Acute life-threatening cardiovascular toxicity with umbilical cord blood infusion: The role of dextran^†

Umbilical cord blood (UCB) is being increasingly used for hematopoietic stem cell transplantation due to its immediate availability. Dimethylsulfoxide (DMSO) and dextran-40 are commonly used for processing and cryopreservation of UCB [1]. Adverse UCB infusion-related events are usually mild. However, reports of severe life-threatening events are now emerging [2, 3]. DMSO has been proposed as a possible cause of infusion-related reactions [3-7]. In this report, we draw attention to an acute near-fatal reaction with UCB infusions resulting in myocardial ischemia and acute renal failure. We propose that dextran-40 in UCB infusion products be considered as a potential causative agent contributing to this infusion-related reaction, based on reports of known adverse reactions to dextran-40 in nontransplant settings [8-12].

Case Report

A 55-year-old man with transformed mycosis fungoides underwent myeloablative conditioning with fludarabine, cyclophosphamide, and total body irradiation. Pretransplant renal and cardiac functions were normal. Keratinocyte growth factor, cyclosporin, ganciclovir, and heparin were given peritransplant. Two 5/6 Human Leucocyte Antigen matched, ABO blood group compatible UCB units (one male, one female, 78 and 131 mL, respectively), were sourced from Stemcyte, CA, and were cryopreserved with DMSO and dextran-40. They were sequentially thawed and administered unmanipulated as per protocol [13]. The first bag was infused over 20 min, the second over 35 min. Total nucleated cell dose was 3.9 × 10⁷ per kg of recipient weight with a CD34+ cell dose of 0.19 × 10⁶ per kg (total volume 209 mL).

Within 10 min of the first UCB infusion, the patient developed central chest pain, associated left arm dysesthesia, and nausea. Blood pressure was 170/100 mmHg with pulse 80/min. Symptoms resolved spontaneously after 5 min with normalization of blood pressure. The second UCB unit was commenced 10 min later with the same symptoms complex and subsequent resolution. Baseline troponin I was <0.01 μg/L with normal electrolytes and creatinine of 68 μmol/L. Thirty minutes following completion of the second unit, the patient developed acute pulmonary edema with hypoxemia (paO₂ 74.3 mmHg). Blood pressure remained elevated. Oxygen, topical nitrates, and diuretics were administered with clinical improvement. Eight hours later, troponin I was 0.75 μg/L and creatinine rose to 204 μmol/L. Urinalysis showed hematuria with no casts or crystals seen. Renal ultrasound revealed diffuse bilateral renal enlargement and loss of corticomedullary differentiation with no obstruction. A transthoracic echocardiogram was normal.

Over the following week, the patient became oliguric with marked weight gain (>10 kg). Creatinine rapidly peaked at 871 μmol/L by day +4 with troponin I at 2.17 μg/L. Hemodialysis was commenced and continued for 7 days. Renal function returned to normal by day +22. Microbiological cultures were negative throughout. Acute cutaneous graft versus host disease (GVHD) developed day +7 and resolved after corticosteroids. Neutrophil engraftment occurred at day +37. The patient deteriorated after day +45 with sepsis, gut GVHD, and hepatic failure and died at day +57. An autopsy was refused.

Discussion

Adverse reactions to UCB infusion are usually mild and reversible. These commonly include hypertension and bradycardia affecting 20–60% of patients [4, 5]. Severe reactions are considered rare. We have identified five almost identical cases with acute cardiac +/− renal complications to UCB infusion [2, 3] (see Table I). DMSO, cell lysis products, and conditioning regimens have been implicated as causative agents [3, 5]. We feel that dextran-40 has been underappreciated as a possible suspect of this type of adverse reaction.

DMSO has been used alone as a cryoprotectant in autologous hematopoietic stem cell transplants for several decades, and “DMSO-related cardiac death has rarely been reported” [14]. The addition of dextran in cryopreservation solution for UCB transplantation has only been in widespread use since the late 1990s. A number of reports of severe adverse reactions following UCB infusion are now emerging and coincide with the introduction of dextran in cryopreservation solution for UCB transplantation in the 1990s [2, 3, 5, 7].

Acute volume expansion appears unlikely to be a causative factor, given total infused volumes are relatively low. Conditioning regime is an unlikely cause as the reaction occurred during infusion and a similar reaction has not been reported in patients receiving allogeneic uncryopreserved adult stem cells. Transfusion-related acute lung injury (TRALI), due to a reaction to leukocyte antigens, is a known cause of noncardiogenic pulmonary edema. TRALI is unlikely to be the cause in this patient as it does not normally cause direct renal and cardiac toxicity. With sepsis excluded as a possible cause and as reactions occurred to both infused units, a donor-related factor is also unlikely and suggests a common factor. Both DMSO and dextran-40 can cause idiosyncratic reactions at low concentrations. In all these cases, DMSO was only present in cryopreservation solution. However, Dextran-40 was present in cryopreservation, washing and final resuspension solutions providing a plausible explanation for this reaction occurring in unmanipulated or manipulated UCB [1].

Dextran-40 is well recognized to cause acute, potentially fatal anaphylactoid reactions that can be triggered by as little as 0.5 mg with an estimated incidence of 1 in 2000 [11, 12]. Acute cardiac, pulmonary, and renal injuries have also been reported [9, 12, 15, 16]. In our case and the other five cases reported [2, 3], all experienced similar symptoms with evidence of cardiac +/− renal damages developed within 24 hr of UCB infusion. Accumulated circumstantial evidence thus points to dextran-40 as the likely contributing cause of this reaction. Importantly, acute vascular ischemia due to dextran-40 is supported by visual observation of acute coronary artery spasm during dextran-40 infusion at coronary angioplasty [9, 10].

This report highlights a distinct severe adverse reaction with UCB infusion. In addition to currently recognized factors, we propose that it is important to consider dextran-40 as a possible contributing factor of severe infusion reactions because of the potential to reduce anaphylactoid reactions from dextran-40 by pretreatment with dextran-1 [12]. Alternative cryopreservation or post-thaw solutions to dextran-containing solution should be considered for processing UCB given its increasing usage worldwide.