of
L-Lactate. There is insufficient data to evaluate the use of acetate-buffered solutions in CRRT. The
metabolism of sodium citrate used for regional anticoagulation during CRRT, generates three moles of
bicarbonate per mole of citrate and functions as an efficacious organic buffer. Use of citrate in the setting of
decreased citrate clearance or when patients receive large doses of citrate during massive transfusions
should be done with individualized adjustment of citrate dose and with close monitoring of plasma ionized
calcium levels. Recommendations for future research: Further studies comparing lactate and bicarbonate in
high volume hemofiltration are required. Optimal acid-base management of patients with permissive
hypercapnia requires further investigation.
Should the buffer concentration be higher in patients with permissive hypercapnia?
In patients with ARDS/ALI on lung protecting ventilator strategies, the resulting respiratory acidosis can be
partially or completely compensated by elevation of plasma bicarbonate with CRRT. The discussion of to
what level should acidemia be corrected is beyond the scope of this discussion.
How should fluids be compounded?
Assuring correct electrolyte formulation by repeat testing as needed, given that serious errors have been
reported when local pharmacies compound without regular monitoring of composition.[116-118]
Recommendations for clinical practice: When dialysis fluids are compounded locally, appropriate
monitoring of RRT fluid composition must be assured.
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Authors:
In alphabetic order:
Jorge Cerda, MD. Division of Nephrology, Albany Medical College and Capital District Renal Physicians Email: [email protected]
Lewis J. Kaplan, MD Department of Surgery; Section of Trauma, Surgical Critical Care and Surgical Emergencies, Yale University School of Medicine Email: [email protected]
John A. Kellum, MD. Department of Critical Care Medicine, University of Pittsburgh School of Medicine. Email: [email protected]
Mitra K. Nadim, MD. Division of Nephrology, Department of Medicine, University of Southern California Keck School of Medicine Email: [email protected]
Paul M. Palevsky, MD. VA Pittsburgh Healthcare System. University Drive Division, Pittsburgh, PA. Email: [email protected]