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Clinical Pattern in Hypotensive Transfusion Reactions

Metcalf, Ryan A. MD*; Bakhtary, Sara MD; Goodnough, Lawrence Tim MD; Andrews, Jennifer MD, MSc§

doi: 10.1213/ANE.0000000000001387
Cardiovascular Anesthesiology: Original Clinical Research Report

BACKGROUND: Hypotensive transfusion reactions (HyTRs) may be underreported and have been associated with patients taking angiotensin-converting enzyme inhibitors (ACEIs) receiving poststorage leukoreduced blood products through negatively charged filters. Although bedside leukoreduction is no longer commonplace, HyTRs still occur and are insufficiently characterized in the prestorage leukoreduction era. We describe recently reported cases at our institution.

METHODS: We reviewed transfusion reaction records at Stanford Healthcare from January 2014 to April 2015. HyTRs were defined by National Health Safety Network Hemovigilance Module classification.

RESULTS: Eleven HyTRs occurred in 10 patients. All were adults (mean age 71.7 years; range 45–92 years), 7 were male, and all underwent major surgery 0 to 2 days before the reaction. Nine patients underwent cardiac or vascular surgery, and all 10 were taking ACEIs with the last dose taken within 48 hours of the transfusion reaction in 9 patients. Nine patients were on extracorporeal circuits within 24 hours before the reaction (median duration 180 minutes; range 87–474 minutes). In 5 reactions, the implicated unit was restarted with resultant recurrent hypotension. Implicated units included 9 packed red blood cells, 1 apheresis platelet, and 1 plasma frozen within 24 hours.

CONCLUSIONS: Contrary to what has been previously reported in the era of prestorage leukoreduction, HyTRs at our institution showed consistent patterns in patients at risk. Patients scheduled to undergo major surgery with cardiopulmonary bypass may benefit from earlier preoperative cessation of ACEIs or temporarily switching to an alternative drug class.

Published ahead of print June 9, 2016

From the *Department of Laboratory Medicine, University of Washington, Seattle, Washington; Department of Laboratory Medicine, University of California–San Francisco, San Francisco, California; and Transfusion Medicine Program and §Department of Pathology and Pediatrics, Stanford University Medical Center, Stanford, California.

Accepted for publication March 29, 2016.

Published ahead of print June 9, 2016

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Ryan A. Metcalf, MD, Laboratory Medicine, University of Washington, 1959 NE Pacific St, Seattle, WA 98195. Address e-mail to

Hypotension can occur in both infectious (eg, septic transfusion reaction) and noninfectious (acute hemolytic transfusion reactions, transfusion-related acute lung injury, anaphylaxis/anaphylactoid reactions, and hypotensive transfusion reactions [HyTRs]) transfusion reactions. HyTRs are characterized by the rapid onset of often significant hypotension early in the transfusion, often in the absence of other signs or symptoms, which improve with cessation of the infusion. To diagnose a HyTR, the other adverse reactions associated with a decrease in arterial blood pressure (BP) must be excluded. Septic transfusion reactions are typically also accompanied by fever. Rigors, tachycardia, and dyspnea may also be present and an organism may be detected. Acute hemolytic transfusion reactions can include many additional signs/symptoms such as chills/rigors, fever, and renal failure, and there may be laboratory evidence of hemolysis with a positive direct antiglobulin test. Transfusion-related acute lung injury includes acute lung injury, hypoxemia, and radiographic evidence of pulmonary edema. Anaphylaxis includes airway symptoms and mucocutaneous symptoms. The National Healthcare Safety Network (NHSN) Hemovigilance Module further defines criteria for decrease in BP, reaction severity, and imputability, which are also described in Table 1.1

Table 1.

Table 1.

Early reports of HyTRs described their association with certain factors: patients taking angiotensin-converting enzyme (ACE) inhibitors and the use of negatively charged poststorage bedside leukoreduction filters.2–6 Negatively charged surfaces can lead to activation of kinin-mediated pathways and downstream increases in the 9-amino acid peptide bradykinin and metabolites, resulting in vasodilatation and increased vascular permeability. ACE inhibitors prevent breakdown of bradykinin because ACE is the primary means of bradykinin catabolism.7 HyTRs have also been reported in patients not taking ACE inhibitors and, in lieu of bedside filtration, prestorage leukoreduction is now commonplace.8

Nevertheless, HyTRs continue to occur, accounting for 2.6% of transfusion reactions voluntarily reported to the NHSN Hemovigilance Module in the United States from 2010 to 2012.9 Serious Hazards of Transfusion (SHOT) summary data from the United Kingdom reported 13 HyTRs in 2013, corresponding to an incidence of 0.046 per 10,000 units issued (0.046%). A recent retrospective study from 2 institutions in the current era of prestorage leukoreduction characterized their experience with HyTRs. In contrast to this current report, they reported HyTRs occurring in a wide variety of patients and clinical settings in the current era of prestorage leukoreduction.10 The purpose of this study was to report the clinical characteristics of HyTRs at our institution in the era of prestorage leukoreduction.

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The study was approved by the appropriate institutional review board, and the requirement for written informed consent was waived by the institutional review board. Patients were not assigned to treatment groups.

Transfusion reaction records from January 2014 through April 2015 at Stanford Healthcare were examined retrospectively, and reports with hypotension not attributable to an alternative transfusion reaction type were identified. These transfusion reaction reports included interpretation of clinical patient data (history, vital sign changes, symptoms, etc) and transfusion laboratory testing (ABO compatibility, antibody screen, direct antiglobulin test, signs of visible hemolysis, etc, if performed).

HyTRs were classified according to the NHSN Hemovigilance Module criteria. Definitive cases required all other adverse transfusion reactions presenting with hypotension to be excluded as well as one of the following: decrease in systolic BP of ≥30 mm Hg and systolic BP ≤80 mm Hg (in adults), >25% decrease in systolic BP from baseline (in patients aged 1 year to 18 years of age), or >25% decrease in baseline value using whichever measurement is being recorded (in patients younger than 1 year or <12 kg). Transfusion reactions were classified as “possible” HyTRs if hypotension did not meet these criteria. Reaction severity was defined as (1) nonsevere: no more than stopping transfusion and symptom management without long-term morbidity from the reaction; (2) severe: hospitalization or prolongation of hospitalization directly attributable or hypotension led directly to long-term morbidity, and vasopressors were not required; or (3) life-threatening: vasopressors required. Imputability was defined as (1) definite: occurs <15 minutes after the start of transfusion and responds rapidly to cessation of transfusion and supportive measures, and patient has no other conditions that could explain hypotension; (2) probable: onset is between 15 minutes after the start and 1 hour after cessation of transfusion or patient does not rapidly respond to cessation of transfusion and supportive therapy, or there are other potential causes present that could explain hypotension, but transfusion is the most likely cause; or (3) possible: other conditions could readily explain hypotension.

We retrospectively reviewed patient electronic health records to obtain pertinent clinical data. These data included patient demographic information (age and gender), primary diagnosis, surgery type and timing related to transfusion reaction, changes in vital signs pretransfusion and postreaction, comorbidities/medical history, patient location, transfusions received during current admission, volume of implicated product infused, medications including timing of last ACE inhibitor dose, extracorporeal circuit use, duration of cardiopulmonary bypass, need for (or increase in) vasopressors, other associated signs/symptoms, and transfusion laboratory workup information.

All units were leukoreduced before storage. Red blood cells (RBCs) were stored in either additive solution or citrate-phosphate-dextrose-adenine anticoagulant preservative solutions. The platelets were collected by apheresis, and the plasma unit was frozen within 24 hours. All units were stored and transported in accordance with American Association of Blood Banks Standards.11

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Eleven reported reactions (in 10 patients) meeting criteria for definitive or possible HyTRs were identified from January 2014 to April 2015. Seven of 10 patients were male, and all patients were adults with a mean age of 71.7 years (range, 45–92 years; Table 2). All 10 patients were in the postoperative state from postoperative day 0 to 2 and 8 of 10 patients underwent major cardiac surgery with significant time on cardiopulmonary bypass (median, 180 minutes; range, 87–474 minutes). The remaining 2 patients underwent an abdominal aortic aneurysm repair and resection of rhabdomyosarcoma of the arm, respectively. This latter patient was on hemodialysis. All patients had multiple comorbidities affecting the cardiovascular system such as hypertension, diabetes, and hyperlipidemia. During the hospital admission for surgery, all patients received multiple units of blood products before the implicated transfusion (median = 5 products; range = 2–33 products).

Table 2.

Table 2.

All patients were taking ACE inhibitor drugs leading up to surgery with the last dose taken between 23 and 60 hours before the HyTR. In all cases but one, the last ACE inhibitor dose was <48 hours before the transfusion reaction. All transfused blood products were leukoreduced before storage.

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HyTR Characteristics

Beside 2 patients, systolic BP decreased by >30 mm Hg and below 80 mm Hg overall from the pretransfusion BP recording. These cases therefore met criteria for definitive HyTR by NHSN classification (Table 3). Only 3 HyTRs occurred >12 hours after surgery. All 5 cases with data available had onset of hypotension within 10 minutes of starting the transfusion, and transfusion was the most likely cause of the hypotensive episode (Table 3). Reported infusion volumes ranged from 30 to 100 mL (median = 50 mL). In 5 instances, the implicated unit was restarted and a subsequent episode of hypotension occurred. Nearly all cases showed minimal changes in other vital signs. All transfusion reactions occurred in the same intensive care unit, and no patients were on extracorporeal circuits at the time of the implicated transfusion.

Table 3.

Table 3.

No patients had a history of transfusion reactions, and 1 patient was premedicated with acetaminophen. Pressors were used to treat the hypotensive episodes in 6 of 9 patients where data were available, and reaction severity was classified as life-threatening according to NHSN criteria. With respect to additional signs beyond hypotension or symptoms, 1 patient reported experiencing dizziness. Another patient, who was 6 hours postcardiopulmonary bypass surgery, experienced a HyTR and subsequently developed pulseless electrical activity requiring a brief stint of cardiopulmonary resuscitation (approximately15 seconds) along with epinephrine and dopamine. The intervention led to recovery of the patient’s pulse and hemodynamics.

One patient died 10 days after the HyTR from multiple system organ failure because of a ruptured abdominal aortic aneurysm; the cause of death was unrelated to transfusion.

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All Transfusion Reactions

During the 16-month review period, 298 transfusion reactions were reported to the transfusion service. The vast majority of transfusion reactions were allergic or attributable to the patient’s underlying conditions. Mild allergic transfusion reactions do not require reporting to the transfusion service for workup at our institution. Of the transfusion reactions reported to the transfusion service, 11 of 298 were HyTRs (3.6%). The overall incidence would correspond to 11 cases of 69,883 units transfused during the review period or 1.57 per 10,000 units transfused.

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Reports of the clinical characteristics of HyTRs in the current time of prestorage leukoreduction are few. This study describes HyTRs at our institution in this present era. Ten patients were identified as having HyTRs during a recent 16-month period. Patients received prestorage leukoreduced blood products and shared pertinent clinical characteristics including recent ACE inhibitor therapy.

Some retrospective studies have reported the rates of HyTRs to be quite variable, ranging from 0.078 up to approximately 10 per 1000 transfusions.12,13 Recently published NHSN Hemovigilance Module data from 2010 to 2012 showed that HyTRs accounted for 2.8% of reported transfusion reactions with a prevalence of 6.3 per 100,000 units transfused. The Serious Hazards of Transfusion summary data from 2013 indicated an incidence of 0.046 per 10,000 units issued (0.046%).14 To determine the true incidence, increased awareness by clinical teams, prompt reporting to the transfusion service, and accurate application of diagnostic criteria by a transfusion specialist would be needed.

HyTRs were classified according to NHSN Hemovigilance Module criteria. All cases described here but 1 met criteria for definitive HyTR and, where sufficient clinical data regarding reaction onset were available, were imputed at least as “probable” HyTR. Other causes of hypotension after major cardiac surgery cannot be entirely excluded, although all cases demonstrated a strong temporal relationship between the hypotension and the transfusion.

Hypotension was primarily an isolated finding in our cohort and occurred early in the transfusion. Data were available for 5 cases, and the time to reaction onset range was 5 to 10 minutes (median = 5 minutes). BP improved on cessation of each implicated transfusion, but recurrent hypotension was observed in 5 patients where infusion of the same unit was restarted (these were before reporting to the transfusion service). We recommend never restarting infusion of the implicated blood component if a HyTR is suspected.

In prior reports of HyTRs, hypotension was often an isolated finding but could be associated with nonspecific symptoms.3,4,10,15–18 Hypotensive episodes, although often dramatic, were usually transient if the transfusion was appropriately stopped and the BP improved to near baseline; long-lasting hypotension appears to be rare.16 If transfusion was restarted or if additional units were transfused, symptoms could recur and only very rarely has death been reported.19 The findings in this current study in the era of prestorage leukoreduction are consistent with many of the earlier studies. The majority of patients in this study were treated with pressors and all recovered rapidly from the HyTR with supportive measures.

In this study, RBCs were implicated much more commonly, whereas HyTRs resulting from plasma or platelets occurred rarely. The rarity of HyTR resulting from plasma is consistent with previous studies both before and in the current era of prestorage leukoreduction. HyTR in the current study resulting from platelet transfusion was rare (1 event), but this may reflect apheresis platelet components being transfused less frequently than RBCs and plasma.

HyTRs were initially found to be associated with the use of bedside leukoreduction filters and ACE inhibitors. Most of our patients were taking lisinopril for the diagnosis of hypertension, which has a half-life of approximately 12 hours, and all but 1 received their last dose of ACE inhibitor within 48 hours of the implicated transfusion.

Surface activation of factor XII to XIIa leads to the eventual conversion of high-molecular-weight kininogen to bradykinin via kallikrein. An in vitro study examining whole blood-derived platelet concentrates and platelet-poor plasma with and without leukoreduction filtration showed widely variable bradykinin levels with peak levels at 5 days and higher levels in filtered products.20 Bradykinin action leads to vasodilation and increased vascular permeability. The primary mechanism for bradykinin metabolism (approximately 75%) is via ACE, whereas aminopeptidase P is also involved in bradykinin catabolism to a lesser degree, and polymorphisms in this latter enzyme have been associated with HyTRs.21,22 The active metabolite Des-Arg9-bradykinin also has vasoactive properties.18 Given the association with ACE inhibitors, if felt to be safe by the treating team, temporarily switching to an alternative drug class in the perioperative period may be preferred if there is a possibility of transfusion. Further study is required to determine the efficacy of this strategy. To our knowledge, there are no guidelines to date addressing this matter.

Leukoreduction is now widely performed shortly after collection during processing at the collection facility (prestorage), and bedside leukoreduction is no longer commonplace. HyTRs can occur with infusion of prestorage leukoreduced products and are not limited to bedside leukoreduction. However, reports of clinical characteristics of HyTRs in this present era of prestorage leukoreduction are few. Pagano et al10 reported the experience of 2 institutions and detailed the characteristics of 35 HyTR cases in the current era of prestorage leukoreduction. Unlike the current study, these reactions occurred in a variety of settings: cardiac surgery, hematology-oncology disease, and general surgery. Nearly half of the patients were put on extracorporeal circuits within the preceding 24 hours, whereas only a small minority (4 of 35) were taking ACE inhibitors 24 hours before the reaction. These findings are in contrast to the clinical characteristics of the current study.

Among the less recent reports, Belloni et al23 did report HyTRs in 5 patients not taking ACE inhibitors. Bradykinin levels increase during cardiopulmonary bypass, and this elevation may cause hypotension.24 The 11 cases in our study show homogeneous clinical features and are strongly associated with recent ACE inhibitor therapy, extracorporeal circuits (cardiopulmonary bypass in particular), and an early postoperative state after major cardiovascular surgery. In terms of prevention, washing RBC blood products to remove bradykinin has been used to prevent HyTR in a patient with a history of this reaction type.25 Further study is needed to determine the benefit of this strategy.

Stagnation of bradykinin catabolism from ACE inhibition, enzyme polymorphisms, or bypassing the ACE-enriched lungs may contribute to a HyTR patient’s inability to tolerate a transfusion. The role of activation of kinin-mediated pathways also deserves attention and requires further study. The issue of limited published reports and evidence was noted by Colman and Scott26 after early reports and remains problematic today.

Patients in a hemodynamically tenuous state after major cardiac surgery could be more prone to these reactions. Cardiac surgery with cardiopulmonary bypass commonly results in hemodynamic instability both intraoperatively and postsurgically. The postcardiac surgery patient, potentially with cardiac dysfunction to go along with bypass-induced vasoplegia and significant fluid shifts, may be primed for HyTRs.

This study is limited in that it was retrospective, lacked a control group for comparison, and there were a limited number of cases given the relative frequency of this reaction type (3.6% of our reported transfusion reactions) and length of the review period. Previously published studies on this transfusion reaction type have similar weaknesses. Future directions could include a prospective, multi-institutional study with larger numbers of HyTR cases to sort out the clinical characteristics and spectrum.

In conclusion, the clinical characteristics of HyTRs in this study showed a strong pattern associated with ACE inhibitors, extracorporeal circuits, and an early postoperative state in patients undergoing major cardiovascular surgery. This is in contrast to what has been reported in the current era of prestorage leukoreduction of blood components.

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Name: Ryan A. Metcalf, MD.

Contribution: This author helped design the study, collect the data, analyze the data, and prepare the manuscript.

Name: Sara Bakhtary, MD.

Contribution: This author helped design the study, collect the data, analyze the data, and prepare the manuscript.

Name: Lawrence Tim Goodnough, MD.

Contribution: This author helped design the study, collect the data, analyze the data, and prepare the manuscript.

Name: Jennifer Andrews, MD, MSc.

Contribution: This author helped design the study, collect the data, analyze the data, and prepare the manuscript.

This manuscript was handled by: Roman Sniecinski, MD.

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