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Contraindication of angiotensin-converting enzyme (ACE) inhibitors for patients receiving therapeutic plasma exchanges.

In 1964, the National Cancer Institute, with the support of the IBM Corporation, developed an instrument used to separate the cellular elements of blood in a continuous flow separator, allowing the return of the plasma and/or red blood cells to the patient (McLeod, 2003). In a therapeutic plasma exchange (TPE) procedure, the plasma is isolated then diverted into a discard container while being replaced with a substitution fluid, typically albumin or fresh frozen plasma. TPE is a non-specific therapy and most appropriate when a specific pathogenic antibody or para-protein can be removed from the patient's plasma while plasma replacement is exchanged. Plasma exchange is essentially a symptomatic therapy because it does not remove the source of the pathogenic factors; therefore, the success of plasma exchange depends upon the accessibility of pathogenic substances through the circulation.

In many neurological disorders, such as Myasthenia gravis, Guillain-Barre syndrome, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), autoimmune antibodies are known to be the cause of dysfunction in the structure and function of the nervous system, and TPE works to remove these antibodies and therefore improve the function of the nervous system. TPE is a primary therapy for humoral transplant rejection in cardiac and renal cases, glomerulonephrifis, glomerulosclerosis, and vasculitis, all due to the removal of immune antibodies. In addition, a class of thrombotic microangiopathy disorders, including thrombotic thrombocytopenia purpura (TIP), hemolytic uremic syndrome, and Hemolytic anemia, Elevated Liver enzymes, Low Platelets (HELLP), syndrome during pregnancy, require TPE as a first-line therapy because of the removal of antibodies in combination with administration of clotting factor activators when exchanged with fresh frozen plasma. TPE is also a beneficial adjunct therapy for drug overdose when timing is optimal for removing the toxic substance from the plasma (McLeod, 2003).

The indication for the use of 5% albumin or fresh frozen plasma as the replacement fluid is disease-specific. Fresh frozen plasma is generally used in coagulopathic diseases, such as TTP and hemolytic-uremic syndrome (HUS), in which the patient is in need of clotting factors and/or molecular enzymes that are only present in donated human plasma. For all other plasma exchanges, 5% albumin is the replacement of choice due to the risk of allergic reactions, antibody development, and transfusion-transmitted infections (McLeod, 2003). Five percent albumin solution is a pharmacygrade product derived from pooled human venous plasma and heat treated to kill contaminants. The albumin solution is a mixture of sterile aqueous dilutent containing 5% as albumin protein. The oncotic effect of this solution is to expand the circulating blood volume approximately equal to what is infused (Talecris, 2006). This solution works well with TPE because it allows the patient's circulating plasma (along with the pathogenic blood component desired for removal) to be extracted and a pharmacy-grade product to be infused without disrupting the patient's total blood volume or plasma oncotic pressure. Fortunately, complications in TPE are of minor significance and can easily be managed by preventative medications and/or by slowing the procedure (Strauss, 1996).

Complications can easily occur in TPE due to technical challenges of the procedure, such as a large extra-corporeal circuit, use of citrate anticoagulant, large bore intravascular access, rapid blood flow rates, replacement fluids, and medication interactions. Although, not recently reported in the United States, according to the Swedish Registry of Apheresis, 14,000 procedures were registered during 1996 to 1999, with adverse reactions reported in 5.6% of plasma exchanges. The most common complications reported were paresthesias (22%) and hypotensive events (20.5%), with less frequent occurrences of urticaria (14.4%), shivering (7.4%), and nausea (7.4%) (Norda, Berseus, & Stegmayr, 2001). The frequent reaction of hypotension has been speculated to result from the use of angiotensin-converting enzyme (ACE) inhibitors when using 5% albumin as the replacement fluid due to an accumulation of bradykinin, a vasodilator which causes hypotension. The research questions for this literature review were:

* Based on the current research and literature, in patients receiving therapeutic plasma exchanges with 5% albumin replacement, is there a correlation between the occurrence of hypotensive episodes and the use of ACE inhibitors?

* If so, what are the guidelines on the discontinuation of ACE inhibitors while receiving plasma therapy?

This article reviews the current literature in an attempt to clarify the correlation between the use of ACE inhibitors and hypotensive patient reactions, as well as examines the need for policy and guideline development regarding the combined therapies, and finishes by further examining future research implications.

Literature Review

In a study by Tom, Dendorfer, De Vries, Saxena, and Danser (2002), the mechanism by which ACE inhibitors potentiate bradykinin is investigated, which substantiates the claim that ACE inhibitors contribute to an accumulation of bradykinin in plasma exchanges, and therefore, contribute to hypotension in patients. The results showed that ACE inhibitors induce potentiation of bradykinin, although not with a direct physical interaction of ACE and B2 receptors as what was previously proposed in studies in isolated cells overexpressing ACE and B2 receptors. Instead, it was discovered that the ACE location is in close proximity to B2 receptors, and thus, determines the bradykinin concentration in the location of the B2 receptor (Tom et al., 2002).

According to a study by Perseghin, Capra, Baldini, and Sciorelli (2001), blood contact with extracorporeal circuits made of artificial substances and negatively charged surfaces, such as blood tubing filters, may induce blood cell and humoral activation. This further potentiates the concern for a hypotensive reaction in TPE. This type of tubing system is used in plasma exchanges, and humoral cell activation will stimulate Factor XII, resulting in bradykinin production and increasing the probability for a hypotensive reaction. In this study, the investigators found that because bradykinin has a plasma half-life of only 15 to 30 seconds and is rapidly broken down by kininases, the probability of a reaction is slim. The concern arises when patients are taking an ACE inhibitor, which is a kininase II blocker and will inhibit the catabolism of bradykinin. In this study, 18 donors, 9 taking ACE inhibitors and 9 not taking ACE inhibitors (control), were observed while undergoing plasmapheresis. Blood pressure was monitored pre and post-pheresis, and bradykinin levels were measured using enzyme im-munoassay from plasma samples collected during and post-procedure. Although no adverse events were observed through the procedures, the results were significant for a higher variation of systolic BP and higher concentrations of bradykinin during and post-procedure for the ACE inhibitor group compared to control group (Perseghin et al., 2001).

In a retrospective study by Owen and Brecher (1994), records of TPEs and atypical reactions characterized by flushing, hypotension, dyspnea, and bradycardia over an 11-year period were examined. Records of 301 patients receiving TPE with albumin replacement were reviewed at the University of North Carolina Hospitals from September 1981 through December 1993. Charts were selected for investigation if adverse reactions occurred or if the patient received simultaneous administration of an ACE inhibitor. Two cases had to be eliminated due to incomplete medication administration records, leaving 299 TPE cases as population sample.

Of the 14 patients receiving ACE inhibitors, 14 (100%) experienced flushing or hypotension, whereas 20 (7%) of the 285 patients not receiving an ACE inhibitor had a reaction. Results were significant for flushing in the ACE group (p < 0.001), hypotension in the ACE group (p < 0.001), and combination of flushing and hypotension (p < 0.001) when compared to patients not taking ACE inhibitors. It was further observed that withholding the ACE inhibitor for at least 24 hours before undergoing TPE eliminated most atypical reactions. Albumin preparations were found to contain a low level of prekallikrein activator, an activator of bradykinin, which was initially thought to be of little significance. In addition, different lots of albumin were observed to contain a variable range of prekallikrein activator amounts. This study hypothesized that the rapid infusion of the prekallikrein-containing albumin during TPE would lead to subclinical elevations in bradykinin concentrations. This, paired with the concurrent use of an ACE inhibitor, which decreases bradykinin catabolism and allows bradykinin levels to reach unsafe concentrations, resulted in hemodynamic complications, such as hypotension, flushing, and vasodilatation (Owen & Brecher, 1994).

In a literature review by Strauss (1996), three major reactions from TPEs were analyzed from previous research studies: citrate reactions, hypovolemia and vasovagal reactions, and ACE inhibitor reactions. Strauss' review of ACE inhibitor reactions yielded results consistent with conclusions previously stated in this article. Hemodynamic complications of hypotension, bradycardia, flushing, and dyspnea during plasma exchanges were mediated by bradykinin and the effects of the kinin system. The kinin system is activated to produce bradykinin when the blood comes in contact with the negatively charged surface of the extra-corporeal circuit and blood filter. ACE inhibitors block kininase II, an enzyme necessary for bradykinin catabolism, which leads to an accumulation of bradykinin in the patient's bloodstream. The discovery of the presence of kallikrein activating factor in modern albumin preparations has also been shown to contribute to the upsurge of bradykinin because kallikrein is an activator of bradykinin. Strauss (1998) recommended that ACE inhibitors be discontinued for 24 to 48 hours, depending on the half-life of the particular ACE inhibitor, before undergoing TPE. Table 1 provides an overview of studies conducted in the last 15 years.

Clinical Implications

Currently, many hemapheresis units do not have specific policies on the discontinuation of ACE inhibitors prior to initiation of TPE with 5% albumin replacement. This lack of policy, in combination with patients' medications being monitored by the primary care team and not the hemapheresis specialty service, causes many patients to continue to receive ACE inhibitors while undergoing plasma therapy. As this review suggests, the risk of patients having a hemodynamic complication involving hypotension, flushing, bradycardia, and dyspnea is a probable reality. Therefore, it is recommended that an explicit policy be in place involving the timing and discontinuation of ACE inhibitors while receiving TPE; this policy should become general practice for the primary care teams requesting plasma exchanges for their patients.

Current research recommends a discontinuation time of 24 to 48 hours previous to plasma therapy for ACE inhibitors, and a 72-hour discontinuation time for longer-acting drugs of this class, such as enalapril and lisinopril (Weinstein, 2001). Further recommendations for research include a randomized control trial involving the formal testing of the effects of ACE inhibitors on patients receiving TPEs with 5% albumin replacement because this type of study has not yet occurred. Present studies have examined the effects retrospectively, and ACE inhibitors were not the controlled, independent variable. A randomized control trial is needed to eliminate any doubt of the precise correlation of ACE inhibitors and hemodynamic complications in TPE by excluding extraneous variables that may have influenced the necessity to discontinue the use of ACE inhibitors while receiving plasma exchange.


McLeod, B.C. (2003). Apheresis Principles and Practice (2nd ed.). Bethesda, MD: American Association of Blood Banks.

Norda, R., Berseus, O., & Stegmayr, B. (2001). Adverse events and problems in therapeutic hemapheresis. A report from the Swedish registry. Transfusion and Apheresis Science, 25(1), 33-41.

Owen, H.G., & Brecher, M.E. (1994). Atypical reactions associated with use of angiotensin-converting enzyme inhibitors and apheresis. Transfusion, 34(10), 891-894.

Perseghin, P., Capra, M., Baldini, V., & Sciorelli, G. (2001). Bradykinin production during donor plasmapheresis procedures. Vox Sanguinis, 81(1), 24-28.

Strauss, R.G. (1996). Mechanisms of adverse effects during hemapheresis. Journal of Clinical Apheresis, 11, 160-164.

Talecris. (2006). Product Monograph: Albumin (Human) 5% Solution, USP [Brochure]. Clayton, NC: Author. Retrieved November 2, 2008, from http://www. percent_2006_104460.pdf

Tom, B., Dendorfer, A., De Vries, R., Saxena, P., & Danser, A.H. (2002). Bradykinin potentiation by ACE inhibitors: A matter of metabolism. British Journal of Pharmacology, 137(2), 276-284.

Weinstein, R. (2001). Hypocalcemic toxicity and atypical reactions in therapeutic plasma exchange.Journal of Clinical Apheresis, 16(4), 210-211S

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In accordance with ANCC-COA governing rules Nephrology Nursing Journal Editorial Board statements of disclosure are published with each CNE offering. The statements of disclosure for this offering are published below.

Paula Dutka, MSN, RN, CNN, disclosed that she is a consultant for Hoffman-La Roche and Coordinator of Clinical Trials for Roche.

Patricia B. McCarley, MSN, RN, NP, disclosed that she is on the Consultant Presenter Bureau for Amgen, Genzyme, and OrthoBiotech. She is also on the Advisory Board for Amgen, Genzyme, and Roche and is the recipient of unrestricted educational grants from OrthoBiotech and Roche.

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Karen C. Robbins, MS, RN, CNN, disclosed that she is on the Speakers' Bureau for Watson Pharma, Inc.

Kylie A. Perkins, BSN, RN, AT(ASCP), is a Clinical Nurse Coordinator, Medical University of South Carolina, Charleston, SC, and a member of ANNA's Palmetto Chapter #203.

Disclosure Statement: The author reported no actual or potential conflict of interest in relation to this continuing nursing education article.
Table 1
Relevant Studies Conducted in the Last 15 Years

Citation                       Sample                   Method

Owen & Brecher         299 patients records     Retrospective chart
(1994)                 undergoing TPE           review/analysis with
                                                selection of charts
                                                with an adverse event
                                                and/or use of ACE

Perseghin, Capra,      18 volunteer donors, 9   BP measured by
Baldini, & Sciorelli   taking ACE inhibitors    trained nurse
(2001)                 and 9 in control group   Bradykinin was
                                                measured by enzyme
                                                immunoassay after
                                                first collection
                                                cycle and at end of

Strauss (1996)         Studies involving        Literature review
                       adverse effects during

Tom, Dendorfer,        Porcine coronary         Fluid samples taken
De Vries, Saxena, &    arteries collected       from organ baths at
Danser (2002)          from pigs at the local   highest bradykinin
                       slaughterhouse           concentration with and
                                                without quinaprilat
                                                and bradykinin levels

Citation                     Instrument                Results

Owen & Brecher         Comparisons of           100% of patients on
(1994)                 frequency of possible    ACE inhibitors had
                       outcomes performed       atypical reaction
                       using Fisher's exact     compared with 7%
                       test; all tests were     from control group
                       two-sided.               (p < 0.001).

Perseghin, Capra,      Pheresis performed       Changes in systolic BP
Baldini, & Sciorelli   with Autopheresis C      for ACE group
(2001)                 device                   significant
                                                (p < 0.0001)
                       Bradykinin assay         Bradykinin
                       performed with           determination
                       electrophoresis          significantly higher
                       instrument               in ACE group for first
                       (Cosmofer[R] 3200)       cycle and post-values
                       and statistical          (p < 0.0001) when
                       analysis                 compared to control
                       performed using          group.

Strauss (1996)         N/A                      ACE inhibitors are
                                                contraindicated in
                                                patients receiving
                                                TPE and should be
                                                discontinued 24 to 48
                                                hours previously.

Tom, Dendorfer,        Bradykinin levels        Bradykinin
De Vries, Saxena, &    measured by high         potentiation induced
Danser (2002)          performance liquid       by ACE inhibitors due
                       chromatography and       to ACE determination
                       photometric detection    of bradykinin at
                       at 210 nanometers.       location of B2
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Title Annotation:Continuing Nursing Education
Author:Perkins, Kylie A.
Publication:Nephrology Nursing Journal
Date:Nov 1, 2008
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