**Table 6.**

*Pragmatical considerations with RRT modalities.*

of urea over the treatment session. It can be estimated with the urea reduction ratio (URR)<sup>4</sup> and the Kt/Vurea<sup>5</sup> for small molecules clearance, while the appreciation of medium-sized molecules removal is inferred by the quantification of beta-2 microglobulin (not done in acute care RRT) [19, 30–32]. However, variations of urea generation and difficulty defining the distribution volume (Vurea) in metabolically unstable patients are serious limitations in acute care settings. While KDIGO-AKI 2012 guideline still recommends an overall Kt/Vurea of 3.9 per week (1A highquality), the European Renal Best Practice (ERBP) 2013 position statement recommends against the use of Kt/Vurea as a measure of dialysis (1A high-quality) but

<sup>4</sup> URR = 100 (1 - [Ct/Co]), in which Ct = BUN at the end of dialysis and Co = predialysis BUN

<sup>5</sup> Kt/Vurea, in which K = clearance, t = time, V = distribution volume estimated as body water volume. For example, Qb 300 ml/min x 180 min = 54,000 ml = 54 L and 70 kg x 0.6 L/kg (60% body weight) = 42 L. Estimated non-adjusted Kt/Vurea = 54/42 = 1.3

More refined equation using pre/post-dialysis BUN is now used to account for UF and physiological BUN generation, known as the Daugirdas equation.

*Renal Replacement Therapies in the Intensive Care Unit DOI: http://dx.doi.org/10.5772/intechopen.105033*


## **Table 7.**

*Landmark RCTs on RRT dosing strategy.*

rather to ensure that intermittent therapy is adapted to maintain volume balance and metabolic homeostasis [19, 33].

One RCT includes intermittent modalities compared to dosing-based strategies. The Acute Renal Failure Trial Network **(ATN)** study included 1124 patients in 27 centers in the United States and compared intensive-therapy (IHD or SLED 6 days/ week if stable and CVVHDF 35 mL/kg/h if unstable) to less-intensive therapy (IHD or SLED 3 days/week if stable and CVVHDF 20 ml/kg/h if unstable) [34]. Targeted Kt/ Vurea was 1.2 to 1.4 for intermittent therapy and additional UF-only session could be done in the less-intensive strategy. No difference was obtained in 60-day mortality, RRT duration, or recovery of kidney function. More hypotension and electrolyte disturbance were seen in the intensive strategy.

## *3.3.2 Continuous modalities*

For CRRT, as the trans-membrane equilibrium is almost achieved at the end of the filter for small solutes, the limiting factor for clearance is therefore the effluent flow rate. Hence, the total delivered effluent rate, normalized to actual weight, is used to quantify clearance. According to the circuit configuration, that total effluent rate corresponds to the sum of the reinjection flow (pre- and post-filter) (if CVVH or CVVHDF) + the rate of dialysate flow (CVVHD or CVVHDF) + UF (see **Figure 3**). Even if the UF rate is included in the equation of the delivered dose, in clinical practice it is added once the targeted dose has been prescribed. First, it usually

### **Figure 3.**

represents a fraction of total effluent in an average size patient.<sup>6</sup> Also, since this rate is regularly modified, its exclusion always allows minimally sufficient delivered dose. Other options to optimize CRRT clearance such as increasing blood flow rate or filter surface have a reduced effect on optimizing clearance efficiency.

Between 2000 and 2008, four major RCTs evaluated the impact of different CRRT doses in critically ill patients. In 2000, using CVVH in 425 patients, three groups were compared [20 vs. 35 vs. 45 (mL/kg/h)] and mortality was significantly higher in the lowest UF rate group at 15 days after stopping RRT [35]. No difference was reported between the two higher rates. In 2002, using CVVH in 106 patients, three groups were compared [early high-volume (48.2 mL/kg/h) vs. early low-volume (20.1 mL/kg/h) vs. late low-volume (19.0 mL/kg/h)] and no mortality benefits was seen at 28 days [36]. In 2006, a study of 206 patients compared two groups [CVVH (25 mL/kg/h) vs. CVVHDF (reinjection rate 25 mL/kg/h + dialysis rate 18 mL/kg/h)] and mortality was significantly higher in the CVVH-only (at 28-day and three months) [37]. In 2008, using CVVHDF in 254 patients [20 vs. 35 (mL/kg/h)] and no mortality benefit was detected [38].

To confirm these previous findings from single-center trials, two multicenter RCTs (USA and AUSNZ) focused on this topic (see **Table 7**). In 2008, the **ATN** study reported no advantage in regards to mortality, duration of RRT, or recovery of kidney function. In 2009, the Randomized Evaluation of Normal Versus Augmented Level Replacement Therapy (**RENAL**) study, with more than 1508 patients from 35 ICUs in Australia and New Zealand and using CVVHDF with post-filter reinjection randomized participants between higher (40 mL/kg/h) vs. lower (25 mL/kg/h) intensity group [39]. As in the ATN study, no difference in mortality was observed. Based on these results, the KDIGO-AKI guideline recommends a delivered effluent volume of at least 20–25 mL/kg/h for AKI patients requiring RRT (1A high-quality). As previously mentioned, a slightly higher dose should be prescribed in order to achieve that

<sup>6</sup> In an 80 kg patient, an UF of 100 mL/h on a total dose of 25 ml/kg/h (2000 mL/h) represents 5%.

target regarding the dose truly delivered [19]. Some situations may require greater rates such as extreme metabolic imbalances or acute liver failure (see *Clinical Pearls* section).

## *3.3.3 Conclusion*

In summary, for both modalities, current evidence does not support using intensive therapy for all patients. For intermittent modalities, it seems appropriate to prescribe IHD at least 3 times a week to maintain volume and metabolic balance as long as there is no sign of underdosing (either a Kt/Vurea < 1.2 per session or URR < 67%). The weekly Kt/vurea does not apply in patients requiring additional IHD sessions to achieve a volume balance, as well as in patients with significant renal function. For continuous therapies, a prescribed effluent volume of 25–30 mL/kg/h is adequate in most scenarios to ensure a delivered dose of at least 20–25 mL/kg/h.

## **3.4 Anticoagulation**

Sustained circuit patency is crucial to optimize delivered RRT and contact of blood with extracorporeal circuit activates platelets and pathways of coagulation [40]. KDIGO-AKI guidelines suggest a flow chart to guide anticoagulation decision [19]. At first, it integrates the risk–benefit ratio of anticoagulation and whether another condition requiring systemic anticoagulation is present. RRT can be performed without or with systemic or regional anticoagulation.

## *3.4.1 No anticoagulation*

Although KDIGO-AKI guideline recommends using anticoagulation when bleeding risk is low, it is still common practice in many centers to deliver RRT without anticoagulation in this scenario unless filter patency is an issue. For example, in the STARRT-AKI trial, 24% of the 3019 included patients had no anticoagulation at the initiation. A key concept in preventing circuit clotting is maintaining a low filtration fraction (FF). Filtration fraction indicates relative fluid removed from blood across the dialysis membrane. Higher percentage means higher concentration of blood constituents. Fractions above >20% are associated with increased clotting [41]. The equation for CRRT (blood flow rate being converted from mL/min to mL/h to standardize units) is:

$$\begin{aligned} \text{FF} &= \frac{\text{Total UF rate}}{(\text{Plasma flow} + \text{Pre} - \text{filter}) \text{ rates}} \\ &= \frac{(\text{pre} - \text{filter} + \text{total UF} + \text{post} - \text{filter}) \text{ rates}}{((\text{1} - \text{hematocrit}) \text{blood flow m} / \text{h} \ge 60 \,\text{min} / \text{h}) + \text{Pre} - \text{filter}) \text{ rates}} \end{aligned}$$

*where total UF usually integrates all intravenous volumes received by the patient (e.g., IV medications, IV fluids, parenteral nutrition) in addition to the net UF (negative volume balance targeted) converted to mL per hour.*

Modifying elements only found to either the numerator or the denominator (marked in bold) have higher impact on the FF. Hence, from a clinical perspective, reducing FF is achievable by modifying flow rates: reduce net UF, increase pre-filter/post-filter ratio, increase blood flow, reduce hematocrit. Additionally, since hematocrit might be

reduced by pre-filter reinjection, it is obvious that administering blood transfusion directly pre-filter should be avoided when possible. Also, the catheter patency is essential by allowing prescribed flow rates, by avoiding stasis induced by alarms (e.g., kinked) and by maintaining a laminar flow (right jugular or femoral access).

For intermittent therapies, major assets helping prevent clotting are shorter sessions and higher blood flows, but clotting may be seen even if using heparin-coated filters, especially when substantial UF volume is removed. If convection is used (HDF or SLEDf), pre-filter reinjection can be used as well.

## *3.4.2 Systemic*

Most used agents are unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH). Mostly reserved for patients with heparin-induced thrombocytopenia (HIT), direct thrombin inhibitors (e.g., argatroban and bivalirudin) or Xa inhibitors (e.g., fondaparinux and danaparoid) have been used in intermittent and continuous therapies, but will not be discussed further [42, 43].

UFH has some advantages (e.g., short half-life, antagonist readily available, low costs, and a large experience), but has substantial drawbacks (e.g., narrow therapeutic, unpredictable kinetics and heparin resistance, HIT) [19]. Thrombocytopenia is frequently encountered in ICU occurring in up to 44% of patients. However, HIT remains relatively uncommon in critically ill patients, with a reported incidence from 0.2–5% [44], and has been reported with intermittent and continuous RRT. When used solely for circuit anticoagulation, both the loading and infusion UFH doses need to be adapted to the patient's bleeding/clotting risk as well as continuously monitored with aPTT.

LMWH has replaced UFH in most dialysis units (intermittent therapies) mainly because of convenience of a single dose at start of session associated with the same efficacy (at preventing circuit thrombosis) and security (bleeding) [45]. In addition, a more reliable response is obtained (no monitoring required) along with a reduced risk of HIT. LMWH has been used for CRRT with monitoring of anti-Xa levels [46], but longer half-life and risk of accumulation combined with incomplete reversal by protamine may limit widespread use.

## *3.4.3 Regional*

When systemic anticoagulation is not warranted by another indication than maintaining RRT circuit, regional anticoagulation is the recommended strategy. Regional heparinization has been described in CRRT (combining pre-filter UFH, and post-filter protamine), but KDIGO recommends against its use, notably in patients with increased bleeding risk [19]. Likewise, use of regional citrate anticoagulation (RCA) has been evaluated in intermittent therapies [47] but is not common practice. Hence, emphasis will be placed on RCA in CRRT.

As demonstrated in **Figure 4**, RCA may be perceived as complex [48] but has undeniable advantages: no risk of HIT, lower risk of bleeding compared to UFH along with longer filter lifespan. It is therefore recommended as first line for anticoagulation in CRRT in KDIGO-AKI guideline if no contraindication [19]. A 2015 meta-analysis demonstrated reduced circuit loss compared to UFH [HR 0.76 (95%CI 0.50–0.98) for systemic and HR 0.52 (95%CI 0.35–0.77) for regional] and reduced bleeding [RR 0.36 (95%CI 0.21–0.60)] [49]. A 2020 German RCT of 638 patients in 26 centers demonstrated longer filter lifespan (47 vs. 26 hours, p < 0.001), no mortality difference

*Renal Replacement Therapies in the Intensive Care Unit DOI: http://dx.doi.org/10.5772/intechopen.105033*

### **Figure 4.**

*CVVHDF with regional citrate anticoagulation (RCA). 1) blood, citrate solution, and optional calcium-free replacement fluid mix pre-filter. 2) citrate chelates circulating calcium (required for intrinsic and common pathways of coagulation). 3) calcium-free dialysate (avoiding calcium diffusion from dialysate to blood compartment) circulates countercurrent. 4) replacement fluid and calcium infusion to normalize calcemia are reinjected post-filter.*

(51.2% vs. 53.6%, p = 0.38), fewer bleeding complications (5.1% vs. 16.9%, p < 0.001), but more infections (68% vs. 55.4%, p = 0.002) in RCA compared to systemic heparin [50].

Thorough protocols and expertise in preventing/monitoring complications are required during RCA. The most immediate risk being unreplaced calcium since most complex (Ca-Citrate) is removed by the filter and may lead to severe hypocalcemia. So, one must be extremely careful if the calcium replacement IV line is assembled independently (e.g., CRRT machine continues, but calcium IV line is no longer potent). Citrate metabolism is the next consideration. The liver metabolizes one citrate into three bicarbonates. Even though low bicarbonate replacement and/or dialysate fluids are usually used, RCA is associated with more metabolic alkalosis than heparin [50]. If the liver cannot metabolize citrate, accumulation can be seen and translate in an anion gap metabolic acidosis associated with rise in total calcium levels, but decline ionized calcium. Thus, monitoring total calcium/ionized calcium ratio is helpful and a ratio > 2.5 is a sign of citrate accumulation which is also associated with hypernatremia and hypomagnesemia. Of note, once believed an absolute contraindication of RCA, it has been used safely in patients with liver diseases. A 2019 meta-analysis of 10 observational studies (1241 patients with liver dysfunction) showed no difference in pH, bicarbonate, metabolic alkalosis, lactate levels and total/ionized calcium ratios compared to patients without liver disease [51]. However, a more careful approach than in usual patients should be taken (e.g., tighter biochemical monitoring, lower citrate dose or lower total calcium/ionized calcium threshold) to regularly reassess its safety.

In summary, sustained circuit patency is required to optimize RRT. Understanding filtration fraction is of great help, mainly if anticoagulation is contraindicated. Otherwise, if no other indication mandates systemic anticoagulation, LMWH is the usual first choice for intermittent therapies and RCA for CRRT.

## **3.5 Stopping RRT**

Literature is lacking to guide discontinuation of RRT initiated in context of AKI as revealed by the KDIGO-AKI recommendation that simply states "when it is no longer required, because kidney function has recovered to meet patient need or because RRT is no longer consistent with goals of care" [19]. Assessment of recovering kidney function in particularly difficult during RRT. While on intermittent therapy, steady state is not attained therefore excluding use of routine clearance measurements. Interdialytic evaluation of urine volume and creatinine, absolute rise of serum biomarkers (creatinine and BUN), but most probably the rising kinetic over time are frequently used. In a prospective observational study, spontaneous urine output was the best predictor of weaning RRT [52]. A recent systematic review found that urine output prior to RRT discontinuation was the most studied variable, but no threshold value could be determined due to heterogeneity of studies [53]. Pooled analysis found a sensitivity of 66% and specificity of 74% to predict RRT discontinuation, but cut-off values varied from 100 mL increase/day to >1720 mL/24 h. Of note, in one RCT, diuretic-induced diuresis had no benefit on repeated need for RRT or renal recovery [54]. In a retrospective study, a 24-hr urine creatinine clearance >15 ml/min was associated with absence of CRRT need at 14 days [55]. In another study, a 24 h urine creatinine of ≥5.2 mmol on day 2 post-RRT had a 86% sensitivity and 81% specificity of not requiring additional RRT treatment [56]. On the other hand, longer duration of RRT, more severe disease (SOFA score) and older age were associated with restarting RRT which correlated with higher mortality [57].

In summary, clear guidance in stopping RRT is lacking and implies at first a minimal diuresis to avoid marked net fluid accumulation. Then, careful monitoring of clinical (weight, volume balance, diuresis) and paraclinical (serum biomarkers, urine creatinine clearance) data are valuable tools.
