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Hypotensive Transfusion Reaction Treated With Vasopressin in a Patient Taking an Angiotensin-Converting Enzyme Inhibitor: A Case Report

Pollard, Richard MD*; Boraski, Meryn CRNA; Block, Jared G. MD

doi: 10.1213/XAA.0000000000000507
Case Reports: Case Report

Hypotensive transfusion reactions, which account for almost 3% of all transfusion reactions, are associated with patients treated with angiotensin-converting enzyme inhibitors. The current hypothesis suggests that they are caused by bradykinin-induced vasodilation in the absence of allergic, hemolytic, or septic mechanisms. The hypotension observed frequently is unresponsive to conventional therapy with catecholamines. The suggested intraoperative management includes cessation of transfusion and washing red blood cells before blood replacement. We present a patient experiencing a severe intraoperative hypotensive transfusion reaction, unresponsive to epinephrine and norepinephrine, in whom we were able to restore blood pressure and continue the transfusion of blood and plasma by infusing vasopressin.

From the *MEDNAX National Medical Group, Charlotte, North Carolina; and Carolinas Healthcare System, Charlotte, North Carolina.

Accepted for publication December 22, 2016.

Funding: None.

The authors declare no conflicts of interest.

Address correspondence to Richard Pollard, MD, MEDNAX National Medical Group, 927 East Blvd, Charlotte, NC 28203. Address e-mail to

Acute hypotensive events during surgical procedures must be managed carefully. When associated with the infusion of a blood product, acute hypotension can be caused by multiple factors. The U.S. Centers for Disease Control and Prevention developed a Hemovigilance Module that provides criteria to classify the different transfusion reactions.1 A hypotensive transfusion reaction (HyTR) is a diagnosis of exclusion defined in adults as hypotension not caused by transfusion-related lung injury, acute hemolytic transfusion reactions, sepsis, or anaphylaxis and associated with a decrease in systolic blood pressure ≥30 mm Hg with the systolic blood pressure ≤80 mm Hg occurring <15 minutes after the start of transfusion. The mechanism for this acute reaction is not clearly understood, but it is thought to be related to increased bradykinin (BK) levels, as seen with the use of negatively charged leukoreduction filters and the use of angiotensin-converting enzyme (ACE) inhibitors.2 The incidence is 2.6% of all transfusion reactions voluntarily reported to the U.S. Centers for Disease Control and Prevention.

Intraoperative management strategies that have been suggested for this condition include the cessation of blood product transfusion,3,4 the delay of surgery until ACE inhibitor washout,5 and the use of washed red blood cells if transfusion is still needed.6 The authors present a unique case in which blood transfusion was necessitated by the surgical procedure, discontinuation of ACE inhibitor was not feasible, and the use of washed packed red blood cells (PRBCs) also resulted in acute hypotensive reaction unresponsive to epinephrine and norepinephrine.

With the patient’s written consent, we discuss the intraoperative management of her HyTR that included treatment with a vasopressin infusion that restored her blood pressure and enabled continuation of transfusion of PRBCs and fresh-frozen plasma (FFP).

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A 78-year-old white female presented for a posterior thoracolumbar (T11–S1) laminectomy and fusion for severe spondylosis and stenosis of L1–S1. The patient was classified as American Society of Anesthesiologists physical status III based on her medical history that was significant for stable coronary artery disease with an earlier myocardial infarction, for which the patient had received a stent placement to the right coronary artery. The patient also had a history of hypertension, hypothyroidism, and osteoarthritis. Home medications included lisinopril, aspirin, and levothyroxine. The patient had no known drug allergies. The starting hemoglobin was 12.9 mg/dL, and cell salvage was made available for the case. Perioperative beta blockade was not used due to concerns about intraoperative hypotension.

An arterial line and 2 large-bore intravenous catheters were placed for fluid management. Induction and maintenance of general anesthesia (propofol and isoflurane) proceeded uneventfully. After 90 minutes of surgery, an infusion of prestorage leukoreduced cross-matched PRBC in citrate-phosphate-dextrose-adenine was initiated via a Hospira (Charlotte, NC) 170-micron filter, blood administration set. After approximately 20 mL of PRBC transfusion, the mean arterial pressure (MAP) fell from 70 to 36 mm Hg. This decrease was not associated with changes in heart rate or peak inspiratory pressures. The transfusion was halted. The blood pressure did not respond to phenylephrine, but it did improve with calcium chloride. Patient exhibited no signs of urticaria, respiratory compromise, or obvious signs of hemolysis.

When transfusion recommenced, an almost immediate drop in MAP from 103 to 39 mm Hg occurred. Once again transfusion was halted and the patient resuscitated (Figure 1). At this point, a presumptive diagnosis of allergic transfusion reaction was made, and the patient was treated with diphenhydramine, ranitidine, metoclopramide, and hydrocortisone intravenously. The partially used PRBC unit was removed and sent to pathology for analysis. After reassurance that the clerical checks and pretransfusion antibody screen were correct, the infusion of 1 unit of FFP through a new blood transfusion set was initiated. Again, there was a drop in MAP from 100 to 42 mm Hg, and the infusion was terminated (Figure 2). Laboratory analysis revealed that the posttransfusion antibody screen and direct antiglobulin test were negative.

Figure 1

Figure 1

Figure 2

Figure 2

At this point in the surgery, the patient’s need for a blood transfusion was becoming marked. Consultation with the transfusion medicine service resulted in the decision to use washed PRBCs to replace the blood loss from surgery. Our procedure for washing PRBCs involves the use of a COBE 2991 cell processor (Rontis AG, Zug, Switzerland). The PRBCs are washed 6 times with a total of 2 L of normal saline to remove additives and impurities. Before the attempted infusion of washed PRBCs, an epinephrine infusion was started. Soon after initiating the transfusion, the MAP fell from 100 to 38 mm Hg and was unresponsive to increases in the epinephrine infusion rates. The transfusion was stopped and a norepinephrine infusion replaced the epinephrine one. Reinitiation of the blood product infusion once again resulted in a decline of the MAP from 85 to 45 mm Hg before the cessation of transfusion. None of these hypotensive episodes were accompanied by changes in hearts rate or peak inspiratory pressures.

The working hypothesis now became BK-mediated acute HyTR, exacerbated by the patient’s concomitant use of an ACE inhibitor. A vasopressin infusion was started, and on the subsequent initiation of transfusion, the blood pressure decreased slightly but was corrected easily by an increase in the vasopressin infusion rate (Figure 3).

Figure 3

Figure 3

The rest of the surgery proceeded uneventfully with the transfusion of 750 mL of PRBC, 325 mL of FFP, 350 mL of cell salvage, and 3500 mL colloid by the completion of the procedure. Estimated blood loss was 1000 mL with a final hemoglobin of 10.1 mg/dL. The patient was extubated and transferred to the intensive care unit (ICU) without further complications.

In the ICU, the patient continued to have significant output from the Hemovac drains. After 800 mL of output, the hemoglobin had dropped to 7.5 mg/dL and a decision to transfuse was made by the critical care team. Despite a careful hand off to the unit staff, the first attempt at transfusion resulted in another hypotensive reaction. This reaction was corrected with the use of a vasopressin infusion during subsequent therapies.

It is interesting to note that 1 month after her initial procedure, the patient underwent another lumbar spine surgery requiring the use of blood products. The patient remained on her ACE inhibitor and was managed by the same anesthesiologist. The case was unremarkable with the use of a vasopressin infusion to correct any blood pressure swings encountered with blood transfusion.

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The medical management of hypertension with ACE inhibitors is accomplished by blocking the renin–angiotensin system at the level of conversion of angiotensin I to angiotensin II. The resultant decrease in production of angiotensin II, as well as the direct inhibition of the breakdown of BK, produces relatively unopposed vasodilation and a decrease in blood pressure (Figure 4). The hypotensive effects of chronic ACE inhibitor therapy during the induction of general anesthesia have been well documented in the past and have led some to suggest withholding ACE inhibitors on the day of surgery.7 Management of this anesthetic-induced hypotension has centered on fluid boluses and the use of vasopressors. The depressant effects of ACE inhibitors on the production of endogenous vasopressin has led some authors to recommended the use of vasopressin to manage refractory hypotension.8,9

Figure 4

Figure 4

Transfusion-related HyTRs also are thought to be caused by the vasodilatory effects of BK. This effect is probably multifactorial, involving the preparation of the plasma before transfusion, the degree of activation of factor XII within the blood product, the type of delivery system used,10 and inherited or acquired defects in the enzymes used for the metabolism of BK. The mechanism of this response has been well described in a recent journal article by Metcalf et al.2 All 10 cases they described occurred in the postoperative period and involved relatively small amounts of transfused product in patients being treated with ACE inhibitors. All cases were treated with the immediate removal of the blood product, with vasopressor administration, and other indicated supportive measures until blood pressure normalized.

Transfusion reactions related to FFP are usually categorized as allergic/anaphylactic reactions. This is thought to involve reactions to residual white cells or immunoglobulin A in the transfusion product. Metcalf et al2 reported hypotensive reactions mediated by BK and leukoreduction filters, whereas Van Rosevelt et al11 linked the use of plasma protein fraction and BK generation to the development of HyTRs. Although the authors did not send titers for tyrptase, immunoglobulin A, or haptoglobins, the clinical presentation of the patient combined with the evanescent nature of the hypotension strongly suggests that BK was implicated in the hypotension caused by the FFP.

There is scant literature regarding intraoperative HyTRs. Arnold et al12 reported 2 cases of HyTR in patients receiving autologous units donated either before the operation, or as part of an acute normovolemic hemodilution technique. In both cases, the patients were on an ACE inhibitor, and they experienced significant hypotension with blood transfusion. Cessation of transfusion resulted in blood pressure normalization. Doria et al5 reported a case of a liver transplant patient, and Dalia et al13 reported experience with a lumbar laminectomy patient. In both these cases, the patient was being treated with an ACE inhibitor, and in both cases, the surgery was not completed. The recommendation was made to postpone surgery until the ACE inhibitor’s effect was eliminated. This limited literature suggests the only treatment options are cessation of the ACE inhibitor therapy before surgery, transfusion cessation, and/or the use of washed red blood cells. In our case, these options were not possible because of the advanced stage of the operation, or were ineffective. Treatment with vasopressin or its prodrug terlipressin bypasses the blockade of the renin–angiotensin system, the anesthetic-induced depression of the sympathetic nervous system, and the relative overabundance of BK to achieve vasoconstriction and hence maintain blood pressure. We feel that the subsequent management of our patient in the ICU, and during the second operation, validates our management strategy.

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The authors present a case of intraoperative HyTR that was treated successfully with vasopressin. The use of vasopressin to ameliorate the BK-induced hypotension provides a preferred mechanism for intraoperative management of HyTRs in the face of ACE inhibitors.

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Name: Richard Pollard, MD.

Contribution: This author helped collect the data, research the paper, and prepare, write, and revise the manuscript.

Name: Meryn Boraski, CRNA.

Contribution: This author helped collect the data, research the paper, and prepare, write, and revise the manuscript.

Name: Jared G. Block, MD.

Contribution: This author helped research the paper, and prepare, write, and revise the manuscript.

This manuscript was handled by: Raymond C. Roy, MD.

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