Jacob Pendergrast

Proceedings of a Consensus Conference: Pathogen Inactivation—Making Decisions About New Technologies

Significant progress has been made in reducing the risk of pathogen transmission to transfusion recipients. Nonetheless, there remains a continuing risk of transmission of viruses, bacteria, protozoa, and prions to recipients. These include many of the viruses for which specific screening tests exist as well as pathogens for which testing is currently not being done, including various species of bacteria, babesiosis, variant Creutzfeld-Jacob disease, hepatitis A virus, human herpes virus 8, chikungunya virus, Chagas disease, and malaria. Pathogen inactivation (PI) technologies potentially provide an additional way to protect the blood supply from emerging agents and also provide additional protection against both known and as-yet-unidentified agents. However, the impact of PI on product quality and recipient safety remains to be determined. The purpose of this consensus conference was to bring together international experts in an effort to consider the following issues with respect to PI: implementation criteria; licensing requirements; blood service and clinical issues; risk management issues; cost-benefit impact; and research requirements. These proceedings are provided to make available to the transfusion medicine community the considerable amount of important information presented at this consensus conference.

A Retrospective Review of Patient Factors, Transfusion Practices, and Outcomes in Patients With Transfusion-Associated Circulatory Overload

Transfusion-associated circulatory overload (TACO) is a common yet underrecognized and underreported complication of transfusion associated with significant morbidity and mortality. The objective of this study was to examine patient and transfusion characteristics in a cohort of TACO cases. A retrospective medical record review of 100 consecutive TACO episodes reported at 2 academic centers was performed. Information related to demographics, medical history, radiologic and echocardiographic investigations, infusion practices, reaction features, management, and outcome were collected. Ninety-eight cases were accessible for review. A history of congestive heart failure (41%), renal dysfunction (44%), and age more than 70 years (56%) were common in TACO patients. Suboptimal fluid status management and inappropriate infusion practices were often seen (eg, verbal orders, double red cell transfusions, rapid infusion rates, lack or improper timing of preemptive diuretics). The median volume of blood ordered was 500 mL, and the median volume of crystalloid or colloid (preceding 24 hours) was 2200 mL. A physician order specifying the infusion rate was documented in 50% of transfusion orders. Preemptive diuretics were ordered in only 29% of cases, most commonly introduced midway or after the transfusion at a dose of furosemide 20 mg intravenously. After TACO, 18% of patients required transfer to the intensive care unit, 8% suffered a major complication, and 2% died. Suboptimal ordering and infusion practices may be contributing to the high incidence and severity of TACO. Research in TACO prevention strategies, such as slow rates of infusion and preemptive diuretics, is warranted.

The relationship between fibrinogen levels after cardiopulmonary bypass and large volume red cell transfusion in cardiac surgery: an observational study.

BACKGROUND:Coagulopathy leading to excessive blood loss and large volume red cell transfusion is a frequent complication of cardiac surgery with cardiopulmonary bypass (CPB) that may be caused by low perioperative fibrinogen levels. We explored the relationship between post-CPB fibrinogen levels and large volume red cell transfusion. METHODS:Patients who underwent cardiac surgery with CPB from 2005 to 2011 at a single institution and had a fibrinogen level measured after CPB were included in this retrospective observational study. The relationship between post-CPB fibrinogen levels and large volume red cell transfusion (defined as ≥5 units transfused on the day of or the day after surgery) was assessed by cubic spline function and receiver operating characteristic analyses. The independent relationship between fibrinogen levels and large volume transfusion was assessed by multivariable logistic regression and propensity score analyses. RESULTS:In the 4606 patients included, the probability of large volume transfusion increased when fibrinogen levels decreased below approximately 2.0 g/L. Using <2.0 g/L as the threshold for low fibrinogen, 1918 (42%) were categorized into the low fibrinogen group, of whom 363 (18.9%) had large volume transfusion compared with 164 (13.5%) of the 2688 patients whose fibrinogen level was ≥2.0 g/L (P < 0.0001). In the low fibrinogen group, the unadjusted odds ratio (95% confidence interval) for large volume transfusion was 1.5 (1.3–1.7). The risk-adjusted odds ratio obtained by logistic regression was 1.8 (1.4–2.2) and by propensity score methods was 1.5 (1.2–2.0). CONCLUSIONS:While this study was not equipped to detect the critical fibrinogen level in bleeding patients, its results suggest that current recommendations that fibrinogen replacement not be initiated in bleeding patients unless fibrinogen levels decrease below 0.8 to 1.0 g/L may be too conservative. Randomized trials are needed to determine whether maintaining higher fibrinogen levels in bleeding patients can reduce blood loss and transfusions and by that means improve clinical outcomes in cardiac surgery.

Platelet dysfunction as measured by a point-of-care monitor is an independent predictor of high blood loss in cardiac surgery.

BACKGROUND:Excessive bleeding carries a heavy burden of illness in cardiac surgery. Although platelet dysfunction is considered to be an important cause, it is not routinely measured. Our objective was to explore the relationship between platelet dysfunction and blood loss in cardiac surgery. METHODS:In 100 consenting patients undergoing cardiac surgery requiring cardiopulmonary bypass, platelet function was measured before, during, and after bypass with a point-of-care device that compares platelet counts before and after exposure to an agonist. Clinicians were blinded to the results of testing. Patients whose calculated blood loss was part of the highest quartile for the cohort were classified as having had high blood loss. The independent relationship between platelet function and high blood loss was measured with the aid of multivariable Poisson regression modeling (with a robust error variance) that controlled for patients’ overall risk of high blood loss. RESULTS:Calculated blood loss was negatively skewed with a median of 798 mL (25th and 75th percentiles of 380 and 1775 mL). Patients whose blood loss exceeded 1770 mL were classified as having had high blood loss, and 25 patients met this criterion. There was 1 death in the high blood loss group unrelated to hemorrhage. After adjusting for bleeding risk, each 10 × 109/L increase in collagen-activated functional platelet count during rewarming and postprotamine, respectively, was associated with a relative risk of 0.89 (95% confidence interval, 0.82–0.97; P = 0.006) and 0.87 (95% confidence interval, 0.78–0.98; P = 0.02) for high blood loss. CONCLUSIONS:Platelet dysfunction, as measured by a point-of-care method during rewarming and postprotamine, is independently associated with high blood loss in cardiac surgery. Additional studies are needed to determine whether the incorporation of this assay into blood management algorithms might help rationalize blood transfusion therapy, potentially reducing blood loss and improving clinical outcomes.

Changes in intravenous immunoglobulin prescribing patterns during a period of severe product shortages, 1995-2000

Background and Objectives  Canadian consumption of intravenous immunoglobulin (IVIG) has increased dramatically since it was first marketed in the early 1980s, and Canada is now the worlds largest per capita consumer. During the late 1990s, worldwide product shortages of IVIG occurred. This study was designed to identify the disease conditions for which IVIG was being prescribed in academic hospitals during this period, and to explore the effects that IVIG shortages had on prescribing patterns.

Passenger Lymphocyte Syndrome With or Without Immune Hemolytic Anemia in all Rh-Positive Recipients of Lungs From Rhesus Alloimmunized Donors: Three New Cases and a Review of the Literature

The passenger lymphocyte syndrome (PLS) is an unusual complication of solid organ transplantation, in which donor lymphocytes produce antibodies reactive with host red blood cell (RBC) antigens. Risks for PLS include highly lymphoid grafts, past sensitization of the donor against relevant RBC antigens, and donor lymphocyte escape of host immune clearance. For a 1-year period at our center, we observed an uncommonly high frequency of post-lung transplant Rhesus PLS, occurring once in every 31 cases. Passenger lymphocyte syndrome resulted from 2 alloimmunized cadaveric donors, in 3 of 3 D+, ABO-identical but HLA-unmatched recipients who initially had nonreactive RBC antibody screens. In case 1, the right lung of a group A, D-negative donor, with antibodies against D, C, and E antigens, was transplanted into a group A, R1R1 recipient. The recipient developed severe hemolytic anemia, direct antiglobulin test (DAT)-positive, on postoperative day (POD) 17. Anti-D and anti-C were identified on both the indirect antiglobulin test (IAT) and the RBC eluate. She required 10 U of RBCs in 40 days as well as plasmapheresis (POD 36-40). When transfusion dependence ceased, anti-D +/- C remained detectable on DAT and IAT for another 6.5 months. In case 2, the group A, R1r recipient of the same donors left lung exhibited anti-D for the first time at posttransplant month 4 on both IAT and DAT. This activity persisted until a rejection episode 5 months later, without ever causing any evidence of hemolysis. In case 3, the group O, R1R1 recipient of both lungs of a group O, D-negative donor, with antibodies against D, C, and V antigens, developed a nonhemolytic DAT and IAT with anti-D +/- C at postoperative month 2, which remained positive at last follow-up (6 months posttransplant). In conclusion, this report suggests a high incidence of Rhesus antibody PLS after lung transplantation, with wide variations in the timing of antibody onset, persistence, and severity. A review of the phenomenon and its implications are discussed.

Acute hemolysis after intravenous immunoglobulin amid host factors of ABO‐mismatched bone marrow transplantation, inflammation, and activated mononuclear phagocytes

Hemolysis may follow intravenous immunoglobulin (IVIG), with product, dosing, and host factors contributing. The importance of recipient features remains unclear.

The role of inflammation in intravenous immune globulin-mediated hemolysis.

Intravenous immune globulin (IVIG) therapy has shown great success in a number of autoimmune and inflammatory conditions and its use continues to increase worldwide. There is growing awareness of significant side effects of high‐dose IVIG: however, particularly severe hemolysis in patients that are non–group O. It has been proposed that IVIG‐associated hemolysis may be heralded by an existing inflammatory condition. In the work presented herein, we have provided a review of the pathophysiology of inflammation, particularly as it applies in immune‐mediated red blood cell hemolysis, and a summary of previous publications that suggest an association between IVIG‐mediated hemolysis and a state of existing inflammation. In addition, preliminary results from a prospective study to address the mechanism of IVIG‐associated hemolysis are provided. These preliminary data support the idea of an existing inflammatory condition preceding overt hemolysis after high‐dose IVIG therapy that: 1) is restricted to non–group O patients, 2) is seen when using IVIG doses of more than 2 g/kg, 3) involves an activated mononuclear phagocyte system, 4) may be presaged by a significant increase in the anti‐inflammatory cytokine interleukin‐1 receptor agonist, and 5) is independent of secretor status.

Seek and you shall find--but then what do you do? Cold agglutinins in cardiopulmonary bypass and a single-center experience with cold agglutinin screening before cardiac surgery.

Cardiopulmonary bypass (CPB) during cardiac surgery can involve deliberate hypothermia of the systemic (22-36 °C) and coronary circulations (as low as 8-12 °C). Adverse sequelae of cold-active antibodies have been feared and reported under such conditions, and some centers thus elect to screen for cold agglutinins before CPB. We reviewed the literature on cold agglutinins in cardiac surgery and described the yields and effects of cold agglutinin screening (CAS) in 14,900 cardiac surgery patients undergoing CPB over 8 years at a single institution. Cold agglutinin screening was positive in 47 cases (0.3%), at an annual testing cost of

Case report: transfusion-related acute lung injury (TRALI) - a clear and present danger.

17,000 CAD. The response of the surgical team to the preoperative discovery of a cold agglutinin was variable, with CPB modified to avoid hypothermia in approximately one-third of cases. In patients discovered to have a positive CAS, postoperative intensive care unit and hospital length of stay were marginally increased (54.6 vs. 42.8 hours, P = .02; 7 [6-14] vs. 7 [5-9] days, P = .04). However, the composite of mortality or severe morbidity (stroke, myocardial infarction, dialysis, low output syndrome, sepsis, and deep vein thrombosis) was not significantly different (14.9% vs. 9.2%, P = .2). Antibody verification found that only 43% of positive CAS patients had true cold agglutinins (20 patients). Furthermore, the rate of adverse events was low in both CAS-positive and true-positive cold agglutinin patients undergoing CPB and cardiac surgery. Finally, modification of CPB to attenuate hypothermia did not decrease adverse events. Based upon historical and local data, preclinical CAS is cost-substantial and nonspecific. Cold agglutinin screening does not promote an algorithm of care that meaningfully improves patient CPB outcomes.