Continuous RRT (CRRT) is a form of RRT that is used in modern intensive care units (ICUs) to help manage AKI, ESKD, poisonings, and some electrolyte disorders. CRRT has transformed the care of patients in the ICU over the past several decades. As has been well documented in prior studies, AKI incidence has been increasing, in large part driven by an older population with more comorbidities (1,2). The delivery of care using CRRT has also evolved over the years, its indications has broadened, and it is being increasingly used. In this setting, it is important to recognize CRRT-associated complications but also up-to-date management of these complications. Some of these complications are minor, but others may be more significant and even life-threatening. Some CRRT-related complications may be related to dialysis factors and others to specific patient factors. Our overarching goal in this article is to review and discuss the most significant CRRT-related complications at different stages of management of CRRT (Figures 1 and 2).
Herein, we describe and discuss the management of clinically relevant CRRT complications on the basis of those related to vascular access, the extracorporeal system, and biomembranes, metabolic support, and electrolytes, and those related to clearance and anticoagulation (Figure 3).
Vascular Access Complications
Vascular access is the lifeline of CRRT. Vascular access complications can arise during placement or during maintenance, whether it is in the acute setting or chronic settings, each of them having their own unique limitations and complications.
During placement, the common complications, similar to all central vascular access line placements, are arterial puncture and venous rupture, leading to bleeding, and, in addition, for chest line procedures, pneumothorax, myocardial rupture, and arrhythmias.
Although these are complications at the time of catheter placement, the catheters can have further complications on the basis of timing of the catheter placement, which can be infectious or noninfectious (Figure 4). Noninfectious complications can be within the duration of CRRT or can persist over a number of years such as central venous stenosis or even difficulty with catheter extraction. The nontunneled catheters have limitations with possible increased risk of infections and also mechanical complications, with comparisons discussed in the section below.
However, with clinical practice guidelines recommending the use of ultrasound-guided techniques to place vascular access, the initial complications have been minimized (3,4). Catheter-related thrombosis is another dreaded complication, and patients on CRRT are at increased risk, given concurrent illness and hypercoagulable state. If found, systemic anticoagulation is indicated as long as the catheter remains in place (5).
Most common vascular access complications are similar to catheter access issues seen during intermittent hemodialysis. Infectious complications of vascular accesses are one of the impediments of caring for patients in ICUs. The infectious process typically starts from the spectrum of skin colonization to biofilm development to local exit site infection to tunnel infection to bacteremia; however, intraluminal bacteremia may also be acquired. Organisms are generally Staphylococcus aureus and coagulase-negative Staphylococcus, but Gram-negative bacteria and candida are other possible causes of sepsis (6). Multiple observational studies and guidelines recommend avoiding femoral catheter sites because of an increased risk of nosocomial infections; however, in a concealed, randomized, multicenter, evaluator-blinded, parallel-group trial of 750 patients of nine tertiary care centers, no clinically relevant benefit of jugular site catheterization was found compared with femoral site catheterization in terms of nosocomial complication in critically ill adults requiring RRT (4). Jugular catheters had a statistically significantly higher rate of hematoma formation compared with the femoral group (4% versus 1%; P=0.03) but no difference in arterial puncture. In regard to catheter-related infections and catheter colonization at the time of catheter removal, there was no statistically significant difference between infection in the jugular and femoral catheter groups. Further, in subgroups analysis, the researchers found a statistically significant higher rate of catheter colonization at the time of catheter removal with femoral catheters in patients in the highest tercile of body mass index (>28.4 kg/m2). Jugular catheters had statistically significantly more Gram-positive bacteria (P=0.04), and femoral catheters had a higher colonization of Gram-negative bacteria (P=0.03). Duration of catheter did not seem to have a statistically significant change in catheter colonization at the time of removal when the two groups compared were ≤5 days and >5 days (4).
The 2019 Kidney Disease Outcomes Quality Initiative guidelines recommend limiting the use of a temporary, noncuffed, nontunneled dialysis catheter to 2 weeks due to increased risk of infections in patients who need emergent vascular access, which certainly has to be reviewed on a patient-to-patient basis as described below (7). There are variations to this practice too on the basis of the patient’s needs and the ability to maintain CRRT patency and minimize treatment or dialysis interruption. This is a change from previous guideline recommendations that a noncuffed, nontunneled dialysis catheter should not exceed 3 weeks for jugular and 5 days for femoral access (8,9). In a retrospective study of 595 patients receiving CRRT, looking at rates of adverse events, other catheter-related complications included bleeding (23%), arterial puncture (1%), hematoma (2.85%), line-related infection (5%), and other (12%; pneumothorax, catheter misplacement, and air embolism) (10). Although nontunneled dialysis catheter placement has been standard and common, a 16-month observational prospective cohort study involving 154 patients showed that compared with nontunneled dialysis catheters, tunneled dialysis catheters were associated with better dialysis delivery and fewer mechanical complications. Interestingly, there was no difference in the rate of positive blood cultures per catheter (11). Further randomized studies are needed to confirm these findings.
Extracorporeal Circuit Complications
AN69 and Angiotensin-Converting Enzyme Inhibitors
AN69 is polyacrylonitrile synthetic dialysis membrane that was developed to improve biocompatibility. AN69 membranes have been associated with anaphylactoid reactions when used in combination with angiotensin-converting enzyme inhibitors due to activation of bradykinin. These reactions have been partially mitigated by surface treatment of the AN69 membrane (AN-69ST) (12).
One of the most noted significant adverse events of CRRT is hypothermia, defined as a temperature <35°C, and was found in up to 44% of patients in one study (10). Below 34°C, hypothermia can cause depressed brain and cardiovascular function and arrhythmia, and mask fevers, delaying recognition of infections and the initiation of antibiotics (13). Critically ill patients on CRRT are predisposed to hypothermia from many factors including, but not limited to, sedation, paralytics, shock, endocrine disorders, intoxications, and central nervous system lesion/injury. Of note, arterial and venous line temperatures differences during CRRT have been studied. The largest temperature difference between blood in arterial and venous lines was 5.5°C±0.2°C when blood flow (Qb) was 100 ml/min and dialysate flow (Qd) was 1500 ml/h. The lowest temperature difference was 1.9°C±0.1°C when Qb was 200 ml/min and Qd was 500 ml/h, showing that slower Qb and higher Qd caused greater energy loss during CRRT (14). In another study, heat loss was calculated to average 750 kcal/d, worsening caloric deficit in these already critically ill patients. However, in some situation, cooling may be beneficial such as in patients with significant hyperthermia and status post cardiac arrest (13). Milder degrees of hypothermia may contribute to more hemodynamic stability by causing an increase in pulse, cardiac output, and systemic vascular resistance. In a prospective crossover randomized study, 30 patients on continuous venovenous hemofiltration had a heating device set to 38°C and 36°C for 6 hours each. The authors found that patients core temperature did not change significantly; however, patients with continuous venovenous hemofiltration with a heating device set at 36°C had higher mean arterial pressure and required lower catecholamine infusion doses (15).
Suggestions for the treatment of hypothermia include passive external rewarming (blankets allow for natural thermogenesis to raise core temperature by 0.5°C/h if shivering mechanism is intact), but also active external rewarming (warming devices are reported to raise temperature by 1–2.5°C/h) and active internal/core rewarming (intravenous fluids warmed up to 42°C, peritoneal dialysate, isotonic crystalloids into the stomach or bladder). Of note, modern dialysis machines are equipped with warming devices to help counter heat loss as well (13).
Because of the nature of the extracorporeal circuit, contact of blood with the biomembranes, and procoagulant state, critically ill patients on CRRT frequently require anticoagulation to prolong the life of the filter and to minimize interruptions to dialysis therapy (16). The most common anticoagulants used during CRRT are intravenous heparin or regional citrate anticoagulation (RCA) (17). The RICH study showed that the patients with intravenous heparin had a higher rate of bleeding compared with RCA, but RCA had a higher rate of culture-proven infection compared with intravenous heparin (18). In addition, it is also important to recognize associated metabolic complications (hypocalcemia, hypercalcemia, hypernatremia, metabolic alkalosis) and citrate toxicity (Figure 5) (19). However, it is important to note that a recent post hoc analysis of the RICH trial revealed that a longer mean filter lifespan (>48 hours) was associated with an increased rate of new infections, independent of the type of anticoagulation used (20).
Citrate toxicity can be identified by a low ionized calcium, a disproportional rise in total calcium with a total calcium/ionized calcium ratio of >2.5, and high anion gap metabolic acidosis or with escalating rates of calcium infusion (19). Citrate excess has also been associated with metabolic alkalosis, which occurs when citrate is metabolized to bicarbonate in the liver (21). These complications can be managed by decreasing the citrate rate or increasing the dialysis or effluent rate, all of which would be geared toward decreasing citrate delivery (22). Importantly, RCA is best avoided in patients who have acute liver failure or cardiogenic shock with high lactate levels (>8 mmol/L) because they have a high risk of impaired citrate metabolism with a high risk of citrate accumulation and citrate toxicity. For other rare instances of citrate dynamics, it is important to recognize there can be three potential scenarios that can cause different acid base and electrolyte disorders. Citrate accumulation can cause metabolic acidosis due to delayed metabolism of citrate, leading to lactic acidosis. This can be fatal, but given intensive monitoring, it is rare. Increased citrate infusion with can lead to metabolic alkalosis and hypernatremia (23,24).
The manifestations of citrate overload depend on the metabolic state, rate of citrate infusion, or type of citrate used. Citrate chelates with calcium, and it has to be used as proximally as possible to the access to reduce the initiation of coagulation cascade. The citrate binds with calcium to form the creatinine calcium citrate complex (CCC), most of which would be cleared with CRRT (21,24). But as it escapes to the systemic circulation, citrate is metabolized to bicarbonate and also releases sodium. Thus, metabolic alkalosis and hypernatremia can occur. The severity of hypernatremia depends on the type of citrate used such as trichloroacetic acid, which has 420 mmol/L of sodium, compared with acid citrate dextrose, which has 224 mmol/L of sodium (24).
Hematologic complications are one of the most underrecognized complications observed in patients during CRRT. These complications could be related to anticoagulation (heparin, citrate) or the result of extracorporeal circuit–related issues. The most common complication is thrombocytopenia, but anemia has also been reported.
CRRT may be associated with thrombocytopenia and can confound the diagnosis and management of other causes of thrombocytopenia seen in critically ill patients such as sepsis, heparin-induced thrombocytopenia (HIT), and drug-related thrombocytopenia (25). The temporal relationship of CRRT and decrease in platelet count with CRRT initiation and follow-up was evaluated at a quaternary regional referral center where 80 patients received CRRT for >48 hours and were followed for thrombocytopenia (defined by a platelet count of <100,000/μL) with a stable platelet count for at least 4 days before CRRT initiation. During a 5-day course, there was significant worsening thrombocytopenia in 59% of patients at day 5, including 30% of patients who developed even more severe thrombocytopenia of <50,000/μl. In this study, only the Sequential Organ Failure Assessment score at time of CRRT initiation on multivariate analysis predicted the development of thrombocytopenia. In regard to HIT, of the 20% of patients suspected and evaluated, 81% had a low to intermediate pretest probability of HIT, but only one patient had laboratory-confirmed HIT (26).
The mechanism of thrombocytopenia in CRRT is unclear and likely multifactorial because critically ill patients on CRRT have many comorbidities that can be associated with thrombocytopenia. Platelet destruction, adsorption, and activation are likely to play a role. In one study, indium-labeled platelets in an in vitro system showed considerable platelet deposition on a variety of dialysis membranes (27,28). Seen in other extracorporeal membranes, platelet activation was postulated to have a role in thrombocytopenia in CRRT through peripheral consumption. However, evidence for platelet activation has been mixed (27,29). Thrombocytopenia may also have prognosis values at the time of CRRT initiation. In a recent study by Griffin et al., the authors reported that a >40% decrease in platelet count was associated with increased risk of secondary infections. Interestingly, the same research group reported that thrombocytopenia was associated with lower rates of renal recovery and higher mortality (28,30,31).
Management is variable and could consist of higher blood flows, which is postulated to decrease transit time, improved rheology, and decreased hemoconcentration (28). Transition to intermittent hemodialysis is postulated to decrease contact time with the dialysis filter. However, not many studies have evaluated thrombocytopenia across different RRT modalities. In one study, CRRT was associated with a platelet decrease compared with intermittent hemodialysis but only in univariate analysis. Nonetheless, the results were attenuated when accounting for severity of illness, liver disease, and filter losses. In the same study, the intermittent hemodialysis group had twice as much filter exposure and more thrombocytopenia compared with the conventional group, but this was not statistically significant (28,32).
Anemia may occur in patients on CRRT for a variety of reasons. In a retrospective study assessing adverse events in adults on CRRT, one study found 31% of the 595 patients to have new-onset anemia, defined as a hemoglobin <10 g/dl. One leading cause of anemia is blood lost through the extracorporeal circuit. A subgroup analysis comparing blood loss in CRRT with that in intermittent hemodialysis showed that patients with CRRT had increased RRT-related blood loss, but the transfusion events were similar (33). The clotting cascade is activated with shearing and turbulence induced by the nonendothelialized surface of the filter, circuit tubing, and catheter. RCA has been evaluated extensively. A meta-analysis of 11 randomized controlled trials of approximately 2000 filters and 1000 patients demonstrated RCA for CRRT was able to reduce the risk of extracorporeal circuit blood loss compared with regional and systemic heparin administration and is the recommended anticoagulant in the most recent Kidney Disease Improving Global Outcomes (KDIGO) guidelines if there are no contraindications (4,34). Compared with systemic heparin administration, circuit loss (circuit termination for any reason) was significantly reduced by 24% with RCA. On the other hand, compared with regional heparin anticoagulation, circuit loss had a 48% significant reduction with RCA. Information regarding filter failure (filter clotting or high transmembrane filter pressure) was available in six randomized controlled trials and was found in the pool data to favor the citrate group, with the important caveat of high intertrial heterogeneity. Catheter dysfunction was similar between both groups. In the nine trials that compared systemic heparin to RCA, the bleeding risk was significantly reduced with RCA (35).
Another reason for anemia observed during CRRT is mechanical hemolysis from the extracorporeal circuit itself. More commonly seen in extracorporeal membrane oxygenator circuits (ECMO), small studies looking into plasma-free hemoglobin (PFHb) from CRRT circuits showed a statistically significant rise in PFHb but not to the levels of clinically significant hemolysis reported in the ECMO literature, whereas filter clotting and peak circuit pressures did not have any statistically significant change in PFHb in another small study (32).
Like many of the adverse events seen in critically ill patients receiving acute dialysis, the etiology of hypophosphatemia is multifactorial as well (34). It is important to note that hypophosphatemia is typically an avoidable complication. Malnourishment, refeeding syndrome, sepsis, insulin, and phosphorous removal during CRRT all contribute to hypophosphatemia in this critically ill population. Some studies that looked at the effectiveness of established phosphate repletion protocols still resulted in patients developing hypophosphatemia (23,36). Even though there is no evidence that intensive CRRT doses improve the survival rate of critically ill patients with AKI, there are instances where intensive CRRT is needed such as acute hyperammonemia or severe labile hyperkalemia (37,38). However, this intensive treatment may increase the risk of developing hypophosphatemia (39). Further, there is no consensus agreement about the phosphate goal during CRRT, but there is evidence that hypophosphatemia at all ranges is associated with worse outcomes (23). Hypophosphatemia <0.6 mmol/L (1.86 mg/dl) has been reported to increase the incidence and duration of mechanical ventilation (38). Similarly, hypophosphatemia <0.67 mmol/L (2 mg/dl) has been associated with an increased need for tracheostomy (40).
Some have advocated for phosphate-containing dialysate as a different approach to prevent CRRT-induced hypophosphatemia. Commercially available dialysate replacement fluid containing phosphate at 1.2 mmol/L has been studied and indeed helped to maintain normophosphatemia in the majority of patients (23,41). However, rare cases of hyperphosphatemia, metabolic acidosis, and hypocalcemia have been reported. Currently, there is no consensus about the optimal phosphorous target in CRRT patients, and importantly, there are concerns about serum levels not being reflective of intracellular phosphorous concentrations and subsequent ATP synthesis (38). So, further studies are needed to evaluate adequate phosphorus targets to avoid complications associated with CRRT-induced hypophosphatemia (38,40). Of note, phosphate-containing solutions contain no glucose, and recently, there have been reports of patients developing normoglycemic ketoacidosis. This phenomenon is increasingly recognized in patients who are using glucose-free CRRT solutions and sometimes even with glucose-containing CRRT solutions. Normoglycemic ketoacidosis is identified with anion gap metabolic acidosis, serum ketones, and low/normal glucose. The treatment of this phenomenon involves an infusion of glucose and insulin (42,43).
In addition to calcium, we also need to monitor magnesium levels while the patient is using RCA because the citrate also chelates magnesium and the patient’s magnesium levels become systematically depleted (44).
In addition to phosphorus, importantly, there is a need to monitor other electrolyte imbalances such as potassium, calcium, and sodium. Although potassium and calcium disorders can be mitigated by changing the dialysate or replacement fluid electrolyte mixture, sodium disorders require additional management. Severe AKI and hyponatremia with risk of overcorrection can be managed by adding hypotonic fluids through the circuit or adjusting the CRRT solutions (45). Customizing CRRT solutions by adjusting the sodium concentrations in the solution is possible with a multidisciplinary effort by pharmacists according to the sodium levels (46). Sodium follows urea kinetics, and using this model, it is possible to predict the change in sodium levels by making changes to the CRRT solution (47). Similarly, circumstances that require hypernatremia, such as acute neurologic injuries including intracranial hemorrhage and stroke, will also require custom CRRT solutions or hypertonic fluids.
Treatment Delivery and Volume Management
Although there is no proven lower threshold of CRRT dose in AKI, the KDIGO guidelines recommend aiming to deliver effluent of 20–25 ml/kg per hour for CRRT in this setting; however, because of downtime for different reasons such as imaging studies, CRRT breakdown, and need for surgery, patients don’t always get the desired dose (48,49). Venkatraman et al. showed that patients who were prescribed 24 ml/kg per hour in fact received 16 ml/kg per hour, with RRT running for 16 hours (67%) on average (50). Therefore, to ensure a minimum delivered dose of 20–25 ml/kg per hour, it may be necessary to prescribe approximately 25–30 ml/kg per hour, and it is also necessary to minimize CRRT downtime to ≤4 h/d (4849–50).
In addition to clearance, more recently we have had a better understanding of the effect of ultrafiltration rates on patient survival. Too aggressive ultrafiltration can cause hypotension and myocardial stunning. In hemodialysis patients, this has shown to increase the risk of sudden cardiac arrest. In critically ill patients, initiation of CRRT has been associated with cardiac stunning (51). Cardiac stunning is not only related in patients with aggressive ultrafiltration but also in patients without aggressive ultrafiltration, and these patients have extremely high mortality (52).
Dialysis Disequilibrium Syndrome
Dialysis disequilibrium syndrome (DDS) is one of the complications that can occur after initiating patients on RRT due to rapid shifts of solutes, although CRRT has been postulated to have slower clearance of solutes, thereby decreasing the risks of DDS; however, there have been a few case reports of DDS occurring in patients receiving CRRT (53). Education on overriding the alarms is needed, with careful adjustment of electrolyte mixtures to prevent further electrolyte derangements, especially with commercially available solutions.
Metabolic Support/Nutritional Losses
Patients in the ICU are typically in a catabolic state and require a high intake of amino acids and micronutrients. In addition, most of these patients are hypoalbuminemic due to their critical illness but also as a consequence of their CRRT treatment. In addition to providing clearance for solute and ultrafiltration, the CRRT membranes also clear micronutrients and macronutrients. Consequently, patients on CRRT lose water-soluble amino acids. Nutritional losses represent a significant concern for patients on RRT. Careful administration of calories and nutrients in close coordination with the nutritionist would be desirable, and while switching modalities, the changing clearance of amino acids and micronutrients needs to be considered. KDIGO guidelines recommend a protein intake of up to 1.7 g/kg per day in patients on CRRT (49,54,55). We also need to adjust the addition of calories with citrate or lactate because they also provide extra calories (56).
One of the barriers to patients receiving CRRT is delayed mobility due to being connected to machines in addition to their critical illness and often endotracheal intubation with mechanical ventilation. However, physical therapy in the ICU has been reported to improve outcomes and even physical functioning. Specifically in the setting of ongoing CRRT treatment, more recently there have been reports showing good safety profile and feasibility of physical therapy. In addition, when possible, the use of hybrid RRT may allow for early mobilization. As a reminder, any attempts to wean off CRRT early should be on the checklist of ICU rounding (57,58).
Drug Delivery and Clearance
Generally, for patients on intermittent RRT, the drug dosing is for a GFR of <10 ml/min per 1.73 m2; however, there is risk of inappropriate drug clearance with CRRT or prolonged intermittent RRT, especially antibiotics in septic patients, resulting in underdosing of antibiotics or any other medications (59). This is important especially if you are treating a patient with septic shock or status epilepticus. There is a paucity of data on individual clearance of medications by CRRT, and there is a different degree of clearance for individual drugs on the basis of the modality and dose of CRRT, volume of distribution, sieving coefficient, and protein binding of the drugs. In addition, the medication dosing can be estimated by multiplying the effluent with (1-protein binding) and adjusting for prefilter dilution (60,61).
CRRT plays a very important role in the modern ICU, and we need to be mindful about the common complications observed with this renal replacement modality and how to mitigate some more difficult to avoid complications associated with CRRT. Often, the patients have a septic profile with increasing comorbidities. There needs to be more vigilance in nutritional support and volume management. Although CRRT has been around for a few decades, there is a need to utilize safety and quality mechanisms to standardize the care, undergo root cause analysis, and collaborate with different types of ICUs (55). Ultimately, excellent coordination with multidisciplinary teams, including nurses, pharmacists, nutritionists, and intensivists, is key to the success of CRRT in the modern ICU setting.
S.C. Gautam reports ownership interest in BNGO, Criper, Invitae (stockholder), Sensonics, and Pacific Biosciences. B.G. Jaar reports honoraria from the American Board of Internal Medicine—Nephrology; patents or royalties from UpToDate; and an advisory or leadership role for the American Board of Internal Medicine, BMC Medicine, BMC Nephrology, the Clinical Journal of the American Society of Nephrology, and the National Kidney Foundation. The remaining author has nothing to disclose.
S.C. Gautam and B.G. Jaar were responsible for the conceptualization; S.C. Gautam and J. Lim wrote the original draft of the manuscript; S.C. Gautam and B.G. Jaar reviewed and edited the manuscript; and B.G. Jaar was responsible for supervision.
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