Cold agglutinins (CAs) are cold-reactive antibodies, usually of the immunoglobin M subtype, that cause red blood cells (RBCs) to agglutinate at low temperatures. Upon rewarming, CAs may then induce complement-mediated hemolysis. Characteristics of CAs include a specific thermal threshold, which is the temperature below which antibody activation occurs; an exponential increase in antibody activity (titer) on cooling below the thermal threshold; and rapid reversibility of antibody activation and RBC agglutination on rewarming .
While CAs are usually of little or no clinical importance, they may cause significant morbidity during hypothermic surgical procedures such as cardiopulmonary bypass (CPB). Adverse events attributed to CAs after surgery have included acute renal failure [2,3], persistent hemolytic anemia [4,5], and intravascular occlusive crises . We describe now CPB in a patient with previously undetected CAs and briefly discuss the intraoperative management of CAs.
A 60-yr-old man presented to the operating room for urgent coronary artery bypass grafting. His past medical history was significant for unstable angina, hypertension, hypercholesterolemia, and a 40 pack/yr history of smoking. The patient denied other significant medical problems including a history of viral syndromes, pneumonitis, and hematologic or connective-tissue disorders. Pertinent laboratory values included a normal coagulation status.
In addition to standard monitoring, a radial and a pulmonary artery catheter were inserted. Induction of anesthesia was performed using intravenous fentanyl (12 micro g/kg) and diazepam (0.12 mg/kg) supplemented with pancuronium (0.1 mg/kg) for muscle relaxation. The pre-CPB course was uneventful (including insertion of a retrograde blood cardioplegia catheter into the coronary sinus). Prior to CPB, the patient was anticoagulated with 300 U/kg of heparin with a resultant activated clotting time of 423 s.
After initiation of CPB, the patient was cooled to a core temperature (esophageal) of 28 degrees C. The aorta was clamped, and an antegrade blood cardioplegia catheter was inserted into the aortic root. When asked to administer both antegrade and retrograde blood cardioplegia (4 degrees C) to the patient, the perfusionist reported being unable to administer the blood cardioplegia due to severely increased pressures (240 mm Hg) in the retrograde cardioplegia catheter (i.e., there was no initial flow). Upon closer inspection of the line, clumped RBC aggregates were noted, and CAs were suspected. Both the antegrade and retrograde cardioplegia catheters were then disconnected from the patient, and the blood cardioplegia was flushed out completely using normal saline connected to the blood inlet side of the cardioplegia system. The cardioplegia catheters were then reconnected and the patient's heart successfully arrested and colled using crystalloid cardioplegia (4 degrees C). Simultaneously, the systemic blood was rewarmed to 37 degrees C, and surgery continued without further incident. Pump blood sent to the laboratory for analysis of CAs was reported as having a titer of less than 1:1000 at 4 degrees C. There was no clinical evidence of hemolysis (i.e., hemoglobinuria) after CPB, and the patient was transfused with warmed, washed, autologous blood collected with the cell-saver device. No microaggregates were grossly noted in the cell-saver blood.
After an uneventful postoperative course, the patient was discharged home on the sixth postoperative day without surgical or anesthetic complications.
CAs are predominantly immunoglobin M antibodies directed against the RBC I or i antigen. The clinical importance of CAs largely depends on their titer and thermal threshold, the highest temperature at which the antibody is active [7,8]. As this is usually lower than ambient temperatures, CAs are usually of little clinical importance, with diagnosed CA disease having an approximate incidence of 1:75,000 . However, in the setting of cardiac surgery, CAs may be of greater clinical importance due to the use of hypothermia for myocardial protection.
Clinically significant CA disease may occur as a primary or secondary process. Primary or idiopathic CA disease usually occurs in the seventh or eighth decades, affecting women more often than men. It is frequently chronic in duration, well tolerated, and is often asymptomatic. Secondary CA disease usually occurs as a sequelae of an infectious process (e.g., mycoplasma pneumonia, cytomegalovirus) or an underlying lymphoproliferative disorder. CAs have also been demonstrated in patients infected with human immunodeficiency virus independent of other infections or neoplasms .
CA disease is characterized by the presence of high antibody titers at 4 degrees C (1:10,000) and low antibody titers at 37 degrees C (1:16). In some patients, however, the antibody shows a flatter thermal spectrum with a moderately high titer at 4 degrees C (1:320) and a readily demonstrable titer at 37 degrees C (1:64) . While RBC agglutination may be profound at low temperatures, disagglutination occurs quickly upon rewarming, with agglutination ceasing at 32 degrees C in most patients. However, complement fixation is a warm-reactive process, and complement-mediated hemolysis may still occur. In general, titers of less than 1:32 are not thought to be clinically significant unless they are of a high thermal threshold. Moore et al. found that patients with nonspecific CAs whose antibodies were characterized by low titers (less than 1:32) and low thermal threshold (less than 28 degrees C) and who lacked clinical symptomatology tolerated hypothermic CPB without increased threat of a hemolytic or vascular occlusive crisis .
Since the first report of an unanticipated CA reaction in a patient who developed persistent intravascular hemolysis after undergoing hypothermic CPB by Wertlake et al.  in 1969, a number of strategies have been proposed for the intraoperative management of patients with known CA disease. Initially, patients were managed perioperatively using exchange transfusion and steroid therapy [3,12]. Subsequent reports demonstrated that exchange transfusion is not necessary provided that the patient's core temperature is maintained several degrees above the antibody's thermal threshold . Current management techniques for patients with known CA disease undergoing hypothermic CPB include normothermic ischemic arrest, warm crystalloid cardioplegia, cold crystalloid cardioplegia, plasmapheresis, and warm blood cardioplegia . Regardless of which technique is used, it is important to minimize systemic cooling during CPB to keep the systemic perfusion temperature above the thermal threshold of agglutinin activity. Anesthetic gases, intravenous fluids, and blood products should be heated. The ambient temperature of the operating room should be increased, and a warming mattress should be placed on the operating table. Since optimal protection of the heart requires myocardial temperatures (4 degrees C) within the activity range of most CAs, isolation of the heart from the systemic perfusate may necessitate bicaval cannulation with tourniquets or clamps for CPB and an insulating pad in the posterior pericardium to prevent contact with the descending aorta and other mediastinal structures. Similarly, before cross-clamp release, the temperature of the heart should be sufficiently rewarmed (37 degrees C) so as to be above the thermal threshold of the CA antibody. Neither heparinization nor dilution with pump prime during CPB is protective against agglutination and hemolysis .
It is not uncommon for CAs to initially manifest during surgical hypothermia in patients with no previous known history of CA disease. The low incidence of CA disease, screening test costs, and the lack of a direct relationship among antibody titer, thermal threshold, and the risk of complications makes routine preoperative screening of CA titers uncommon. In the case of the patient with known CA disease, preoperative determination of the thermal threshold of the CA antibody may improve patient management, as the temperature at which agglutination is likely to occur may be avoided. Cooling the perfusate in the blood cardioplegia system and watching for agglutination before systemic cooling of the patient has been suggested as one alternative to preoperative screening [15,16]. If agglutination is detected in the blood cardioplegia system, the cardioplegia apparatus should be warmed to room temperature and the blood flushed from the cardioplegia apparatus and catheters. Crystalloid cardioplegia can then be initiated at room temperature while immediately beginning to recool the cardioplegia. This allows for initial warm washout followed by rapid cooling and cardiac stand-still. The heart may then be cooled to 4 degrees C as usual, using crystalloid cardioplegia, while minimizing systemic cooling to keep the systemic perfusion temperature above the thermal threshold of agglutinin activity. Using these methods and with careful preparation on the part of the anesthesia, surgical, cardiopulmonary perfusion, and nursing teams, hypothermic CPB may be conducted safely even in patients with CAs of persistently high titer and thermal threshold.
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