Cardiac surgery with cardiopulmonary bypass in patients with cold agglutinin disease

INTRODUCTION — Cardiopulmonary bypass (CPB) is a form of extracorporeal circulation in which the patient's blood is diverted from the heart and lungs and rerouted outside of the body during cardiac surgery. The normal physiologic functions of the heart and lungs (including circulation of blood, oxygenation, and ventilation) are temporarily taken over by the CPB machine.

This topic will discuss perioperative management of cardiac surgery with CPB in patients with cold agglutinin disease. Other aspects of routine CPB are discussed separately:

●(See "Initiation of cardiopulmonary bypass".)

●(See "Management of cardiopulmonary bypass".)

●(See "Weaning from cardiopulmonary bypass".)

ANESTHESIA CONSIDERATIONS

Cold agglutinins versus cold agglutinin disease — Cold agglutinin disease is a form of autoimmune hemolytic anemia in which autoantibodies of the immunoglobulin M (IgM) class cause agglutination of red blood cells (RBCs) at cooler temperatures. These agglutinated RBCs can obstruct capillaries and can lead to ischemia. The antibodies also fix complement, which can produce intravascular hemolysis, with severe anemia and other complications.

Diagnosis of cold agglutinin disease involves documenting hemolysis with a positive direct Coombs test for complement C3d (usually negative for IgG) and determining the thermal amplitude of the cold agglutinin. A typical cold agglutinin titer is ≥64 at 4°C. (See "Cold agglutinin disease", section on 'Diagnostic evaluation'.)

Some patients present for cardiac surgery with known cold agglutinin disease. Routine preoperative screening to detect cold agglutinins before cardiac surgery with cardiopulmonary bypass (CPB) is not supported by evidence [1,2]. However, the presence of cold agglutinins has been discovered when RBC agglutination and/or acute intravascular hemolysis occurs after exposure to cold temperatures in settings such as CPB in patients with circulating cold agglutinins but no overt symptomatic disease [1]. Although rare, cases of catastrophic hemolysis and organ failure have been described during cardiac surgery with hypothermic CPB [3]. Thus, it is necessary to institute measures to reduce hemolysis once agglutination is discovered. (See 'Cold agglutination discovered during CPB' below.)

Risks to the patient — In patients with cold agglutinin disease undergoing CPB, hemolysis is the major concern.

Intravascular complement-mediated hemolysis can cause life-threatening anemia and complications of intravascular free heme. Any surgery can increase the chance of complement-mediated hemolysis due to the increased risk of complement activation.

Case reports have described agglutination that includes clogging of components of the bypass circuit (eg, the cardioplegia heat exchanger) (movie 1 and movie 2) [4].

PATIENTS WITH KNOWN COLD AGGLUTININ DISEASE

Preoperative assessment — In most cases, cold agglutinin disease is known or suspected based on a clinical history of unexplained hemolysis or cold-induced symptoms. In some cases, aggregation of red blood cells (RBCs) is noted in the patient’s preoperative blood samples in the clinical laboratory or the blood bank. In such cases, the properties of the cold agglutinin should be evaluated with adequate time to form an appropriate preoperative plan before elective cardiac surgery with cardiopulmonary bypass (CPB). (See "Cold agglutinin disease", section on 'Diagnostic evaluation'.)

As illustrated in the figure, close coordination among consultants is needed to optimize surgical management (algorithm 1).

Close consultation with a hematologist or transfusion medicine specialist with expertise in this area is advised to determine [4]:

●The underlying cause. Some causes of cold agglutinin disease are transient (such as with infection); others require therapy that may take several months or more to administer. (See "Cold agglutinin disease", section on 'Primary CAD-associated lymphoproliferative disorder' and "Cold agglutinin disease", section on 'Associated disorders'.)

●The thermal amplitude of the autoantibody (the temperature below which the cold-reactive autoantibody binds to its antigen).

●Whether further diagnostic testing is needed.

●Which preoperative and intraoperative therapies are indicated and how much time is needed to implement treatment.

Consultation with the surgeon is also necessary to determine:

●Urgency of the surgery. This determines whether there is time to treat the underlying cause of cold agglutinins versus use a rapidly acting therapy to remove cold agglutinins and prevent hemolysis.

●Whether hypothermia can be avoided. Many cardiac surgical procedures can be performed without the need to induce hypothermia during CPB. Exceptions include procedures that require deep hypothermia such as ascending aortic surgery. (See 'Procedures requiring CPB with deep hypothermia' below.)

Optimization for elective cardiac surgical procedure with routine CPB — For patients undergoing elective cardiac surgery with CPB, the procedure should be delayed if necessary to appropriately treat cold agglutinin disease.

Preoperative assessment and planning — Preoperative strategies to reduce the cold agglutinin titer depend on the underlying cause.

●Primary cold agglutinin disease – Primary cold agglutinin disease is a bone marrow lymphoproliferative disorder. Anti-B cell therapy is administered, typically over the course of several months. (See "Cold agglutinin disease", section on 'Therapies directed at the pathogenic process'.)

The cold agglutinin titer and thermal amplitude should be reassessed prior to surgery whenever possible.

For institutions that do not have sutimlimab readily available, the patient should be referred to a center where this treatment is available or the surgery should be delayed for arrangements to procure the medication.

●Secondary cold agglutinin disease

•Infection – Ideally, surgery is delayed until infection-related cold agglutinin disease has resolved. If appropriate, antibiotic treatment is administered. Typically, cold agglutinins do not persist after resolution of infection. The patient is reassessed shortly before surgery. If cold agglutinins are absent, no additional testing or interventions are required. (See "Cold agglutinin disease", section on 'Infections and autoimmune disorders'.)

•Autoimmune disorder – Therapy appropriate for the specific disorder is instituted, with reassessment of the agglutinin titer and thermal amplitude shortly before surgery. (See "Cold agglutinin disease", section on 'Infections and autoimmune disorders'.)

•Lymphoproliferative disorders – Therapy appropriate for the specific disorder is instituted, with reassessment of the agglutinin titer and thermal amplitude shortly before surgery. (See "Cold agglutinin disease", section on 'Lymphoproliferative disorders'.)

Most patients will have a good response to the instituted therapy. However, some may have chronic cold agglutinin-related symptoms, and some will have persistent circulating cold agglutinins.

Strategies in the immediate preoperative period — Our approach to perioperative management includes the following strategies (algorithm 1):

●Planning to avoid hypothermia during the procedure – If surgery can be done without hypothermia, maintain systemic temperature above the thermal amplitude of the cold agglutinin.

●Complement blockade (sutimlimab) – Sutimlimab is a monoclonal antibody directed at the C1 component of complement. It can dramatically reduce cold agglutinin-mediated intravascular hemolysis, but it does not treat cold-induced RBC agglutination. (See "Cold agglutinin disease", section on 'Complement inhibition'.)

For all patients with cold agglutinin disease undergoing CPB, we suggest sutimlimab prior to surgery. A single dose is used, and the effect is likely to be nearly immediate. This will dramatically reduce hemolysis, as it acts on both complement-mediated hemolysis pathways.

If sutimlimab is not available (and cannot be obtained for the patient prior to surgery), eculizumab is an alternative. However, eculizumab only acts on one complement-mediated hemolysis pathway and is expected to provide less protection against hemolysis.

Efficacy of sutimlimab and eculizumab administered to patients with cold agglutinin disease undergoing cardiac surgery with CPB or other major surgery has only been described in case reports, and the two agents have never been directly compared [5,6]. Our preference for sutimlimab is based on our experience in managing cold agglutinin disease and our understanding of disease pathophysiology.

Efficacy in nonsurgical patients with cold agglutinin disease is presented separately. (See "Cold agglutinin disease", section on 'Anti-complement therapies'.)

●Plasmapheresis to remove the cold agglutinins – Cold agglutinins are almost always IgM, which is retained intravascularly due to its large size (IgM is a pentamer) and effectively removed by plasmapheresis (also called therapeutic plasma exchange [TPE]). Albumin is used as the replacement fluid. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'Replacement fluids'.)

If surgery cannot be accomplished with normothermic conditions in a patient who has circulating cold agglutinins, we recommend plasmapheresis prior to surgery to reduce the amount of circulating cold agglutinin. While some circulating cold agglutinins may remain after plasmapheresis, the risk of adverse consequences is likely to be reduced. This strategy applies to individuals who require deep hypothermia with elective circulatory arrest (DHCA) [7-10]. (See "Anesthesia for aortic surgery with hypothermia and elective circulatory arrest in adult patients".)

Removal of the IgM cold agglutinin by plasmapheresis is expected to prevent hemolysis and cold-induced RBC agglutination during surgery. However, data regarding the efficacy of plasmapheresis for this indication are scant in both surgical and nonsurgical patients. (See "Cold agglutinin disease", section on 'Plasmapheresis or IVIG as a temporizing measure'.)

Notably, plasmapheresis requires advance planning with the plasmapheresis team and attention to possible complications. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'Technology' and "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)

●Transfusions – RBC transfusions are administered as needed for severe anemia. (See "Cold agglutinin disease", section on 'Transfusions'.)

RBC transfusions may be life-saving in individuals with severe anemia, but they do nothing to halt hemolysis or RBC agglutination; they are only a temporizing measure until the interventions above are able to stop hemolysis and RBC agglutination.

Details regarding these therapies are discussed separately. (See "Cold agglutinin disease", section on 'Management'.)

Emergency or urgent cardiac surgery with CPB — If emergency or urgent surgery is necessary, only rapid-acting therapies and cold avoidance will be useful. These include (algorithm 1):

●Cold avoidance – Avoiding hypothermia is appropriate for all patients when possible.

●Plasmapheresis to remove the cold agglutinin – As with elective surgery, we recommend plasmapheresis for individuals who cannot avoid hypothermia. This may require rapid mobilization of the plasmapheresis team. (See 'Procedures requiring CPB with deep hypothermia' below.)

●Complement blockade (sutimlimab) – For all patients with cold agglutinin disease who require emergency or urgent cardiopulmonary bypass, we suggest sutimlimab as soon as possible. Only one dose is needed. (See "Cold agglutinin disease", section on 'Sutimlimab (anti-C1)'.)

If sutimlimab is not available, we suggest one dose of eculizumab.

If there is insufficient time to give a dose of complement-blocking therapy preoperatively or intraoperatively, it can be given postoperatively. (See 'Postoperative management' below.)

●Transfusions – Transfusions may be required for severe hemolytic anemia. (See "Cold agglutinin disease", section on 'Transfusions'.)

As noted above, transfusion is only a temporizing measure and does not reduce hemolysis or RBC agglutination. (See 'Strategies in the immediate preoperative period' above.)

Other therapies to treat the underlying cause of cold agglutinin disease that require months to work are not relevant for emergency procedures. For example, therapies directed at B cells that are used to treat primary cold agglutinin disease and other underlying conditions (autoimmune, lymphoproliferative) require days to weeks to reduce cold agglutinin production and are not appropriate for emergency or urgent procedures. (See "Cold agglutinin disease", section on 'Therapies directed at the pathogenic process'.)

Procedures requiring CPB with deep hypothermia — Some cardiac surgical procedures such as ascending aortic surgery are performed using deep hypothermia with (elective) circulatory arrest (DHCA). (See "Anesthesia for aortic surgery with hypothermia and elective circulatory arrest in adult patients".)

If possible, such procedures are postponed to allow time for more detailed analysis of antibody titer and thermal amplitude, treatment of possible causes of cold agglutinin production, and careful planning for surgery. (See 'Optimization for elective cardiac surgical procedure with routine CPB' above.)

Although details are individualized, in most cases this planning includes (algorithm 1):

●Preoperative plasmapheresis to remove cold agglutinins to minimize risk of potentially catastrophic agglutination. (See "Cold agglutinin disease", section on 'Plasmapheresis or IVIG as a temporizing measure'.)

●Preoperative complement blockade with sutimlimab to minimize hemolysis. (See "Cold agglutinin disease", section on 'Anti-complement therapies'.)

Therefore, for cases requiring deep hypothermia, the procedure should be performed at a center with a multidisciplinary team that supports plasmapheresis and has access to sutimlimab and other strategies and treatments that are outlined above. (See 'Optimization for elective cardiac surgical procedure with routine CPB' above.)

In the rare situation when DHCA is needed on an emergency basis, cooling is minimized as much as possible, and modified cardioplegia techniques are used, as noted below [4]. (See 'Management during CPB' below.)

COLD AGGLUTINATION DISCOVERED DURING CPB — The relative likelihood of cold agglutinin disease being discovered during cardiopulmonary bypass (CPB) is unknown. Although rare, it may be catastrophic.

Incidental discovery of cold agglutinin disease is suspected when agglutination is noticed during blood priming of the cardioplegia heat exchanger, or in the surgical field after cooling and application of the aortic cross-clamp (movie 1 and movie 2) [4].

If cold agglutination is first discovered during cooling after initiating CPB, the patient is immediately rewarmed and body temperature maintained at 36° to 37°C for the duration of the procedure. (See 'Intraoperative considerations' below.)

Cold agglutinin testing can be sent from the operating room and results may be available during the procedure, depending on the institution's laboratory facility. Although these results help in guiding management, warming and other measures should not be delayed while awaiting them. (See "Cold agglutinin disease", section on 'Antibody titer and thermal amplitude'.)

Other measures noted above are also implemented (algorithm 1). These include (see 'Strategies in the immediate preoperative period' above):

●Plasmapheresis if maintenance of normothermia is not possible and resources allow rapid mobilization

●Sutimlimab if available

●Eculizumab if sutimlimab is not available

●Transfusion if needed for severe anemia

Details are described above and separately. (See 'Intraoperative management pre- and post-CPB' below and 'Management during CPB' below and "Cold agglutinin disease", section on 'Emergency and supportive therapies for anemia'.)

INTRAOPERATIVE CONSIDERATIONS

Intraoperative management pre- and post-CPB — During cardiac surgery with cardiopulmonary bypass (CPB), the patient's blood should be kept at a temperature above the thermal amplitude of the autoantibody (the temperature below which the cold-reactive autoantibody binds to its antigen). Strategies include:

●Use of whole-body patient warming devices during periods before (and after) CPB minimizes peripheral extremity cooling.

●All intravenous fluids are administered through a warmer, particularly red blood cells (RBCs) and plasma, which are stored at cold temperatures. Notably, if the thermal amplitude of the cold agglutinin is higher than room temperature, then blood in the recirculation line must be recirculated during periods when the CPB pump is off to avoid stagnation of this extracorporeal whole blood at room temperature.

●Despite theoretical concerns regarding agglutination, use of cell saver technology is not contraindicated. Since plasma proteins and antibodies are routinely washed away, and a 40 micron filter is used during reinfusion, administration of any aggregates is unlikely. Furthermore, using a blood warmer during reinfusion mitigates risk. (See "Surgical blood conservation: Intraoperative blood salvage", section on 'Washing' and "Surgical blood conservation: Intraoperative blood salvage".)

Management during CPB

●Control of blood temperature is achieved using the heat exchanger in the CPB circuit. If the thermal amplitude of the cold agglutinin is near body temperature, the heat exchanger should be used to maintain body temperature above the thermal amplitude during CPB.

●Cardioplegia delivery may be modified by:

•Keeping the blood or crystalloid cardioplegia induction dose at a temperature above the thermal amplitude or flushing the coronary arteries with warm crystalloid before switching to cold crystalloid cardioplegia.

•Thereafter, depending on the requirements for an individual case and the surgeon's preferences, either continuous warm blood cardioplegia, or only intermittent cold crystalloid cardioplegia is administered, rather than cold (2 to 4°C) blood cardioplegia [11].

●If necessary, before cross-clamp removal (depending on the myocardial temperature), the myocardium can be rewarmed with a crystalloid cardioplegia "hot shot" (ie, a warm crystalloid flush via the cardioplegia cannula) [4,12-14].

POSTOPERATIVE MANAGEMENT — In the postoperative period, normothermia is achieved and maintained by using warming devices (convective forced air warmer, fluid warmers) and warming the room temperature. (See "Perioperative temperature management", section on 'Postoperative temperature derangements'.)

Close monitoring for hemolysis, anemia, and kidney dysfunction are important in the postoperative period.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of cardiopulmonary bypass" and "Society guideline links: Anemia in adults".)

SUMMARY AND RECOMMENDATIONS

●Definitions and risks – Cold agglutinin disease is an autoimmune hemolytic anemia in which IgM autoantibodies agglutinate red blood cells (RBCs) at cooler temperatures and fix complement, which can produce intravascular hemolysis at cold temperatures used for cardiopulmonary bypass (CPB). Although some individuals have asymptomatic circulating cold agglutinins that become clinically significant during hypothermic CPB (movie 1 and movie 2), we do not perform routine preoperative screening for cold agglutinins. (See 'Anesthesia considerations' above.)

●Elective procedures with CPB – Close consultation with the hematologist or transfusion medicine expert and the surgeon is necessary to determine the status of cold agglutinin disease, the thermal amplitude of the autoantibody, urgency of the surgical procedure, whether hypothermia will be necessary, and planning for administration of complement blockade and possibly plasmapheresis. The figure summarizes our approach (algorithm 1). (See 'Preoperative assessment' above.)

•Delay surgery if needed – Patients with untreated cold agglutinin disease should have surgery delayed when possible until the underlying cause resolves (eg, infection) or is treated (eg, autoimmune or lymphoproliferative disorder). Delay is also appropriate if possible to obtain sutimlimab. (See 'Preoperative assessment' above and 'Optimization for elective cardiac surgical procedure with routine CPB' above.)

•Complement blockade (sutimlimab) – For all patients, we suggest sutimlimab rather than other therapies or no therapy for complement blockade (Grade 2C). A single dose is used, and the effect will be nearly immediate. If sutimlimab is not available and cannot be obtained, eculizumab may be used, but complement blockade may be less. (See "Cold agglutinin disease", section on 'Complement inhibition' and "Cold agglutinin disease", section on 'Anti-complement therapies'.)

•Avoid hypothermia or use plasmapheresis – For all patients, avoid hypothermia when possible. (See 'Management during CPB' above.)

For rare patients who require deep hypothermia with elective circulatory arrest for ascending aortic surgery, management by a multidisciplinary team typically includes preoperative plasmapheresis to minimize potentially catastrophic RBC agglutination, as well as preoperative complement blockade with sutimlimab to minimize hemolysis, which may be catastrophic. (See 'Procedures requiring CPB with deep hypothermia' above and "Cold agglutinin disease", section on 'Plasmapheresis or IVIG as a temporizing measure'.)

•Transfusions of red blood cells (RBCs) – Transfuse as necessary as a temporizing measure for severe anemia. (See "Cold agglutinin disease", section on 'Transfusions'.)

●Emergency/urgent procedures or cold agglutinins discovered during CPB – The above principles apply but may be more challenging to institute due to time constraints. (See 'Emergency or urgent cardiac surgery with CPB' above and 'Cold agglutination discovered during CPB' above.)

●Intraoperative management – During surgery, keep the blood temperature above the antibody's thermal amplitude using whole body warming devices. Administer all intravenous fluids and blood products through blood warmers, and maintain the extracorporeal blood above the thermal amplitude of the antibody. Continuous warm cardioplegia is ideal. If necessary, the myocardium can be warmed with a crystalloid cardioplegia "hot shot" before cross-clamp removal. (See 'Intraoperative considerations' above.)

●Postoperative management – Use warming devices and room heat to maintain normothermia. Closely monitor hemolysis, anemia, and kidney function. (See 'Postoperative management' above.)

●Additional information

•Cold agglutinin disease – (See "Cold agglutinin disease" and "Diagnosis of hemolytic anemia in adults".)

•CPB – (See "Initiation of cardiopulmonary bypass" and "Management of cardiopulmonary bypass" and "Weaning from cardiopulmonary bypass".)