Coronary artery disease is highly prevalent in patients with end-stage renal disease (ESRD), and cardiovascular complications remain the most common cause of death in this patient population. Accordingly, many cardiac surgical procedures requiring cardiopulmonary bypass support are performed on these patients each year, with morbidity and mortality rates far exceeding patients without ESRD. Anuric patients lack the normal renal homeostatic functions which typically allow for physiologic protection from challenges during the operation, such as volume overload, hyperkalemia, and acidemia. Careful preoperative planning and coordination to provide pre-, intra-, and postoperative renal replacement therapies for such patients are imperative. Many different strategies have been reported in the literature. Zero-balance ultrafiltration is a newer strategy which utilizes convective ultrafiltration much like pre-filter continuous renal replacement therapy and utilizes pre-existing connections on the cardiopulmonary bypass pump performed by the perfusion team. This allows for control of potassium concentration throughout the operation with existing personnel and minimal additional equipment. Here, we describe the unique challenges caring for patients receiving renal replacement therapy undergoing cardiac surgical procedures requiring cardiopulmonary bypass.

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Burden of Cardiovascular Disease and Mortality in Patients with Reduced Renal Function

Cardiac surgical procedures requiring cardiopulmonary bypass (CPB) provide potential long-term functional improvement with significant short-term morbidity and mortality associated with the procedure itself. Increasing baseline cardiovascular disease burden and a greater number of comorbidities leads to higher complication rates and higher mortality. Estimates from the Adult Cardiac Surgery Database (ACSD) from the Society of Thoracic Surgeons (STS) show an overall mortality 2–6%, and combined morbidity and mortality of 17–28% [1]. This risk is even greater in patients undergoing cardiac surgical procedures who have end-stage renal disease (ESRD) who are on maintenance dialysis in the preoperative period. Given the high co-prevalence of ESRD and CAD, many procedures requiring CPB support are performed on these patients each year; the most common cause of death in these ESRD patients is from cardiovascular complications [2]. The first case report of a cardiac surgical procedure with CPB performed in a patient on preoperative hemodialysis (HD) dates as far back as 1968 [3].

Since then, longitudinal outcomes for this patient population have highlighted the significant risk associated with preoperative dialysis dependency, and dialysis status is now one of the key risk variables used in the ACSD STS model for predicting morbidity and mortality [4]. Based on simulated STS risk calculations, ESRD patients undergoing coronary artery bypass grafting have a 2.4-fold increased risk of perioperative death and a 1.9-fold increased risk of the composite of short-term death or morbidity (stroke, prolonged ventilation, deep sternal wound infection, and reoperation) compared to a matched control with normal renal function. These stark differences in short-term outcomes following cardiac surgical procedures become even more apparent with combined coronary artery bypass grafting plus valve surgeries (2.1-fold increase in mortality and a 1.7–1.8-fold increase in combined morbidity and mortality) [1]. A number of prospective and retrospective studies have shown consistent short- and long-term outcomes in this patient population, with 13–25% 30-day mortality [5-8], 18–19% 1-year mortality, 59–83% 5-year mortality, and an 81% 10-year mortality (median survival 4.3 years) [7, 9]. This patient population also frequently requires complicated cardiac and aortic surgical procedures, and these more complex surgical procedures are also associated with higher short- and long-term morbidity and mortality compared to patients not on dialysis [10-12]. These findings highlight the dramatically increased morbidity and mortality in these patients, and help this population make informed decisions with their surgeons before pursuing intervention.

Major Perioperative Challenges for Patients on Renal Replacement Therapy Requiring CPB

Patients undergoing surgical procedures requiring CPB who are already receiving preoperative HD (either for ESRD or for acute kidney injury) are particularly challenging for the clinicians caring for them. Anuric patients lack the normal renal homeostatic functions which typically allow for physiologic protection from the unique intraoperative challenges such as volume overload, acidemia, and hyperkalemia. Without these homeostatic functions, these perioperative perturbations translate into increased duration of mechanical ventilation, increased intensive care unit (ICU) length of stay, increased infection, and bleeding risk and likely contribute to the increased morbidity and mortality previously highlighted [13].

While treating clinicians must address all intraoperative physiologic derangements (e.g., volume overload, acidemia), hyperkalemia is the most consequential intraoperative complication of impaired renal clearance and is the focus of the remainder of this review. A cardioplegic solution with a potassium concentration of approximately 26 mEq/L is infused into coronary artery ostia intraoperatively to induce cardiac standstill – allowing the surgeon to perform the operation without cardiac motion [14]. To liberate from CPB, however, this solution must be cleared from the body. A normal plasma potassium concentration must be re-established to allow for successful native cardiac conduction and return of spontaneous circulation. In addition to the cardioplegia solution, other sources of both exogenous and endogenous potassium releases are summarized in Table 1. One significant source of exogenous potassium throughout the case is from transfusions of stored red blood cells; the potassium concentration of the supernatant of stored blood increases predictably and linearly over time and is approximately equal to the number of days it has been in storage [15, 16]. Some studies have reported levels reaching 15–30 mEq/L after 2–3 weeks of storage with the potential for levels greater than 50–60 mEq/L within 5–6 weeks of storage [17, 18]. One strategy to attenuate the potassium load associated with intraoperative transfusions is to use an auto-transfusion device (cell saver) to wash blood which has been shown to decrease the potassium concentration of the packed red blood cell supernatant from 39.6 mEq/L down to 2.3 mEq/L [19]. There is also transcellular flux of potassium as a consequence of in-vivo or in-circuit hemolysis, the rewarming phase of iatrogenic hypothermia, acidemia, and from rhabdomyolysis [20]. Inadequate or delayed control of hyperkalemia can lead to persistent cardiac asystole and an inability to liberate from CPB support. Without native renal clearance, other methods must be employed for such cases; intraoperative kidney replacement therapies will be detailed later in the review.

Table 1.

Contributors to the development of hyperkalemia while on CPB grouped by mechanism

Preoperative Optimization

There are several different strategies implemented by different institutions to provide renal replacement therapy (RRT) in the pre-, intra-, and postoperative period (Table 2). Great attention must be paid to volume status and electrolyte derangements by optimizing dialysis for patients in the preoperative period. For stable patients undergoing elective procedures, the general approach is to provide their outpatient modality of RRT (either conventional HD or peritoneal dialysis [PD]) within 24 h of their operation [21-23]. For patients who are critically ill or have demonstrated intolerance to intermittent modalities (acute coronary syndrome, hemodynamic instability), utilizing preoperative continuous RRT (CRRT) in an ICU setting is the preferred strategy.

Table 2.

Perioperative RRT modalities utilized in cardiac surgical procedures requiring CPB

Intraoperative Management

Early descriptions of the management of ESRD patients undergoing surgical procedures requiring CPB describe medical management only (rather than dialytic therapies); however, it is now recognized that intraoperative dialytic therapy is preferred over medical management given the unique intraoperative risks to this patient population. The earliest description of such patients successfully undergoing a surgical procedure with CPB dates back to 1968 where pre- and postoperative HD was employed but not intraoperatively [3]. It was not until the 1970s and 1980s where more case reports and case series start describing an intraoperative management plan that includes dialysis for such patients [24-26]. Employing intraoperative HD allows for both controls of volume throughout the case and is also extremely effective at clearing exogenous potassium loads that are delivered throughout the cases [27]. Different centers have described various strategies in both the timing and the type of dialytic modality provided (Table 2). For example, one center performs HD the day before the operation, intra-op HD while on CPB, then HD on postoperative day 1 [22]. Another center’s perioperative approach is daily HD on each of the 3 days leading up to the operation and then performs intra-op HD [21]. Others have described the use of continuous modalities such as CRRT in parallel to CPB instead of HD [28]. Finally, some groups use a mix of these different modalities, typically with preoperative HD, intraoperative HD, then postoperative CRRT [21, 29, 30]. One group reports that implementing a protocol that delivers pre-, intra-, and postoperative dialytic therapy (various modalities) can significantly reduce the high morbidity and mortality typically seen in this patient population (compared to matched controls) [30].

Providing pre-existing dialytic modalities (HD or CRRT) intraoperatively was previously the standard of care for many centers but presented logistical challenges. Physical constraints of operating room space and the complexity of the coordination of timing with dialysis technicians and either dialysis nurses or ICU nurses to provide these therapies while on CPB are challenging. Zero-balance ultrafiltration (ZBUF) is an alternative to the traditional intraoperative therapies and was first described in the pediatric population in the 1990s [31]. It is a form of convective ultrafiltration that utilizes pre-existing connections on the CPB circuit and a hemoconcentrator placed in parallel to in the circuit and has been shown to control intraoperative hyperkalemia [32]. The simplified CPB circuit is depicted in Figure 1, showing venous blood from the patient flowing into a cardiotomy reservoir before being pumped through an oxygenator and then returned to the patient. A high-flux polyethersulfone membrane hemoconcentrator is connected in parallel to the CPB circuit, with the inlet to the hemoconcentrator coming off of a shunt from the oxygenator and the outlet of the hemoconcentrator returning to the venous line from the patient and ultimately returning to the venous reservoir (Fig. 1) [31, 33]. Plasma is then ultrafiltered out of the blood and across the membrane using convective forces, and a commensurate volume of replacement fluid is added to the venous reservoir to prevent significant hemoconcentration and to allow for potassium-free washing of the blood (in a manner similar to pre-filter continuous veno-venous hemofiltration). This is a continuous modality and should be performed for the entire duration the patient is on CPB. It is important to note that while zero-balance volume change is the a priori goal using this pre-filter convective modality, while on CPB, the intraoperative teams (CT surgery, CT anesthesia, and perfusion) communicate throughout the case in order to adjust the volume status by using the hemoconcentrator to achieve a negative fluid balance if needed with rates of up to ∼100 mL/min of ultrafiltration using the upper limit of the manufacturers who recommended blood flows and transmembrane pressure [34, 35].

Fig. 1.

Cardiopulmonary bypass circuit modified for convective ultrafiltration. Deoxygenated blood from the patient flows into a venous cardiotomy reservoir before being pumped through an oxygenator and returned to the patient. To provide convective ultrafiltration, a high-flux polyethersulfone membrane hemoconcentrator is connected in parallel to the standard circuit (blood coming from the oxygenator and hemoconcentrated blood returning to the venous line and ultimately returning to the venous reservoir). Hydrostatic forces are applied (positive pressure on the blood side and a negative pressure on the effluent side) to establish a transmembrane pressure gradient which generates the ultrafiltrate. A commensurate volume of replacement fluid is added to the venous reservoir.

Different solutions have been described for this purpose, including crystalloids (0.9% normal saline, lactated Ringer’s, Plasma-Lyte®, Normosol®), CRRT dialysate solutions, and CRRT replacement fluids [20, 32, 33, 35-38]. Because high-volume normal saline is associated with hyperchloremic acidosis [33], most centers use a more balanced physiologic solution. While some groups have described using CRRT dialysate solutions in their protocols, these solutions are not FDA-approved to enter the bloodstream [33, 36, 37], so using a CRRT replacement fluid is preferred [35]. Some of the key differences in the composition of these different solutions are highlighted in Table 3.

Table 3.

Comparison of the composition of different candidate replacement fluids used in convective ultrafiltration while on CPB

At our institution, we utilize a weight-based protocol driven by the patient’s most recent plasma potassium concentration, which is measured every 15 min [35]. This ultrafiltration strategy utilizes the pre-existing resources of the intraoperative team (e.g., the CPB circuit for access and the perfusion team) and simplifies the workflow in the OR, as the perfusion team is already present and there is no need to coordinate with additional teams for either CRRT or HD. It is important to note, however, that ultrafiltration can only be provided while the patient is heparinized and on CPB. If an intraoperative, emergent indication for RRT arises after separation from bypass, management would require a multidisciplinary discussion between the surgical, anesthesia, and nephrology teams for deploying either CRRT or HD. Preoperative multidisciplinary discussions also occur in preparation for anticipated complex cases with prolonged cardiac ischemia times and cases with deep hypothermia protocols (in select cases, conventional HD is kept on standby in the OR). In general, however, ZBUF is the preferred modality at our institution for the above logistical reasons and to also balance the required clearance rate with the safe clearance rate. While intraoperative conventional HD is very effective at clearing potassium rapidly, there are also other untoward consequences of such rapid clearance. Many perioperative prophylactic antibiotics are readily cleared by conventional HD. Additionally, intermittent HD can also rapidly lower osmolality due to high clearance rates and lead to increased intracranial pressure depending on how well optimized the patient’s dialysis plan was preoperatively. PD is not utilized intraoperatively at our institution due to possible pleuro-peritoneal leaks, poor splanchnic perfusion, increased transdiaphragmatic pressures from fills, and coordination of the PD treatment team in the OR.

Special consideration must be given to intraoperative dosing of medication due to the potential for extra-corporeal clearance (dependent on the size, charge, protein binding of the medication, and the blood flow and therapy fluid flow rates). Our protocol utilizes therapy fluid dosing most similar to accelerated RRT or PIRRT dosing (32–48 mL/kg/h). While there are no robust in-vivo pharmacokinetic studies examining appropriate dosing of medications for such modalities, there are a number of in-silico Monte Carlo simulations examining predicted achieved concentrations and clearance on these hybrid modalities [39-42]. Whenever possible, therapeutic drug monitoring should be used given the uncertainty of predicted versus actual achieved dose in any patient on RRT.

Postoperative Monitoring and Management

The immediate postoperative period is a particularly vulnerable time for these patients, with many being intolerant to any significant volume overload. The choice and timing of modality will be dictated by each individual patient’s clinical condition. Performing CRRT or convective ultrafiltration using the CPB circuit intraoperatively should not be thought of as replacing a conventional thrice weekly HD session (and even HD may not be enough to replace a normal HD session given the short bypass times for some cases). For this reason, many centers aim to provide RRT in the ICU by postoperative day 1. Patients who have hemodynamic instability and remain critically ill will require CRRT if it is available while a minority who are more clinically stable are able to tolerate intermittent HD in the immediate postoperative period. While some centers have reported continuing PD in the immediate postoperative period [43], given the increase in splanchnic circulation resistance and decreased perfusion of the peritoneal membrane in shock, the potential for transdiaphragmatic leaks, and increased transdiaphragmatic pressures which may limit ventilation, most centers do not rely on PD for at least 2–4 weeks postoperatively. Once they have recovered from their critical illness, these patients are transitioned back intermittent HD.

Conclusion

Cardiac surgical procedures with CPB support in patients on dialysis present several challenges, particularly hyperkalemia. Different strategies are employed to safely manage these patients in the pre-, intra-, and postoperative period. Implementing a convective ultrafiltration protocol using pre-existing connections on the CPB pump performed by the perfusion team allows for control of potassium concentration with existing personnel and minimal additional equipment.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors have no funding sources to report.

Author Contributions

Manuscript preparation and editing: Jacob S. Stevens, Jonathan M. Hastie, Jessica Spellman, Aaron Mittel, James Beck, Dana A. Mullen, Kenmond Fung, Michael Argenziano, Hiroo Takayama, and Jai Radhakrishnan. Tables and figures: Jacob S. Stevens.

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