Which medication is most strongly associated with an acute primary hypotensive reaction following transfusion of blood products?

ACE Inhibitors (Perindopril) Are Most Strongly Associated with Acute Hypotensive Transfusion Reactions

Perindopril (option e), an ACE inhibitor, is the medication most strongly associated with acute primary hypotensive reactions following blood product transfusion.

Mechanism of ACE Inhibitor-Associated Hypotensive Transfusion Reactions

The pathophysiology centers on bradykinin metabolism dysregulation:

• ACE inhibitors block the primary degradation pathway for bradykinin, which is normally metabolized by angiotensin-converting enzyme 1, 2
• During transfusion, bradykinin accumulates in the circulation because the ACE-mediated breakdown is impaired 1
• A secondary enzyme, aminopeptidase P, becomes critical for bradykinin clearance, but patients on ACE inhibitors may have inherently low aminopeptidase P activity, creating a "double hit" that prevents bradykinin degradation 1, 3
• Elevated bradykinin levels cause profound vasodilation, leading to the characteristic abrupt hypotension seen in acute hypotensive transfusion reactions (AHTR) 2, 4

Clinical Presentation and Diagnostic Features

AHTR presents distinctly from other transfusion reactions:

• Hypotension is the sole or predominant feature, typically with systolic blood pressure dropping to 60-90 mmHg 1, 4
• Onset is immediate—within minutes of starting transfusion 2, 4
• Blood pressure recovers rapidly once transfusion is stopped, distinguishing it from other serious reactions 2, 4
• Re-challenge with additional blood products reproduces the hypotension, confirming the diagnosis 1, 4
• Other typical transfusion reaction symptoms are absent—no fever, rash, respiratory distress, or hemolysis 2, 4

Evidence Supporting ACE Inhibitor Association

The clinical evidence is compelling:

• In heart transplant patients, 47% (14/30) experienced severe hypotensive reactions during filtered transfusions, and 79% of these patients were on ACE inhibitors pre-operatively 5
• Multiple case reports document AHTR exclusively in patients receiving ACE inhibitor therapy 1, 2, 4
• Laboratory confirmation shows severely reduced aminopeptidase P enzyme activity in affected patients on ACE inhibitors, with impaired degradation of des-Arg9-bradykinin 1, 3
• The Naranjo adverse drug reaction probability scale indicates a "probable" association between ACE inhibitor therapy and AHTR 2

Why Other Options Are Incorrect

The other medications listed have no established association with primary hypotensive transfusion reactions:

• Aspirin (option a) and ibuprofen (option b) are not implicated in any transfusion-related hypotensive reactions in the medical literature
• Hydralazine (option c) is a direct vasodilator used to treat hypertensive emergencies 6 but has no documented association with transfusion reactions
• Metoprolol (option d), a beta-blocker, may cause hypotension as a medication side effect but is not associated with transfusion-triggered hypotensive reactions

Critical Management Principles

When AHTR occurs in a patient on ACE inhibitors:

• Stop the transfusion immediately—this is the single most important intervention 2, 4
• Provide hemodynamic support with vasopressors (epinephrine, ephedrine, phenylephrine, or vasopressin) as needed 4
• Exclude other causes of transfusion-related hypotension through direct antiglobulin testing, serum hemolysis testing, and antibody screening to rule out acute hemolytic reactions 4
• Recognize that AHTR is a diagnosis of exclusion after ruling out hemolysis, bacterial contamination, TRALI, and anaphylaxis 2, 4

Prevention Strategies

For patients requiring transfusion who are on ACE inhibitors:

• Discontinue ACE inhibitors and switch to a different antihypertensive class before elective procedures with anticipated transfusion needs 1, 2, 4
• This is particularly important for patients with high Model for End-Stage Liver Disease (MELD) scores awaiting liver transplantation 1
• If surgery cannot be delayed, prepare for potential AHTR with vasopressors readily available and close hemodynamic monitoring 4

Important Caveats

AHTR can occur with any blood product type:

• Reactions have been documented with leukoreduced products stored before transfusion, not just bedside-filtered products 3
• Even autologous blood and non-leukoreduced acute normovolemic hemodilution blood can trigger AHTR in susceptible patients 3
• Rapid transfusion using blood warmers may increase risk, though the mechanism is unclear 3