Page 1368 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 98: Renal Replacement Therapy in the Intensive Care Unit 941

arterial limb of the CRRT circuit. The PTT is targeted to approximately for the coagulation cascade). The advantage of regional citrate antico-
1.5 to 2 times the upper limit of normal. Low-molecular-weight hepa- agulation is in its very targeted effect without the risk of HIT and a lower
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rin (LMWH) offers an alternative to unfractionated heparin (UFH) for risk of bleeding compared with heparin. Multiple observational and
systemic anticoagulation to maintain the CRRT circuit. Importantly, controlled trials have demonstrated longer filter time with fewer bleed-
LMWH is usually renally cleared and, thus, has a greater duration of ing complications with the use of citrate versus heparin for anticoagula-
action in the setting of renal dysfunction. Further, protamine is not as tion. A single-center, randomized trial of 20 patients receiving CVVH
effective to correct/reverse anticoagulation from LMWH. Nevertheless, with anticoagulation compared filter time in the 12 patients receiving
LMWH anticoagulation can be carried out safely by monitoring systemic heparin and 8 patients receiving regional citrate. Median cir-
anti-Xa activity. 59,60 A safe protocol appears to be an initial prefilter cuit lifetime was 40 hours in the heparin group versus 70 hours in the
bolus of enoxaparin at 0.15 mg/kg followed by a maintenance infu- citrate group (p = 0.0007). A separate, single-center, randomized trial
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sion of 0.05 mg/kg/h titrated to maintain an anti-Xa level between also compared filter time in 16 patients receiving regional citrate versus
0.25 and 0.30 IU/mL. Direct thrombin inhibitors (DTI) remain the 14 patients receiving systemic heparin while on CVVHDF. The median
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alternative form of systemic anticoagulation when heparin use is filter survival was 124.5 hours in the group receiving citrate versus
contraindicated. Lepirudin, bivalirudin, and argatroban are the com- 38.3 hours in the heparin group (p < 0.001). Overall circuit clotting was
mercially available DTIs. Importantly, Lepirudin is exclusively renally much less common in the citrate group occurring in 16.7% of subjects
cleared, with a markedly prolonged half-life in renal failure, and has versus 53.5% in the heparin group. The sum of the data appears to
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no antidote. Significant bleeding complications have been observed support the use of regional citrate as CRRT circuit anticoagulation over
with the use of lepirudin for CRRT anticoagulation, and thus it is not systemic heparin. It is important to note that there are limited data
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recommended. Argatroban, on the other hand, is cleared by hepatic comparing citrate to regional heparin with protamine.
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metabolism, has been used safely in the setting of AKI, and is accord- Citrate infusion is not without its potential for complication. Serum
ingly the preferred anticoagulant in the setting of AKI and HIT. calcium, especially the ionized calcium value, must be monitored closely
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A loading dose of 250 µg/kg, followed by an infusion of 2 µg/kg/min to prevent hypocalcemia. Once citrate enters the blood, it is metabolized
to target the aPTT to 1.5 to 2 times the upper limit of normal was a in the liver, creating three molecules of bicarbonate for every one mol-
previously accepted dosing strategy; however, more recent data sug- ecule of citrate. Thus, if this buffer load is not accounted for with regard
gest that lower maintenance doses can be used (0.5 µg/kg/minute, to the composition of replacement solutions, there is the potential risk
or less in some patients). Specifically, Link and colleagues evaluated of developing metabolic alkalosis. Finally, the conversion of citrate to
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30 critically ill individuals with AKI requiring CRRT and concomitant bicarbonate requires a functional liver. Therefore, individuals with liver
history of HIT. Each individual was initially treated with an argatroban dysfunction may develop severe metabolic acidosis with an increased
loading dose of 100 µg/kg, followed by an infusion of 1 µg/kg/min. anion gap if they are unable to metabolize the citrate, because of
Dosing was then modified to target a PTT of 1.5 to 3 × the upper limit (anionic) citrate accumulation and the failure of anticipated bicarbonate
of normal. Once a maintenance dose was identified, the investigators generation from citrate. An important additional clue to the develop-
examined the association between severity of illness (via the APACHE ment of citrate overdose/toxicity is the development of a “calcium gap.”
II score, SAPS II score and indocyanine green plasma disappearance The “calcium gap” is observed when the total plasma calcium continues
rate [ICG-PDR]) and maintenance dose to develop an equation to predict to increase (or is above the upper limit of normal) and the ionized cal-
the maintenance dose of argatroban required in individuals dependent on cium remains low. Since the measurement of total calcium includes both
severity of illness. The study provided two conclusions: First, the mean ionized and bound calcium, increasing total calcium with unchanged
maintenance infusion rate was lower than 1 µg/kg/min (0.7 µg/kg/min) ionized calcium reflects an increased bound percentage. Calcium can be
for the majority of individuals, consistent with other literature suggesting increasingly bound to albumin (such as in the setting of alkalemia) or to
a decrease in the nonrenal clearance of argatroban in critically ill patients citrate in the setting of citrate-based anticoagulation when systemic citrate
(even with apparently normal liver function). Second, based on the study levels are increasing due to impaired metabolism. Rather than directly
results, the investigators found that the maintenance dose of argatroban measuring citrate levels, calculating the total plasma calcium to postfil-
required could be predicted using severity of illness assessment. Specifically, ter ionized calcium ratio strongly correlates with citrate concentration.
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the argatroban maintenance infusion rate based on APACHE II was A total calcium (in mmol/L): ionized calcium (in mmol/L) of greater
2.15-0.06 × APACHE II score, based on SAPS II was 2.06-0.03 × SAPS II than 2.1 had a sensitivity of 89% and specificity of 100% to identify a
score, and based on ICG-PDR was 0.35 + 0.08 ×_ICG-PDR value. 65,66 This citrate concentration greater than 1 mmol/L. Inability to metabolize
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evolving literature continues to provide valuable information to optimize citrate leading to citrate “overdose” can occur even in the absence of ful-
efficacy and safety in the use of argatroban in high-risk patients with HIT minant hepatic failure. Therefore, while using regional citrate anticoagu-
and renal failure. However, the use of predictive equations such as that devel- lation, one should carefully monitor for the development of a “calcium
oped by Link and colleagues requires further prospective validation studies. gap.” Finally, an attractive alternative remains to withhold anticoagula-
The options for regional anticoagulation include regional heparin tion while initiating therapy and only institute therapy if circuit patency
with protamine and citrate. Regional heparin carries less risk with becomes a problem. This strategy can be used with both diffusive and
regard to bleeding than systemic heparin. However, establishing the convective modalities where bleeding is a concern.
optimal dose of heparin and protamine remains difficult and the risk of
HIT remains. Heparin is administered prefilter and protamine is admin-
istered postfilter to neutralize the heparin, after which the heparin- SUPPORTIvE CARE
broken down. A ratio of 100 IU of heparin to 1 mg of protamine has been ■ NUTRITIONAL SUPPORT
protamine complex is taken up by the reticuloendothelial system and
suggested with usual doses of 1000 to 1500 IU of heparin administered In recent years, the role of nutritional support in the critically ill has
intravenously prefilter and 10 to 12 mg/h of protamine is administered become an important topic of increased investigation. 72,73 Patients with
postfilter. The unpredictability of the actual heparin/protamine dosing, critical illness, especially severe sepsis, septic shock, and multiorgan
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the technical aspects of pre- and postfilter infusions, and the efficacy of system failure (MOSF) are especially at high risk for severe malnutri-
regional citrate anticoagulation have made regional heparin-protamine tion. Many patients who develop MOSF have comorbid disease that
an uncommon anticoagulation strategy. contributes to a generalized state of malnutrition. Further, MOSF is a
Regional citrate remains the strategy of choice when anticoagulation catabolic state, where lean body mass breakdown is the rule leading to
is being used strictly to maintain the CRRT circuit. Prefilter infusion of a state of even more severe malnutrition. This tissue breakdown will
citrate works as anticoagulant by chelating calcium (a required cofactor alter creatinine kinetics. States of acute malnutrition impair patients’

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