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American Journal of Therapeutics 19, e90–e94 (2012) Acute Hypotensive Transfusion Reaction With Concomitant Use of Angiotensin-Converting Enzyme Inhibitors: A Case Report and Review of the Literature Ankur Kalra, MD,1 Chandrasekar Palaniswamy, MD,2* Ritesh Patel, MD,1 Ankit Kalra, MBBS,3 and Dhana R. Selvaraj, MD2 Hypotension can be a manifestation of transfusion reactions, including acute hemolysis, bacterial contamination, transfusion-related acute lung injury, and anaphylaxis. In addition to hypotension, these reactions usually present with other characteristic symptoms and signs. In rare cases, hypotension is the only manifestation of a transfusion reaction. This reaction, characterized by early and abrupt onset of hypotension that resolves quickly once the transfusion is stopped, is referred to as acute hypotensive transfusion reaction (AHTR). We report a case of AHTR observed in a patient on angiotensin-converting enzyme inhibitor therapy. The Naranjo adverse drug reaction probability scale score indicated that the association between angiotensin-converting enzyme inhibitor therapy and AHTR was probable. If a patient on angiotensin-converting enzyme inhibitor therapy develops AHTR, it is important to recognize the need to switch to another class of antihypertensive medication, at least while the patient continues to require transfusion. Keywords: hypotension, transfusion, angiotensin-converting enzyme inhibitors, bradykinin, acute hypotensive transfusion reaction INTRODUCTION CASE REPORT Acute hypotensive transfusion reaction is characterized by early and abrupt onset of hypotension, which is often severe, other than signs or symptoms that are attributed directly to the drop in systolic blood pressure. Once the transfusion is stopped, the hypotension rapidly resolves without specific therapy.1 An 81-year-old man presented to emergency department with lethargy of 3 days’ duration. This was insidious in onset and not associated with headache, fever, loss of consciousness, bladder or bowel dysfunction, seizures, or focal neurologic deficit. The patient’s medical history was significant for diabetes mellitus, chronic kidney disease, coronary artery disease, atrial fibrillation, gout, and recurrent staphylococcal spinal osteomyelitis. Medications included allopurinol, celecoxib, furosemide, spironolactone, insulin, and warfarin. Physical examination revealed an elderly man, lethargic and slow to respond but oriented to time, place, and person with no focal neurologic deficit. Pertinent laboratory data included hemoglobin of 14.6 g/dL, white blood cell count of 16,000/mm3, and serum creatinine of 2.6 mg/dL. Furosemide and spironolactone were held secondary to renal 1 Department of Medicine, Cooper University Hospital, UMDNJRobert Wood Johnson Medical School, Camden, NJ; 2Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY; and 3Department of Medicine, Kalra Hospital & SRCNC, New Delhi, India. The authors have no conflicts of interest to declare. *Address for correspondence: New York Medical College, Westchester Medical Center, 95 Grasslands Road PMB 503, Valhalla, NY 10595. E-mail: [email protected] 1075-2765 Ó 2012 Lippincott Williams & Wilkins www.americantherapeutics.com AHTR insufficiency. The patient was started on empiric antibiotics for sepsis. A nontender left clavicular mass, 3 3 4 cm, was also noted, the biopsy of which revealed osteomyelitis. The patient improved while being treated with empiric antibiotics, vancomycin and aztreonam. Blood cultures subsequently grew methicillin-resistant Staphylococcus aureus; a total of 6 weeks of therapy was planned. The hospital course was complicated by acute blood loss anemia, presumably secondary to a gastrointestinal bleed that required blood transfusion. Meanwhile, renal function had showed a steady improvement and lisinopril was added to the existing regimen. The patient continued to remain anemic and needed to be transfused further. Within 15 minutes of initiation of the second blood transfusion, the patient developed lightheadedness. The heart rate was 82 beats/minute, and the blood pressure had abruptly dropped from his baseline of 110/74 mmHg to 67/37 mmHg that was confirmed by repeat automatic and manual measurements. Oxygen saturation by pulse oximetry was 97%. The rest of the physical examination was unremarkable. Transfusion was immediately stopped, and intravenous fluid bolus was initiated. After this, blood pressure rapidly normalized to his baseline values. Analysis of the blood products revealed no crossreacting antibodies or bacterial contamination. Workup for hemolysis was negative. It is notable that the second set of blood transfusions was ordered after initiation of angiotensin-converting enzyme (ACE) inhibitor therapy. The onset of hypotension was abrupt with the start of blood transfusion with rapid resolution of hypotension once the transfusion was stopped. This phenomenon is referred to as acute hypotensive transfusion reaction (AHTR) and ACE inhibitors are known to play a key role in the pathogenesis of this phenomenon. The association of ACE inhibitor use with AHTR in our patient was not definitively proven, because there could have been other plausible explanations. To assess this probability, we used the Naranjo adverse drug reaction probability scale.2 This scale aids in systematically eliminating all other possible origins of a reaction as well as correlating the onset of symptoms with suspect drug administration. Using the Naranjo adverse drug reaction probability scale, the patient’s score indicated that the association of ACE inhibitor therapy to AHTR was probable. ETIOLOGY AND PATHOGENESIS Reports of hypotensive reactions from plasma derivates date back to the 1970s, when plasma protein fraction (PPF), a partially purified derivative of plasma www.americantherapeutics.com e91 fractionation, was used as colloid replacement. In 1978, Alving and colleagues published a report linking hypotensive reactions associated with the use of PPF to the presence of factor XII in those plasma derivates.3 Later in 1982, another report linked the use of PPF and bradykinin (BK) generation to the development of hypotensive transfusion reactions. In an open-label, nonrandomized study comparing PPF versus albumin as colloid replacement during open heart surgery, PPF was found to be associated with more episodes of rapid onset of hypotension.4 This correlated with levels of factor XII and BK in PPF; albumin lacked both factor XII and BK, and its use did not cause hypotensive reactions. Albumin became the colloid of preference and the use PPF was abandoned. The use of leukocyte reduction of cellular blood products by depth filtration became widespread in the 1990s with the objectives of decreasing the rates of febrile transfusion reactions, alloimmunization, and the transmission of leukocyteborne infectious diseases. In 1993, the American association of blood banks (AABB) reported 25 cases of acute hypotensive reactions with the infusion of platelet products.5 It was suggested that there might be interactions with the medications the patients were taking and the use of platelet product filters, but no clear explanation for that phenomenon was available at that time. To further characterize these reactions, the AABB transfusion practice committee sent questionnaires to the institutions reporting severe and/or unusual reactions to platelet transfusions and also to all AABB institutional members. From those questionnaires, they identified 17 reactions that were primarily characterized by hypotension.6 Of these hypotensive reactions, 88% occurred within 1 hour of the beginning of the transfusion and 82% resolved rapidly after the cessation of transfusion. Of note, 88% of the implicated products had been leukoreduced, mainly with bedside filters. A significantly increased levels of BK was observed when platelet concentrates were filtered through negatively charged depths filters but not positively charged filters.7 Elevated venous blood levels of BK were observed when platelet concentrates were filtered through negatively charged filters and transfused to patients with low ACE activity.8 The occurrence of hypotensive reactions related to the use of ACE inhibitors in patients undergoing apheresis procedures has been well documented, and the medication is recommended to be discontinued at least 24 hours before the patient undergoes apheresis. Of 301 patients undergoing plasma exchange, all 15 patients taking ACE inhibitors experienced hypotension or flushing during a procedure, whereas only a small fraction (11%) of the patients not taking the American Journal of Therapeutics (2012) 19(2) e92 medication had similar problems.9 Hypotensive reactions have also been reported with the use of dextran sulfate columns and staphylococcal protein A columns.10,11 The combination of ACE inhibitors and negatively charged dialysis membranes has been implicated in the development of hypotensive reactions, mainly through the mediation of des-Arg9-BK.12 An understanding of the pathophysiology of AHTR depends on knowing BK function and metabolism13,14 (Fig. 1). BK is a vasoactive peptide that is produced by the activation of the contact system. The starting point of the activation process requires the interaction of activated factor XII with negatively charged surfaces such as glass, dialysis membranes, and blood filters. Once activated, factor XIIa transforms prekallikrein, a plasma glycoprotein that freely circulates bound to high-molecular-weight kininogen into its active form kallikrein that is responsible for generating BK from high-molecular-weight kininogen. The carboxyterminal arginine residue of BK stimulates normally present B2 receptors on the endothelium and mediates the pharmacologic effects of BK, which include hemodynamic, analgesic, and proinflammatory actions. Although not widely expressed in normal tissues, B1 receptors can be upregulated by injury and inflammation. Once hydrolyzed by carboxypeptidases N and M, BK is transformed into des-Arg9-BK, a metabolite that can also have vasoactive activity, chiefly binding to B1 receptors. Bradykinins are hydrolyzed by several Kalra et al metallopeptidases, which include kininase I enzymes (carboxypeptidases N and M), kininase II enzymes (ACE and neutral endopeptidase), and aminopeptidase P. Under normal conditions, ACE is responsible for 75% of BK inactivation. Carboxypeptidases are responsible for the metabolization of the remainder of BK, removing the Arg9 from the carboxyterminal end and producing des-Arg9-BK. In the presence of ACE inhibition through antihypertensive medications, or in the face of abnormal polymorphisms or low levels of aminopeptidase P or ACE, larger amounts of desArg9-BK can form and a set up for the development of hypotension and associated effects resulting from the activation of B1 receptors.15–17 DIFFERENTIAL DIAGNOSIS Acute hypotension can be a manifestation of other transfusion reactions, including bacterial contamination of blood products, acute hemolysis, transfusionrelated acute lung injury, and anaphylaxis. Bacterial contamination of blood products Although hypotension can occur at the time of transfusion of contaminated blood products by bacteria, other symptoms such as chills and fever are usually present. FIGURE 1. Bradykinin metabolism. Factor XII is activated by contact with negatively charged surfaces. This leads to the activation of prekallikrein bound to high-molecular-weight kininogen (HMWK) into kallikrein (KK). Kallikrein cleaves the HMWK to liberate bradykinin (BK), which is metabolized mainly by the angiotensin-converting enzyme (ACE) and also by carboxypeptidases and aminopeptidase P (APP). Des-Arg9-BK is inactivated by ACE and APP. American Journal of Therapeutics (2012) 19(2) www.americantherapeutics.com AHTR Acute hemolytic transfusion reactions Hypotension is not the initial symptom and appears later in the course of the reaction. Before hypotension manifests, other symptoms such as nausea and vomiting, back pain, fever, chills, hematuria, and other signs of hemolysis are present. Transfusion-related acute lung injury This typically takes place within 1 to 6 hours after the beginning of the transfusion. It chiefly manifests as sudden onset of severe dyspnea, hypoxia, and the development of diffuse pulmonary infiltrates. Fever and hypotension, although they can be present, are minor components of the reaction. Anaphylactic transfusion reactions These are characterized by an acute onset of hypotension early in the transfusion. Other symptoms that are typical of an allergic reaction can also be present, including urticaria and pruritus, laryngeal edema, and respiratory tract obstruction leading to difficulty breathing. Stopping the transfusion is not enough to reverse the process and patients require antihistamines, steroids, and epinephrine as part of the treatment to prevent sometimes fatal progression. Understanding the manifestations of other transfusion reactions that can present with hypotension makes it easier to identify purely isolated AHTRs. These reactions are characterized by the early and abrupt onset of hypotension, which is often severe, with a drop of the systolic blood pressure below 70 or 60 mmHg without many other signs or symptoms aside from lightheadedness or anxiety attributed directly to hypotension. Other symptoms that have been occasionally reported include low-grade fever, flushing, urticaria, dyspnea, and gastrointestinal symptoms. However, hypotension is always the predominant symptom and clearly overshadows all others. Another typical characteristic of this type of reaction is that once the transfusion is stopped, the hypotension rapidly resolves without specific therapy. MANAGEMENT Once an episode of AHTR occurs, the most important measure is to stop the transfusion immediately. Symptoms usually subside quickly as the transfusion is discontinued. The patient should not be rechallenged with that same product, because symptoms are expected to recur as a result of activation substances presumed to be present in the product. In most instances, no other treatment is required, although in some cases when the hypotension does not www.americantherapeutics.com e93 immediately correct with the interruption of the transfusion, the use of a bolus of intravenous fluids may be helpful. Vasoactive drugs are rarely indicated. Our patient responded to prompt interruption of the transfusion alone, although a fluid bolus was also started immediately. Because ACE inhibitors play a major role in these reactions, once a patient who is taking this type of drug develops an AHTR, it is important to recognize the need to switch to another class of antihypertensive medication, at least while the patient continues to require transfusions or apheresis procedures. Some experimental methods have been suggested in the setting of repetitive AHTRs in patients who need dialysis or pheresis. They include washing of cellular blood products for removal of supernatant and the use of kallikrein blockade with nafamostat mesilate. In the absence of clinical validation, these methods cannot be endorsed. CONCLUSION With increasing use of ACE inhibitors in clinical practice, the incidence of AHTR is likely to increase further. Physicians should be aware of this potentially serious complication associated with the use of ACE inhibitors. Understanding the implicated factors in the etiology of AHTR and its clinical manifestations is the key to providing care to patients who develop this complication and for future prevention. REFERENCES 1. Popovsky MA. Transfusion Reactions. Bethesda, MD: AABB Press; 2001:222. 2. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;80:286–291. 3. 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Acute hypotensive transfusion reaction during liver transplantation in a patient on angiotensin converting enzyme inhibitors from low aminopeptidase P activity. Liver Transpl. 2008; 14:684–687. www.americantherapeutics.com