How To Prescribe And Troubleshoot Continuous Renal Replacement Therapy: A Case-Based Review

Abstract

Continuous RRT (CRRT) is the preferred dialysis modality for solute management, acid-base stability, and volume control in patients who are critically ill with AKI in the intensive care unit (ICU). CRRT offers multiple advantages over conventional hemodialysis in the critically ill population, such as greater hemodynamic stability, better fluid management, greater solute control, lower bleeding risk, and a more continuous (physiologic) approach of kidney support. Despite its frequent use, several aspects of CRRT delivery are still not fully standardized, or do not have solid evidence-based foundations. In this study, we provide a case-based review and recommendations of common scenarios and interventions encountered during the provision of CRRT to patients who are critically ill. Specific focus is on initial prescription, CRRT dosing, and adjustments related to severe hyponatremia management, concomitant extracorporeal membrane oxygenation support, dialysis catheter placement, use of regional citrate anticoagulation, and antibiotic dosing. This case-driven simulation is made as the clinical status of the patient evolves, and is on the basis of step-wise decisions made during the care of this patient, according to the specific patient’s needs and the logistics available at the corresponding institution.

Introduction

AKI affects up to half of patients who are critically ill, admitted to intensive care units (ICU) (¹,²). In patients with AKI and hemodynamic instability, continuous RRT (CRRT) is the preferred dialysis modality for solute management, acid-base stability, and volume control. ICU mortality in this vulnerable population is as high as 75%, but kidney recovery occurs in up to two thirds of survivors (^12–3). Several factors contribute to these deleterious outcomes, including overall severity of acute illness, multiorgan failure, or the pathophysiologic effects of AKI itself (⁴,⁵).

CRRT is a lifesaving RRT modality for patients who are critically ill with AKI (⁶). CRRT removes toxins and excessive fluid, and replenishes substances that are needed. It offers multiple advantages over conventional hemodialysis in the critically ill population, such as greater hemodynamic stability, better fluid management, greater solute control, lower bleeding risk, and a more continuous (physiologic) approach of kidney support. In the recent years, technology for the provision of CRRT to patients who are critically ill has evolved and some standardization in practice has been achieved, such as the consensus on delivered effluent flow rates of 20–25 ml/kg per hour (⁷); however, several aspects of CRRT delivery are still not fully standardized, or do not have solid evidence-based foundations (⁸). Therefore, there is wide heterogeneity in clinical practice for the provision of CRRT and, for some patients, suboptimal care (⁶,⁹).

In this study, we provide a case-based review and recommendations of common scenarios encountered during the provision of CRRT to patients who are critically ill, with a focus on initial prescription and iterative adjustments as the case evolves, which somehow simulates real-time scenarios encountered frequently at the bedside.

Patient Vignette

LC is a 68-year-old woman (weight before hospitalization 120 kg), with a medical history of hypertension, coronary artery disease status post percutaneous coronary intervention, and gastroesophageal reflux, who was transferred to a tertiary care center for extracorporeal membrane oxygenation (ECMO) consideration after being treated for acute respiratory failure at an outside hospital for 7 days. Then 2 weeks before admission, she developed upper respiratory symptoms and was prescribed an antibiotic, which she took without improvement. At the outside hospital, she required intubation and mechanical ventilation, and had worsening hypoxia despite antibiotics, steroids, diuretics, and inhaled epoprostenol, prompting her transfer for ECMO support. She had a computed tomography scan with intravenous contrast before transfer that showed bilateral ground glass opacities. Nephrology was consulted 24 hours after ECMO cannulation for oliguric AKI.

At the time of consultation, she was intubated, mechanically ventilated, on veno-venous (VV) ECMO and systemic heparin. She was on an NE infusion, and treated with azithromycin, piperacillin-tazobactam, vancomycin, and oseltamivir. She had been anuric for the past 12 hours, despite a high-dose diuretic challenge. Admission sodium was 130 mEq/L and had been slowly drifting down over the hospital course. The patient at time of CRRT initiation had a 15 L positive fluid balance and >10% fluid overload from ICU admission. Her current weight at time of consultation was 135 kg (baseline 120 kg). See Table 1 for a summary of clinical data.

Table 1. - Summary of patient’s clinical data fluid overload from intensive care unit admission to outside hospital to continuous RRT initiation: +15 L >10% from before hospitalization (current weight 135 kg)

Parameter	Result
No Known Drug Allergies
ECMO assessment	VV-ECMO
ECMO type	Maquet Cardiohelp
Clots on oxygenator	Not present
Quality of oxygenator	Good
ECMO total flow	6.21
RPM	4600
ECMO sweep gas flow	5 L/min
ECMO FiO2	100%
ECMO preoxy pressure	253 mm Hg
ECMO postoxy pressure	207 mm Hg
ECMO delta pressure	46
Ventilator settings
Minute ventilation	1.02 L/min
Vent rate set	10 br/min
I: E ratio	1:2.00
Vent mode	SIMV
O2 delivery device	Ventilator
Volume exchange	102 ml
Spontaneous rate	5 br/min
Peak airway pressure	34 cmH20
Plateau pressure	29 cmH20
FiO2	100%
Pressure set	22 cmH20
PEEP/CPAP set	12 cmH20
PS level set	20 cmH20
Labs at consultation
Sodium (mEq/L)	119
Potassium (mEq/L)	5.4
Chloride (mEq/L)	96
Bicarbonate (mEq/L)	18
BUN (mg/dl)	64
Creatinine (mg/dl)	3.0
Calcium (mg/dl)	9.9
Albumin (g/dl)	3.1
Lactate (mMol/L)	2.5
AST/ALT (U/L)	78/53 (nl: 12–39/7–52)
PT/INR/PTT (s)	33/3.14/48
Arterial blood gas	7.36/38/20/50
White blood cell (103 cells/mm3) 15
Hemoglobin (g/dl)	10.1
Hematocrit (%)	30%
Platelet (103 cells/mm3)	61
Total bilirubin (mg/dl)	2.5 (nl: 0.3–1.4)
Plasma haptoglobin (mg/dl)	110
LDH (U/L)	987
Urine microscopy	Multiple granular casts
Vasopressor requirement	NE

ECMO, extracorporeal membrane oxygenation; VV, veno-venous; SIMV, synchronized intermittent mechanical ventilation; PEEP, positive end expiratory pressure; CPAP, continuous positive airway pressure; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time; INR, international normalized ratio; PTT, partial thromboplastin time.

Scenario 1: Initial CRRT Prescription

LC is critically ill with multiorgan failure, including respiratory failure, shock, and anuric AKI. In addition, evolving fluid overload at a level consistently associated with mortality (>10%) (³,^1011–12) and biochemical abnormalities such as metabolic acidosis prompt CRRT initiation (¹³). For this patient, CRRT will be added in tandem to the ECMO circuit, so there will be no need to place an additional catheter for CRRT. Beyond access, the initial considerations when prescribing CRRT include:

1. What CRRT modality? Continuous VV hemofiltration (CVVH, convective clearance) versus CVV hemodialysis (CVVHD, mostly diffusion) versus CVV hemodiafiltration (CVVHDF, diffusion and convection). Despite diffusion and convection being distinct dialysis physiologic processes (Figure 1), in terms of hard clinical outcomes (e.g., mortality or kidney recovery), there is no evidence to support one modality as more beneficial over the other for the overall CRRT population (¹⁴). Therefore, one should decide according to the available protocols, expertise, and logistics of the specific hospital in which CRRT is being delivered. For our patient, LC, we will prescribe CVVHDF.
2. What effluent dose? The effluent fluid rate is a surrogate of solute clearance provided by CRRT and is reported in milliliters per hour and adjusted by the patient’s weight in kilograms (ml/kg per hour). When determining CRRT dose, it is recommended to use the most updated patient weight (at the time of prescribing CRRT), as it theoretically accommodates acute increases in volume of distribution due to fluid overload. The recommended average delivered effluent dose is 20–25 ml/kg per hour for patients with AKI requiring CRRT on the basis of data from the Veterans Affairs / National Institutes of Health Acute Renal Failure Trial Network Study and Randomized Evaluation of Normal versus Augmented Level Replacement Therapy Study (⁷,¹⁵,¹⁶). However, one should recognize that the prescribed dose is not always delivered due to multiple patient-related reasons, such as off-room diagnostic procedures, interventions, or CRRT-related downtime as a result of replacing filters, bags, tubing, or catheter-malfunction problems (¹⁷,¹⁸). Therefore, a patient on CRRT requires an iterative evaluation of goals of care (solute and volume control) to adjust CRRT dose and prescription as needed (⁶). When prescribing high-dose CRRT (>30 ml/kg per hour), careful monitoring of electrolyte disturbances (e.g., hypophosphatemia), nutritional deficits, and drug dosing (e.g., antibiotics) is necessary to prevent complications. For our patient, LC, we will prescribe an effluent dose of approximately 30 ml/kg per hour (4000 ml/h) accommodating for an expected 5%–10% downtime and the predilution factor.Table 2 summarizes similar effluent doses under different CRRT modalities, including the adjustment for predilution if needed.
3. What net ultrafiltration (UF)? Due to objective data of fluid overload in our patient (e.g., cumulative fluid balance, computed tomography of the chest, and respiratory status), tailored fluid removal is recommended to improve the patient’s chance of survival and organ recovery. However, data on the rate of fluid removal are mostly observational and likely confounded by indication (^1920–21). Given the lack of clinical trials addressing this important aspect of the CRRT prescription, and the lack of fully validated methods of predicting and assessing fluid removal tolerance and need, significant heterogeneity in practice exists (²²). Although the prescription of net UF is highly dynamic and commonly individualized, it is recommended not to exceed 1.5–2.0 ml/kg per hour of net UF as a general rule. For our patient, LC, we will prescribe a net UF rate to achieve a goal of negative 50 ml/h until she is reassessed later in the treatment course.
4. What blood flow? A minimum blood flow of 150 ml/min maximizes clearance for prefilter replacement fluid rates of up to 1500 ml/h and dialysis fluid rates of up to 3600 ml/h (²³,²⁴). For our patient, LC, we will prescribe a blood flow of 200 ml/min.
5. What anticoagulation? Our patient is currently on systemic anticoagulation with heparin (²⁵) at therapeutic levels prescribed for VV ECMO, therefore we will not use regional citrate anticoagulation (RCA) (²⁶) at this time for CRRT.
6. Summary of CRRT prescription (Table 3). CVVHDF, blood flow rate 200 ml/min, dialysate fluid rate 2000 ml/h, preblood pump (prefilter replacement fluid) 1000 ml/h, postfilter replacement fluid 1000 ml/h, net UF goal of net negative 50 ml/h, solutions composition: sodium 140 mEq/L, potassium 4 mEq/L, chloride 113 mEq/L, calcium (Ca) 2.5 mEq/L, lactate 3 mEq/L, bicarbonate 32 mEq/L, glucose 110 mg/dl, osmolarity 300 mOsm/L.

Figure 1.: Conceptual differentiation between diffusive and convective clearance with continuous RRT (CRRT). In diffusive clearance (A), solutes move across the hemodialyzer from a high concentration to a low concentration. Movement continues until equilibrium is reached. This method is good for small solutes. In convection clearance (B), movement of solutes is associated with fluid movement (solute drag). Movement is depended on the rate of fluid movement (total ultrafiltration rate). No gradient is needed, middle-sized solutes are pushed out along with the fluid (replacement fluid is needed).

Table 2. - Simulation of effluent dosing under different continuous RRT modalities in our patient, assuming 100 ml/h of fluid removal rate is required to achieve a net ultrafiltration goal of net negative 50 ml/h as prescribed

Simulation of effluent dosing under different CRRT modalities
CVVHDF: total ultrafiltration rate (2000 ml/h) a + dialysate rate (2000 ml/h) + fluid removal rate (100 ml/h) = effluent dose of 30.4 ml/kg per h → 26.8 ml/kg per h after predilution adjustment (30.4×0.88) b assuming 50% of replacement fluid as prefilter (preblood pump =1000 ml/h)
CVVH: total ultrafiltration rate (4000 ml/h) a + fluid removal rate (100 ml/h) = effluent dose of 30.4 ml/kg per h → 23.7 ml/kg per h after predilution adjustment (30.4×0.78) b assuming 50% of replacement fluid as prefilter (preblood pump =2000 ml/h)
CVVHD: dialysate rate (4000 ml/h) + fluid removal rate (100 ml/h) = effluent dose of 30.4 ml/kg per h

Plasma flow rate (ml/h), blood flow rate (ml/min) ×60 (min/h) × (1-HCT); where HCT is the current hematocrit of the patient (HCT 30% for the case of our patient). CVVHDF, continuous veno-venous hemodiafiltration; CVVH, continuous veno-venous hemofiltration; CVVHD, continuous veno-venous hemodialysis.

^aTotal ultrafiltration rate (ml/h) = preblood pump or prefilter replacement fluid rate + postfilter replacement fluid rate.

^bDilution factor for predilution: Plasma flow rate (ml/h)/[Plasma flow rate (ml/h) + prefilter replacement fluid rate (ml/h)] = 0.88 for our patient (1000 ml/h prefilter replacement fluid in CVVHDF) and 0.78 (assuming 2000 ml/h of prefilter replacement fluid in CVVH).

Table 3. - Summary of initial continuous RRT prescription

Parameter	Prescription
Modality	CVVHDF
Filter type	HF1400 (per protocol)
Dose	30 ml/kg per h
Anticoagulation	Systemic heparin per ECMO protocol
Blood flow	200 ml/min
Preblood pump	4K/2.5Ca *140Na
Preblood pump rate	1000 ml/h
Dialysis fluid	4K/2.5Ca *140Na
Dialysis fluid rate	2000 ml/h
Replacement fluid (post)	4K/2.5Ca *140Na
Replacement fluid (post) rate	1000 ml/h
Net UF goal	Net negative 50 ml/h
Calcium chloride rate	None

ECMO, extracorporeal membrane oxygenation; UF, ultrafiltration; CVVHDF, continuous veno-venous hemodiafiltration.

Scenario 2: Addressing Rapid Correction of Serum Sodium in Patients on CRRT

Patients with chronic hyponatremia and kidney failure who require RRT pose a special therapeutic challenge. Rapid correction of serum sodium concentration places these patients at risk for osmotic demyelination syndrome (²⁷,²⁸). Although serum sodium concentration increase with CRRT is less rapid than hemodialysis, it can far exceed recommended correction limits (≤8 mEq/L) if factors affecting sodium change are ignored (²⁹). Therefore, the CRRT prescription may need to be individualized on the basis of the duration and/or severity of hyponatremia if the anticipated change exceeds the recommended therapeutic targets.

• (1) What is the expected rise in serum sodium at 24 hours with the above CRRT prescription?

Sodium kinetic models have been shown to predict end-dialysis plasma water sodium concentration (³⁰). Some reported equations are complex and may be prohibitive for daily use. Instead, a single-pool, fixed-volume, sodium kinetic equation may be used in a manner similar to urea kinetics for the quantification of sodium changes during CRRT (Figure 2). The patient’s serum sodium at 24 hours from CRRT initiation can be estimated using Equation 1 in patients with negligible nonisotonic fluid gains or losses (²⁹,³¹). Bedside application of the single-pool, fixed-volume sodium kinetic model has been reported by several groups since it was first described by Yessayan et al. (²⁹,³²,³³).(1)$N{a}_{\left(t\right)}= N{a}_0+ \left(N{a}_{dial/RF}- N{a}_0\right)\times \left(1-e^{\frac{-Dt}{V}}\right)$where Na_dial/RF is the dialysate/replacement fluid sodium concentration, Na₀ is the initial serum sodium concentration, D is the effective sodium dialysance, which is nearly equal to effective urea clearance, t is the time elapsed since CRRT initiation, and V is the total body water volume. An estimate of V can be calculated using the Watson formula applied to the patient’s euvolemic weight (before hospitalization) and adding to this any estimated edema volume. In our case, the Na₀ is 119 mEq/L, Na_dial/RF 140 mEq/L, D is roughly equal to the sum of dialysate and replacement fluid rates (4 L/h), and V is approximately 60 L (45 L of total body water estimated through the Watson formula applied to her dry weight and 15 L of edema). By applying the above sodium kinetic model and substituting for patient and CRRT prescription variables, the predicted serum sodium concentration at 24 hours with the above prescription will be approximately 136 mEq/L, and thus will exceed the recommended limits of correction:(2)$N{a}_{\left(t\right)} =119 + \left(140-119\right)\times \left(1-e^{\frac{-4\times 24}{60}}\right)=136 \text{mEq/L}$

• (2) What strategies could be used to avoid serum sodium overcorrection and maintain serum sodium within a desired range?

Figure 2.: Graphic simulation of serum sodium correction over 24 hours. Continuous RRT (CRRT) solutions were utilized with sodium concentration of 129 mEq/L (dotted line, the case of our patient) versus 140 mEq/L (solid line, standard CRRT solutions).

Strategies to avoid overly rapid correction of chronic hyponatremia include using hyponatremic CRRT solutions, using separate hypotonic infusions, and regulating the overall and hourly clearance delivered by CRRT using kinetic principles (³¹). In those with concomitant clinically significant abnormalities of other solutes (e.g., hyperkalemia, metabolic acidosis), decreasing the CRRT dose should be avoided. Although these strategies are helpful in predicting the rate of change in serum sodium level, frequent laboratory confirmation is still advised. Clinical factors that affect serum sodium may change over time, and readjustment of the approach may be necessary (³¹).

• (3) If you chose to use hyponatremic CRRT solutions as your strategy, what sodium concentration in the CRRT solutions should be used to maintain the patient’s serum sodium within a desired range of ≤8 mEq/L?

Commercial hyponatremic CRRT solutions are lacking. Therefore, commercially available CRRT fluids need to be diluted with free water to achieve the desired sodium concentration. This approach can be adopted at institutions with adequate pharmaceutical support. A stepwise switch every 24 hours to CRRT solutions with higher sodium concentration than the patient’s current serum sodium can be considered. The CRRT solution sodium concentration needed to maintain serum sodium within desired limits of correction can be estimated using the following formula (²⁹):$CRRT solution \left[N{a}^{+}\right]=\frac{desired \Delta serum \left[N{a}^{+}\right]}{\left(1-e^{- \frac{D \times 24 hr}{V}} \right)}+ initial serum \left[N{a}^{+}\right]$For a desired change of 8 mEq/L at 24 hours, and an initial serum sodium of 119 mEq/L and sodium dialysance of 4 L/h, a CRRT solution with sodium concentration of 129 mEq/L will be required. The approach of using solutions with successively higher sodium concentration may be reliable in avoiding any overcorrection in serum sodium due to CRRT. The dilution can be achieved by injecting free water into the CRRT solution bag or exchanging a volume of CRRT solution with an equivalent volume of water. Both dilution methods have been described in detail previously (²⁹). Tables 4 and 5 demonstrate the effect of adding different volumes of sterile water to a 5 L dialysate/replacement fluid bag, or exchanging different volumes of a 5 L dialysate/replacement fluid bag with sterile water on sodium and other electrolyte concentrations.

• (4) Your hospital does not have adequate pharmaceutical support to dilute the CRRT solutions. At what rate should 5% dextrose water (D5W) solution be administered to maintain the patient’s serum sodium within a desired range of ≤8 mEq/L?

Table 4. - Effect of adding different volumes of sterile water to a 5 L dialysate/replacement fluid bag (NxStage PureFlow dialysate solutions RFP 401)

Volume Added (ml)	Sodium Final (mEq/L)	Potassium Final (mEq/L)	Bicarbonate Final (mEq/L)	Calcium Final (mEq/L)	Magnesium Final (mEq/L)	Chloride Final (mEq/L)
0	140.00	4.00	34.00	3.00	1.00	113.00
250	133.33	3.81	32.38	2.86	0.95	107.62
429	128.94	3.68	31.31	2.76	0.92	104.07
500	127.27	3.64	30.91	2.73	0.91	102.73
713	122.53	3.50	29.76	2.63	0.88	98.90
750	121.74	3.48	29.57	2.61	0.87	98.26
1000	116.67	3.33	28.33	2.50	0.83	94.17
1250	112.00	3.20	27.20	2.40	0.80	90.40

Reprinted from ref. (²⁹), Copyright Elsevier (2014).

Table 5. - Effect of exchanging different volumes of a 5 L dialysate/replacement fluid bag with sterile water (NxStage PureFlow dialysate solution RFP 401)

Volume replaced (ml)	Sodium Final (mEq/L)	Potassium Final (mEq/L)	Bicarbonate Final (mEq/L)	Calcium Final (mEq/L)	Magnesium Final (mEq/L)	Chloride Final (mEq/L)
0	140.00	4.00	32.00	3.00	1.00	113.00
250	133.00	3.80	30.40	2.85	0.95	107.35
429	127.99	3.66	29.25	2.74	0.91	103.30
500	126.00	3.60	28.80	2.70	0.90	101.70
713	120.04	3.43	27.44	2.57	0.86	96.89
750	119.00	3.40	27.20	2.55	0.85	96.05
1000	112.00	3.20	25.60	2.40	0.80	90.40
1250	105.00	3.00	24.00	2.25	0.75	84.75

Reprinted from ref. (²⁹), Copyright Elsevier (2014).

Infusing electrolyte-free water as a D5W solution into the patient or into the return limb (venous return port) of the CRRT blood circuit is another approach to decrease the rate of correction of serum sodium. Safety concerns with this technique include the theoretical risk of worsening hyponatremia with filter clotting and rapid correction of sodium if consecutive D5W bags run out while the CRRT continues. The D5W infusion rate to maintain serum sodium below a desired target level could be estimated using the following formula (³¹):(4)$D5W rate=\frac{CRRT solution \left[N{a}^{+}\right]-target serum \left[N{a}^{+}\right]}{CRRT solution \left[N{a}^{+}\right]}\times desired clearance$For example, in this patient with initial serum sodium of 119 mEq/L, CRRT solution [Na⁺] of 140 mEq/L, effluent rate or clearance of 4.0 L/h, the D5W infusion should be administered at a rate 0.314 L/h (314 ml/h) to keep the serum sodium concentration at or below 127 mEq/L. The net UF setting should be increased by the rate of the D5W infusion (314 ml/h). For our patient, we will dilute the CRRT solutions (dialysate and replacement fluid) to an initial sodium concentration of 129 mEq/L in the first 24 hours, with anticipated successive adjustment of sodium concentration in CRRT solutions according to the patient’s most current serum sodium in the following 24 hours.

Scenario 3: Considerations of ECMO-CRRT in Tandem Connections

Use of ECMO has increased over the last decade as techniques, technology, and protocols have advanced. ECMO may be considered for patients with severe acute hypoxemic and/or hypercapnic respiratory failure who fail conventional mechanical ventilation. The most common ECMO modality utilized for respiratory failure is VV support. Less commonly, veno-arterial ECMO or a hybrid method of support may be utilized (³⁴). Several studies have been performed over the last decade, examining ECMO for respiratory failure, with mixed results (^{3536373839–40}). Two prospective, multicenter trials of ECMO for severe respiratory failure or acute respiratory distress syndrome (Conventional Ventilatory Support versus Extracorporeal Membrane Oxygenation for Severe Adult Respiratory Failure and the ECMO to Rescue Lung Injury in Severe Acute Respiratory Distress Syndrome) showed: (1) a survival benefit with early referral to a tertiary ECMO center; and (2) no difference in 60-day mortality when ECMO was compared with conventional mechanical ventilation with ECMO rescue (⁴¹,⁴²).

For patients requiring both CRRT and ECMO, the CRRT machine may be connected directly to the ECMO circuit, or CRRT and ECMO may be performed independently (Figure 3). There are advantages and disadvantages to both options, but it is important to note that connecting CRRT with ECMO is not currently a US Food and Drug Administration–approved strategy. Combining CRRT with the ECMO circuit avoids additional catheter-associated complications, including risks associated with catheter insertion, infection, and mechanical complications. However, combined CRRT and ECMO may result in abnormal pressures in the ECMO circuit (low-pressure alarms when the CRRT drainage or return access is placed before the blood pump, and high-pressure alarms when placed after the blood pump) (⁴³). High pressure in the CRRT circuit may result in treatment interruptions or stop the circuit. As a result, alarm adjustments may be necessary on some CRRT devices. Newer-generation CRRT devices can be programmed to account for pressure changes when connecting to the ECMO circuit or automatically recognize an ECMO connection. There may be other complications related to combining CRRT with ECMO, including infection, clotting, air embolism, thromboembolism, flow limitations, and hemolysis. Whether connecting CRRT to the ECMO circuit ultimately reduces complications, as compared with providing each independently, is yet to be examined in a prospective manner.

Figure 3.: Continuous RRT (CRRT) and extracorporeal membrane oxygenation (ECMO) example. Blood flows from the patient into the ECMO circuit toward the blood pump and membrane oxygenator. In this example, blood flows to the CRRT circuit from a site distal to the oxygenator. Blood returns from the CRRT device to the ECMO circuit at a position before the oxygenator. Other configurations that combine CRRT with ECMO are also possible.

Strategies for combining CRRT and ECMO have previously been described (^{44454647–48}). An in-line hemofilter or CRRT circuit may be integrated into the ECMO circuit. The inlet limb (access port) of a hemofilter can be connected after the blood pump, and the outlet limb (return port) is typically connected before the membrane oxygenator. This approach is less costly compared with CRRT, but disadvantages include a lack of pressure alarms and poor control of net UF. A stopcock or similar instrument to restrict blood flow can be added but may increase the risk of thrombosis or hemolysis. Alternatively, the CRRT and ECMO circuits can be joined together, thereby allowing for circuit pressure monitoring and better net UF control. Depending on the ECMO device utilized, the inflow to the CRRT device can be placed before or after the blood pump, or in some patients between the blood pump and oxygenator when these components are separated. Blood from the CRRT device is typically returned to the ECMO circuit before the membrane oxygenator to reduce the risk of systemic emboli. Extracorporeal carbon dioxide removal can also be achieved by inserting a membrane oxygenator, rather than full ECMO support, into the CRRT circuit (⁴⁹,⁵⁰). This technique has been used to permit protective lung ventilation in severe acute respiratory distress syndrome and to improve acidosis in hypercapnic respiratory failure.

For our patient, a Maquet Cardiohelp was used for ECMO support. In this device, the blood pump and membrane oxygenator are integrated. To combine CRRT with ECMO, the CRRT inlet line can be connected to an access port in the ECMO circuit after the membrane oxygenator. The CRRT outlet line is connected to an access port, proximal to the blood pump/oxygenator. In addition to monitoring circuit pressures, several parameters should be followed when CRRT is connected with ECMO. Anticoagulation can prolong circuit life and can be monitored by activated clotting time, anti-Xa level, coagulation studies (partial thromboplastin time and prothrombin time), or thromboelastography. Plasma-free hemoglobin levels can be monitored for hemolysis. Additional laboratory studies, including serum chemistries, complete blood count, platelet count, fibrinogen level, liver function profile, antithrombin level, and arterial blood gases are monitored to assess patient status and circuit performance. RCA can be used with or without systemic heparin when CRRT is combined with ECMO.

Scenario 4: Considerations About Dialysis Catheters for CRRT

LC was successfully decannulated from VV ECMO and her overall clinical status improved. However, she remains anuric without signs of kidney recovery at present. The nephrology team was called to determine the best practices for CRRT dialysis access placement.

It is critical to recognize that a functional vascular access is necessary for CRRT delivery, particularly because adequate blood flow is required to achieve CRRT goals. The latter is more relevant when prescribing convection (e.g., CVVH or CVVHDF) due to its effect on filtration fraction with postfilter mode and the relationship between blood flow and clearance when using prefilter mode (6:1 blood flow rate to prefilter replacement fluid ratio to maximize clearance) (²³,²⁴). Furthermore, infection control maneuvers should be routinely employed to minimize catheter-related infections in patients on CRRT.

Theoretically, the optimal dialysis catheter should provide adequate blood flow (low resistance and low recirculation) during a long lifespan (approximately 14 days for internal jugular catheters and approximately 7–10 days for femoral catheters) and with low rate of complications (infection, thrombosis, mechanical). Current Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend (1) use of a nontunneled temporary dialysis catheter; (2) insertion of the catheter in the right internal jugular (RIJ) as the first option, femoral site as the second option, and left internal jugular as a third option, and to avoid subclavian insertions (⁵¹); (3) use of a catheter with a length of 12–15 cm for RIJ, 15–20 cm for left internal jugular, and 19–24 cm for femoral sites, with a diameter of 11.5–14 F; and (4) location of the catheter tip in the midatrium with the arterial lumen facing the mediastinum, but not allowing the catheter tip to touch the atrium floor (⁷). A summary of characteristics, monitoring, and complications of dialysis catheters for CRRT is provided in Table 6.

Table 6. - Characteristics, monitoring and complications of dialysis catheters for continuous RRT (⁷,⁵²,⁵³)

Characteristic	Recommendation	Additional Considerations
Type	Nontunneled temporary catheter (level of evidence 2D)	Avoid subclavian catheters, use ultrasound guidance for insertion; obtain chest x-rays before use (IJ or subclavian); no need for topical antibiotics or antibiotic locks for nontunneled dialysis catheters
Catheter length	RIJ 12–15 cm, LIJ 15–20 cm, Fem 19–24 cm
Catheter diameter	12–13 Fr
Position	Catheter tip in the SVC (caval-atrial junction, <4 cm from RA) with arterial lumen facing the mediastinum
Monitoring	Trigger for alarm	Action
Access pressure	>50–70 mm Hg pressure ∆ from operating point	Evaluate for catheter malfunction (clots, kinks, malposition)
Return pressure	>50–70 mm Hg pressure ∆ from operating point	Evaluate for catheter malfunction (clots, kinks, malposition)
Complications
Acute complications (<1% to 2%)	Hemorrhage/hematoma, venous perforation, arterial puncture, pneumothorax, air embolism
Subacute complications	Infection a : CR-BSI 1.6–5.5 episodes/1000 catheter d or exit site infection
	Catheter malfunction: fibrin sheath formation, thrombus within catheter, catheter kinks, catheter fracture or disconnection, catheter malposition or migration, catheter tip adherent to vessel wall

RIJ, right internal jugular; LIJ, left internal jugular; Fem, femoral; Fr, French; SVC, superior vena cava; RA, right atrium; ∆, change; CR-BSI, catheter related-blood stream infection.

^aExtrapolated from data of tunneled hemodialysis catheters (⁵⁴,⁵⁵).

As blood flow is susceptible to low refill rates, low stroke volume, circuit backflow, and catheter malposition or malfunction, distinct levels of high negative arterial (inflow) pressures or high positive venous (outflow) pressures are typically encountered during CRRT. Therefore, continuous monitoring of pressure parameters on flowsheets and early recognition of patterns suggesting catheter dysfunction are recommended, starting with the bedside ICU nurse and rounding ICU teams. If these alarms are not quickly recognized and interventions instituted (e.g., catheter change or repositioning), blood stagnation in the circuit occurs, resulting in clotting, circuit loss, and treatment interruptions.

Our Patient, LC, Underwent Successful Insertion of a RIJ Dialysis Catheter to Continue CRRT

Scenario 5: Considerations About Use of RCA for CRRT

Clotting of the hemofilter or CRRT circuit can markedly decrease the effectiveness of CRRT. Membrane clotting can be detected by closely monitoring the transmembrane pressure (TMP) and filter pressure drop. The TMP is the pressure exerted on the filter membrane and reflects the pressure difference between the fluid and blood compartments of the filter. During treatment, membrane permeability decreases due to the protein coating on the blood side and causes “clogging” of the filter, resulting in an increase in TMP. The filter pressure drop is the pressure reduction that occurs as blood flows through the filter. Microclotting in the hollow fibers causes the pressure drop to increase over time. A high TMP without as much of a concurrent rise in the filter pressure drop is more often due to clogging of the filter, whereas a high TMP along with a high filter pressure drop indicates clotting of the hemofilter. With filter clogging, the circuit can be salvaged by methods to decrease the filtration fraction or by adding anticoagulation, but with filter clotting, the hemofilter must be replaced.

The filtration fraction is the ratio of UF rate to plasma water flow rate and represents the fraction of plasma that is removed from the blood during hemofiltration. Maintaining a filtration fraction of <20% to 25% can prolong hemofilter patency. When blood flow, hematocrit, and total effluent flow rates are held constant, purely convective modes of therapy, such as CVVH, always have a higher filtration fraction compared with diffusive therapies (e.g., CVVHD). Hemofilter survival can be prolonged by using higher blood flow rates and predilution replacement fluid to reduce the filtration fraction in convective CRRT. Despite these measures to improve filter survival, anticoagulation is often required for CRRT.

The KDIGO guidelines for CRRT anticoagulation recommend that RCA be preferentially used over heparin (⁷). Citrate is infused into the blood at the beginning of the extracorporeal circuit and provides anticoagulation by chelating ionized Ca (iCa⁺⁺). Optimal regional anticoagulation occurs when the iCa⁺⁺ concentration in the extracorporeal circuit is below 0.35 mmol/L, which corresponds to approximately 3–4 mmol of citrate per liter of blood. A portion of the Ca-citrate complex is lost across the hemofilter, whereas the rest enters the systemic circulation where citrate is metabolized by the liver to bicarbonate and Ca is released into the circulation. Ca is infused back to the patient to replace the Ca lost across the hemofilter (²⁶,^565354–55).

LC’s initial CRRT prescription without anticoagulation results in clotting of the filter, despite an appropriate dialysis access and filtration fraction <25%. We will therefore prescribe RCA. The decision of using citrate (²⁶) or other form of anticoagulation (systemic heparin [²⁵]) should be customized according to local expertise and available monitoring protocols. In a meta-analysis including 14 randomized controlled trials (1134 patients on CRRT), there was no difference in mortality when providing CRRT with RCA versus systemic heparin. However, there was less risk of bleeding and prolonged filter life span (the latter specifically when using CVVH) with RCA versus systemic heparin. There were also more episodes of hypocalcemia in the RCA group (⁶⁰). Therefore, careful Ca monitoring (e.g., patient’s total Ca and iCa) is mandatory when using CRRT with RCA (⁶¹).

Ensuring adequate citrate anticoagulation in the circuit can be done by either measuring the postfilter iCa⁺⁺ and titrating the citrate rate to maintain the circuit iCa⁺⁺ <0.35 mmol/L, or fixing the citrate and blood flow rate to achieve a concentration of 3–4 mmol/L in the circuit without measurement of postfilter iCa⁺⁺ levels. Table 7 lists the fixed citrate rate needed for various blood flow rates to maintain a citrate concentration of 3 mmol/L in the circuit using the most commonly used citrate solutions, 4% trisodium citrate and 2.2% anticoagulant dextrose-A.

Table 7. - Dose of common formulations of citrate for fixed blood flow rate: amount of citrate delivered to achieve blood citrate concentration of 3 mmol/L in the circuit

Blood Flow Rate (ml/min)	4% TSC (ml/h)	2.2% ACD-A (ml/h)
100	132	159
125	165	200
150	199	239
200	265	319

TSC, trisodium citrate; ACD-A, anticoagulant dextrose-A.

LC is not allergic to citrate and, despite evidence of coagulopathy, mild elevation in aspartate aminotransferase and alanine aminotransferase, and thrombocytopenia, we will prescribe citrate as we can carefully monitor the RCA protocol in the ICU. For our patient, LC, we will prescribe citrate in the form of anticoagulant dextrose-A (3% combined trisodium citrate 2.2 g/100 ml and citric acid 0.73 g/100 ml; contains glucose 2.5%; total amount of citrate: 10–11 mmol/100 ml) at a rate of 250 ml/h (1.5 times blood flow of 170 ml/min, decreased from 200 ml/min) plus a continuous infusion of Ca chloride or equivalent (20 g of Ca chloride in 1 L of 0.9% sodium chloride or 10 g of Ca chloride in 0.5 L of 0.9% sodium chloride = 20 mg/ml or 0.136 mmol/ml of elemental Ca) at 25 ml/h to maintain the systemic iCa⁺⁺within normal range.

Scenario 6: Recognizing Complications of RCA during CRRT

LC initially does well with RCA, with no further clotting issues. However, her clinical condition deteriorates with new sepsis, and she develops worsening hypotension with a lactic acid level of 10 mmol/L. She now has an increasing anion gap, a decreasing serum bicarbonate concentration, and requires an escalating Ca infusion to maintain iCa⁺⁺ in a normal range. Because of the concern for citrate accumulation, RCA is stopped. Common metabolic signs of citrate accumulation/toxicity are described in Table 8 (⁶²).

Table 8. - Metabolic complications of citrate utilization with continuous RRT

Complication	Mechanism	Diagnosis	Management
Citrate excess	Metabolic conversion of citrate to bicarbonate resulting in excess buffer	Metabolic alkalosis	Decrease blood flow rate
		Total Ca++/iCa++ <2.5	Increase dialysate flow rate, or decrease buffer concentration in other CRRT solutions
Citrate toxicity	Decreased metabolic conversion of citrate resulting in accumulation of citrate-calcium complexes in blood	Anion gap metabolic acidosis	Decrease blood flow rate, or increase dialysate flow rate, or discontinue citrate
		Total Ca++/iCa++ >2.5
		Escalating Ca++ infusion rate
Citrate deficit	Metabolic conversion of citrate to bicarbonate resulting in insufficient buffer	Metabolic acidosis	Increase blood flow rate
		Total Ca++/iCa++ <2.5	Decrease dialysate flow rate
			Increase buffer concentration in other CRRT solutions

Ca⁺⁺, calcium; iCa⁺⁺, ionized calcium; CRRT, continuous RRT.

Patients with severe shock liver and lactic acidosis may not be able to metabolize citrate (⁶³,⁶⁴). Citrate toxicity is characterized by low systemic serum iCa⁺⁺ level, elevated serum total Ca level, total Ca to systemic iCa⁺⁺ ratio >2.5, increasing anion gap acidosis, and escalating Ca infusion requirements. Citrate accumulation can be managed by decreasing the blood flow and corresponding citrate infusion rate, increasing the effluent rate, decreasing the target citrate concentration in the hemofilter, or changing to an alternate form of anticoagulation. To minimize the systemic effects of citrate, we recommend a blood flow rate between 100 and 180 ml/min.

Besides citrate accumulation, metabolic acidosis can also result if the amount of citrate delivered is insufficient to adequately buffer the acidosis. In this situation, there is no evidence of citrate accumulation and the total Ca to systemic iCa⁺⁺ ratio remains <2.5. This can be corrected by increasing the blood flow, thereby requiring an obligatory increase in the citrate rate to achieve the target iCa⁺⁺ in the filter, or by decreasing the effluent rate, resulting in less citrate lost across the hemofilter. Both methods result in the delivery of more citrate to the patient, and therefore, more bicarbonate generation when citrate is metabolized.

Scenario 7: Considerations About Antibiotic Dosing during CRRT

Medications with primary renal elimination (>25%) will likely be removed through CRRT (⁶⁵). Volume of distribution (Vd), protein binding, and molecular weight (MW) are the three most important physiochemical determinants of removal by CRRT. A drug with a low Vd (<2 L/kg), low protein binding (<80%), and a MW smaller than the pore size of the CRRT filter (typically <20,000 days) will be removed through convection (⁶⁶). Convective clearance has a positive linear relationship to replacement fluid rate. An UF rate of 2.5 L/h provides a creatinine clearance of 40 ml/min (2500/60=40 ml/min); for every 0.5 L/h increase in convection, expect the clearance to increase by 10 ml/min (⁶⁷). This provides an eGFR to use for medication dosing, recalling prefilter replacement fluids can reduce convective clearance up to 20% (⁶⁵,⁶⁸).

Diffusion-based modalities differ in solute removal because diffusion passively and preferentially removes drugs with a small MW (<500 days), such as beta-lactam antibiotics and antiepileptics. Clearance for larger molecules becomes inversely related to MW (⁶⁵,⁶⁹). Thus, for middle-sized molecules such as vancomycin or daptomycin, the diffusive clearance will be lower than an equivalent dose of convective clearance.

Because total body clearance is a factor of both clearance and Vd, volume status assessment is vital, at CRRT initiation and throughout therapy. One should recognize that many patients are volume overloaded before CRRT initiation (¹⁰,⁷⁰). Loading doses of hydrophilic antibiotics are paramount to optimize pharmacokinetic/pharmacodynamic parameters. Conversely, as euvolemia is achieved over the course of therapy, total body clearance will decrease. In addition, the convective and diffusive clearance of drugs decreases over the course of therapy (⁶⁵,⁶⁶). Taken together, there is high potential for medication accumulation to occur after 48 hours of CRRT, which has been observed in the literature (⁷¹,⁷²).

Beta lactam medications (piperacillin-tazobactam) should be dosed aggressively (full, unadjusted doses) with prolonged or continuous infusions for at least the first 72 hours of therapy for any patient on CRRT with >2 L/h of effluent dose (⁷¹,⁷³). Vancomycin should be dosed according to the estimated clearance provided by the CRRT effluent dose, recalling convective clearance is more effective for larger molecules than diffusive clearance, and predilution fluid reduces solute clearance. Therapeutic drug monitoring of all antimicrobials should occur when available. For our patient, LC, the recommended initial doses of antibiotics include piperacillin-tazobactam 4.5 g every 6 hours, infused over 3 hours; vancomycin loading dose of 25 mg/kg (3250 mg) to account for increased Vd due to body habitus, volume overload, and critical illness, followed by 1750 mg (approximately 14 mg/kg) every 24 hours, as our CRRT prescription provides an eGFR of 40–50 ml/min for vancomycin, accounting for the dilution factor, and diffusive clearance. Therapeutic drug monitoring should be done at a steady state. Also recommended is oseltamivir 75 mg twice daily and azithromycin 500 mg every 24 hours. Azithromycin has primary hepatic clearance and no renal dosage recommendations, thus can be given at full unadjusted doses, per indication. Specific considerations and rationale of medication dosing are provided in Table 9.

Table 9. - Summary of dosing recommendations during continuous RRT for common antimicrobials utilized in patients who are critically ill

CRRT Dose	Estimated clearance	Vancomycin	Cefepime	Piperacillin-Tazobactam	Meropenem	Amikacin	Acyclovir	Oseltamivir
References	Churchwell and Mueller (65)	Churchwell and Mueller (65)	Moriyama et al. (73)	Moriyama et al. (73)	Moriyama (et al. 73)	D’Arcy et al. (74)	Churchwell and Mueller (65)	Flannery Thompson Bastin (75)
		Lexicomp	Seyler et al. (71)	Seyler et al. (71)	Seyler et al. (71)	Lam and Bauer (76)	Lexicomp	Lexicomp
			Chaijamorn et al. (77)	Lexicomp	Lexicomp	Taccone et al. (78)
			Shaw and Mueller (79)			Roger et al. (80)
			Lexicomp			Lexicomp
Replacement 1 L/h prefilter 1 L/h postfilter	2000 ml/h + 2000 ml/h+ 200 ml/h =70 ml/min	25 mg/kg loading dose (3250 mg)	2 g loading dose	4.5 g loading dose	2 g loading dose	Approximately 25 mg/kg (adjusted BW of 90 kg)	10 mg/kg (IBW 68 kg) loading dose	75 mg q 12h
Dialysate 2 L/h		(14 mg/kg actual BW) 1750 mg q24h	2 g q8h extended or continuous infusion	4.5 g q6h extended or continuous infusion	1–2 g q8h extended infusion	2250 mg q48h	680 mg 680 mg q8h
UF 200 ml/h							10 mg/kg (IBW) q8h (encephalitis dosing)
Physiochemical properties	Always assess for residual UOP during therapy, and take into consideration set downtime	MW: 1485 d	MW: 480 d	MW: 500 d	MW: 383 d	MW: 585 d	MW: 225 d	MW: 312 d
		PB: 55%	PB: 20%	PB: 30%	PB: 2%	PB: 11%	PB: 33%	PB: 3%
		Vd: 0.7 L/kg	Vd:0.28 L/kg	Vd: 0.24 L/kg	Vd: 0.2 L.kg	Vd: 0.25 L/kg	Vd: 0.8 L/kg	Vd: 0.37 L/kg
Maintenance dose on the basis of		40–50 ml/min eGFR	70 ml/min	70 ml/min	70 ml/min	70ml/min	70 ml/min	70 ml/min
Caveats		Convective clearance > diffusive clearance. Can use population PK estimated for dosing interval, once determined from CRRT Rx.	Total clearance of 70 ml/min requires full unadjusted dose, consider dose reduction after 48–72 h on the basis of cultures, indication etc.			TDM after first dose.	Will require adjustments if eGFR <50 ml/min.	Excellent absorption even in shock/CRRT/ECMO. Supratherapeutic levels achieved with normal dosing.
		TDM at steady state.

BW, body weight; IBW, ideal body weight; MW, mol wt; PB, protein binding; V_d, volume of distribution; UOP, urine output; TDM, therapeutic drug monitoring; CRRT, continuous RRT; ECMO, extracorporeal membrane oxygenation; Rx, prescription.

Discussion

CRRT is a method of dialysis support commonly utilized in patients who are critically ill with AKI. However, several aspects of CRRT delivery are still not fully standardized and do not have solid evidence-based foundations. In this study, we discussed the stepwise decision-making process made for the care of a specific patient, according to specific clinical needs and the logistics available at the corresponding institution. We provided a framework for evidence and considerations in relation to initial prescription, CRRT dosing, and adjustments related to severe hyponatremia management, concomitant ECMO support, dialysis catheter placement, use of RCA, and antibiotic dosing. This CRRT simulation highlights the importance of iterative assessment and adjustments of goals of therapy for patients on CRRT, and the need for effective communication among all multidisciplinary stakeholders involved in the care of this debilitated ICU population.

Disclosures

A. Tolwani reports a patent to 0.5% citrate solution issued, licensed, and with royalties paid. A. Tolwani, J.A. Neyra, and M. Thompson Bastin have provided consultations for Baxter Healthcare. All remaining authors have nothing to disclose.

Funding

J.A. Neyra is supported, in part, by National Institute of Diabetes and Digestive and Kidney Diseases grants R56 DK126930 and P30 DK079337.

Acknowledgments <NEED TO FORMAT ACK HEADER>

The authors wish to thank Ms. Kela Beans, Ms. Sofi Belle, Ms. Luka Liu, and Mr. Leo Ikati for their assistance with the preparation and critical review of this manuscript. We dedicate this work to all caregivers who work tirelessly to improve the delivery of care to AKI patients.