REVIEW
URRENT
C
OPINION
Renin–angiotensin system inhibitors and
angioedema: anesthetic implications
Ljuba Stojiljkovic
Purpose of review
Angioedema is a serious complication of renin--angiotensin system inhibitor therapy. The incidence is
0.1--0.7%. It consists of nonpitting edema and involves the face and lips. In severe cases, it extends to
pharyngeal and laryngeal structures.
Recent findings
Decreased degradation of bradykinin and its metabolites is thought to be a culprit. When the angiotensinconverting enzyme is inhibited, bradykinin metabolism is dependent on degradation by neutral
endopeptidase, dipeptidyl peptidase IV, and aminopeptidase P. When these enzymes are inhibited, as in
treatment of diabetes or in transplant recipients, the incidence of angioedema increases significantly.
African-Americans, people over 65, women, and those with a history of smoking are especially at risk.
A fiberoptic laryngeal examination should be performed in all patients. Patients with rapid progression of
symptoms are at risk for airway compromise. Supportive treatment with steroids and antihistamines is not
very effective. Recently, icatibant, a bradykinin receptor antagonist, has been used to successfully shorten
the resolution of edema.
Summary
Trauma of the airway, especially during difficult intubation, may precipitate severe angioedema. In cases
with laryngeal involvement, fiberoptic intubation may be necessary. After the episode of angioedema,
lifetime discontinuation of all renin--angiotensin inhibitors may be warranted.
Keywords
airway edema, angioedema, angiotensin-converting enzyme inhibitors, bradykinin, renin--angiotensin system
INTRODUCTION
The renin–angiotensin–aldosterone system (RAAS) is
a key player in human physiology. It regulates blood
pressure homeostasis, water balance, renal function,
and cellular growth. Hyperactivation of RAAS is
involved in the development of end-organ damage
in a variety of cardiovascular and renal diseases. The
beneficial effects of RAAS inhibition extend beyond
the antihypertensive effect and include significant
cardioprotective and renoprotective effects [1]. The
therapies that modulate RAAS have emerged as
important armamentarium in the treatment of
patients with various cardiovascular and renal disorders. Pharmacological inhibition of RAAS can be
obtained via three different mechanisms: inhibition
of conversion of angiotensin I (AngI) to active angiotensin II (AngII) via angiotensin I converting enzyme
inhibitors (ACEIs); selective inhibition of angiotensin
receptor 1 (AT1) via angiotensin receptor blockers
(ARBs); and direct inhibition of AngI production
via direct renin inhibitors (DRI).
Pharmacological inhibitors of RAAS are among
the most commonly prescribed therapeutics in the
USA. ACEIs alone were ranked 5th in the total US
healthcare market with 168.7 million prescriptions
dispensed in 2010 [2]. These medications are usually
well tolerated, and the long-term tolerability is
similar to other commonly prescribed antihypertensives [3 ]. The most common adverse effects are
headache, dizziness, and fatigue; more serious
side-effects include hypotension, hyperkalemia,
and renal failure [4]. The overall incidence of
&
Department of Anesthesiology, Northwestern University, Feinberg
School of Medicine, Chicago, Illinois, USA
Correspondence to Ljuba Stojiljkovic, MD, PhD, Associate Professor of
Anesthesiology, Department of Anesthesiology, Northwestern University,
Feinberg School of Medicine, Feinberg Pavilion, Suite 5-704, 251 E.
Huron Street, Chicago, IL 60611, USA. Tel: +1 312 926 8369;
e-mail: [email protected]
Curr Opin Anesthesiol 2012, 25:1–7
DOI:10.1097/ACO.0b013e328352dda5
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Anesthesia and medical disease
KEY POINTS
Angioedema is a life-threatening condition that may
develop in patients treated with any medications that
inhibit RAAS.
The pathophysiology of angioedema is related to
changes in the metabolism of the kallikrein-kinin system.
Management of angioedema includes prompt
recognition and triage with mandatory fiberoptic
examination of pharyngeal and laryngeal structures as
well as intubation for airway protection in severe cases.
Anesthesiologists should be aware that airway trauma,
especially during difficult intubation, may trigger
angioedema in susceptible patients who are on
RAAS inhibitors.
An episode of angioedema may require lifelong
discontinuation of all RAAS inhibitors.
adverse events is about 4–7% [5]. However, in
susceptible individuals these medications may
induce severe and life-threatening angioedema.
Angioedema consists of subcutaneous or submucosal nonpitting, nonpruritic, painless edema.
Angioedema may involve any part of the body;
however, the most common sites involve tongue,
oropharynx, periorbital, and perioral areas [6–8].
Supraglottic and laryngeal extensions of the edema
can quickly progress to airway compromise and may
require endotracheal intubation for airway protection [9]. Less commonly, angioedema may involve
the gastrointestinal wall (visceral angioedema),
which may present as a diagnostic challenge [10,11].
ACEIs are most commonly implicated in angioedema formation and the incidence ranges between
0.1 and 0.68% [12,13]. The incidence of angioedema
following ARBs administration is slightly less and
occurs in 0.1–0.4% of patients [14,15 ]. Incidence
of angioedema in patients taking aliskiren is around
0.4% [16,17]. Recent analysis of the adverse events via
the US Adverse Event Reporting System revealed that
aliskiren has had the highest reporting ratio for
angioedema among all RAAS inhibitors, including
two deaths [18]. At this time, it is not clear whether
aliskiren has a higher risk of life-threatening angioedema compared to other RAAS inhibitors.
&
BALANCE BETWEEN THE RENIN–
ANGIOTENSIN SYSTEM AND THE
KALLIKREIN–KININ SYSTEM
RAAS and kallikrein–kinin system (KKS) interact on
several levels in a complex array of crosstalk [19,20].
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At some levels they potentiate, and at others they
oppose each other; under normal physiologic conditions, they are in equilibrium [20]. Any intervention that affects one system will have a profound
effect on the other on multiple levels [21]. ACE is a
key enzyme that links these two systems together
[20]. Thus, drugs that inhibit RAAS exert their
beneficial effect also by potentiating KKS [22–25].
However, the beneficial effect in increasing KKS
comes at a certain price. In susceptible individuals,
alterations in KKS can lead to severe and sometimes
life-threatening angioedema [3 ,18,26,27].
Bradykinin is a nonapeptide cleaved from high
molecular weight (HMW) kininogen by activated
plasma kallikrein assembled with Factor XIIa on
endothelial cell membranes. Bradykinin is rapidly
metabolized, with a plasma half-life of only 15–17 s.
Kallidin (Lys-BK) is a decapeptide generated by enzymatic degradation of low molecular weight (LMW)
kininogen by tissue kallikrein. Both Bradykinin and
Lys-BK exert their action primarily via B2 receptors
[21]. B2 receptors are constitutively and widely
expressed on endothelial cells in many tissues. B2
receptor activation leads to release of nitric oxide
and prostacyclin (PGI2), and causes vasodilatation,
hypotension, and increased vascular permeability
[20]. Under normal physiologic conditions, kinins
exert their effect in an autocrine and a paracrine
manner, with little systemic effects due to a rapid
degradation by endothelial-based enzymes. Bradykinin and Lys-BK are rapidly metabolized to inactive
products via endothelial cell-based ACE, neutral
endopeptidase (NEP), aminopeptidase P (APP),
and dipeptidyl peptidase IV (DPP-IV) (Fig. 1). Degradation of Bradykinin and Lys-BK via plasma carboxypeptidase N (CPN) produces active metabolites
Des-Arg9 Bradykinin and Lys-Des-Arg9 Bradykinin,
which are potent activators of B1 receptors (Fig. 1).
B1 receptors have low intrinsic expression; however,
their expression can be induced by tissue trauma,
inflammatory cytokines, and endotoxin stimulation.
Inducible activation of B1 receptors mediates inflammatory response, exacerbates tissue edema, and may
lead to severe vasodilatation, hypotension, and fluid
extravasation seen in endotoxic shock.
Inhibition of ACE leads to alterations in the
RAAS via decreased production of a potent vasoconstrictor and proliferative agent, AngII, from a
precursor, AngI. ACE inhibition also profoundly
affects the KKS by decreasing the degradation of
Bradykinin and Lys-BK, which leads to their
accumulation in the tissues, especially in the heart
and in the kidneys. Increase in tissue Bradykinin and
Lys-BK is at least partly responsible for the cardioprotective and renoprotective effects of ACEIs.
ACEIs may also act as allosteric enhancers of B2
&
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Renin–angiotensin system inhibitors and angioedema Stojiljkovic
↑ NO
↑ Prostacyclin (PGI2)
Vasodilatation
Hypotension
↑ Vascular permeability
B2 receptors
HMW kininogen
Plasma kallikrein
Bradykinin
ACE
(kininase II)
APP
NEP
(DPP-IV)
Tissue kallikrein
LMW kininogen
Inactive metabolites
Lys-bradykinin
Tissue kallikrein
Carboxypeptidase N
(kininase I)
Lys-Des-Arg9 Bradykinin
Des-Arg9 Bradykinin
Inactive metabolites
B1 receptors
ACE
APP
Inflammatory response
Tissue edema
Vasodilatation
Hypotension
Fluid extravasation
FIGURE 1. Bradykinin and Lys-Bradykinin are peptides produced from high molecular weight (HMW) and low molecular
weight (LMW) kininogens by the action of plasma and tissue kallikrein enzymes. Both peptides are further metabolized to
active metabolites Des-Arg9 Bradykinin and Lys-Des-Arg9 Bradykinin by kininase I (carboxypeptidase N). Angiotensinconverting enzyme (ACE) is the main enzyme that metabolizes all kinin peptides into inactive products. In the presence of ACE
inhibitors, kinin peptides metabolism is increasingly dependent on other enzymes (APP, NEP, and DPP-IV). When these
enzymes are inhibited, as in patients on DPP-IV inhibitors or immunosuppressants, kinin peptides accumulate. Action of kinins
via B2 receptors induces hypotension and vasodilatation because of the increased levels of nitric oxide (NO) and prostacyclin
PGI2. This effect is thought to be beneficial in patients with hypertension, heart failure and diabetic nephropathy. However,
higher levels of kinins may produce exaggerated inflammatory response, tissue edema, fluid extravasation and hypotension
via action through B1 receptors. This effect may lead to the development of angioedema.
receptors [22]. The binding of ACEIs to ACE induces
a conformational change in ACE which is transmitted to a B2 receptor, resulting in potentiation
of its effect. Moreover, ACEIs directly activate B1
receptors in the same range as Des-Arg9 Bradykinin
and Lys-Des-Arg9 Bradykinin [22].
ARBs selectively inhibit AT1 receptors and
increase the levels of AngII (2–2.5-fold) and AngI
(3–3.7-fold) [24]. They also increase Bradykinin
levels by approximately two-fold [24], similar to
the increase in Bradykinin levels seen during ACEI
therapy [28]. ARBs improve coronary artery endothelial function by a Bradykinin-dependent mechanism in both animals [5] and humans [29]. Possible
mechanisms of the effect of ARBs on KKS include
AT1 receptor-mediated decrease in NEP activity,
which increases Bradykinin levels [30], as well as
AngII-mediated activation of angiotensin receptor 2
(AT2) receptors in the presence of AT1 receptor
blockade. AT2 receptor activation induces an
increase in kinin generation and directly stimulates
the B2 receptor (AT2–B2 receptor crosstalk) [31].
DRI aliskiren affects KKS by increasing tissue
kallikrein levels, and subsequently Bradykinin
formation in the heart by renin-independent mechanism [25].
PATHOPHYSIOLOGY OF THE RENIN–
ANGIOTENSIN–ALDOSTERONE SYSTEM
INHIBITORS-INDUCED ANGIOEDEMA
In the presence of ACEIs, Bradykinin metabolism is
increasingly dependent on NEP, DPP-IV, and APP to
produce inactive metabolites. Additionally, ACE
inhibition shifts Bradykinin and Lys-BK metabolism
toward the production of active metabolites,
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Anesthesia and medical disease
Des-Arg9 Bradykinin and Lys-Des-Arg9 Bradykinin,
by CPN. These active metabolites are degraded to
inactive metabolites primarily by ACE, and in the
presence of ACEIs their metabolism is increasingly
dependent on the action of APP (Fig. 1). Any further
environmental or genetic imbalance in any of the
enzymes involved in KKS metabolism may lead to
excessive accumulation of Bradykinin and Lys-BK,
as well as their active metabolites. Experimental
evidence supports this hypothesis and shows significantly higher accumulation of Des-Arg9 Bradykinin
in patients taking ACEIs who developed angioedema, compared with patients taking ACEI who
did not [32]. Des-Arg9 Bradykinin and LysDes-Arg9 Bradykinin activate proinflammatory B1
receptors, resulting in vasodilatation and fluid
extravasation leading to edema [33]. In addition,
B1 receptor activation on sensory neurons leads to a
local accumulation of neuropeptide substance P
[34,35]. Release of substance P produces the symptoms of neurogenic inflammation and edema via
the NK1 receptors located on endothelial cells and
mast cells in the capillaries, further aggravating the
edema induced by activation of KKS [35]. Metabolism of substance P is highly dependent on the
action of ACE and, in the presence of ACE inhibition, it primarily depends on degradation by NEP
and DPP-IV. Therefore, it is not surprising that vasopeptidase inhibitor omapatrilat (Valnev), which
inhibits both ACE and NEP, caused an unacceptably
high rate of angioedema (2.16%) as compared to
enalapril (0.67%) during the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial [36].
The OCTAVE trial included more than 25 000
patients and led to the rejection of omapatrilat by
the Food and Drug Administration (FDA).
DPP-IV is another enzyme that plays a supporting role in the degradation of Bradykinin and substance P. However, DPP-IV has an important role in
the inactivation of incretin hormones, such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide [37]. Diabetic patients have
increased DPP-IV activity, which contributes to
impaired glucose control and insulin resistance
[37]. DPP-IV inhibitors emerged as promising agents
in the treatment of diabetes mellitus type 2 (DMT2).
In 2006, the first DPP-IV inhibitor sitagliptin (Januvia) was approved by the FDA for the treatment of
DMT2 [38], followed by saxagliptin (Onglyza) in
2009. The American College of Endocrinology
now places DDP-IV inhibitors in the first line of
treatment for DMT2 [39]. However, in 2008, Medwatch, the FDA Safety Information and Adverse
Event Reporting Program released a postmarketing
experience of serious hypersensitivity reactions,
including angioedema in patients treated with
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sitagliptin [40]. Recent meta-analysis showed that
another DPP-IV inhibitor vildagliptin is associated
with an increased risk of angioedema, especially
when used concomitantly with ACEI (odds ratio
4.57) [7,41]. As HTN and DMT2 occur commonly
together, anesthesiologists should be aware of the
potential risks of angioedema in patients concomitantly treated with ACEI/ARB/DRI and DPPIV inhibitors.
DPP-IV also has an important role in human
T-cell biology as a CD26 leukocyte surface antigen
[42]. Its DPP-IV enzymatic activity enhances the
T-cell response to external stimuli, and the CD26/
DPP-IV surface antigen plays an important role in
T lymphocyte activation and proliferation [42,43].
As CD26/DPP-IV cellular expression and activity
are strongly correlated with transplant rejection
[44,45], all immunosuppressant medications inhibit
its activity. Indeed, graft survival in transplant recipients is inversely proportional to CD26/DPP-IV
activity [45]. However, decreased DPP-IV activity
in transplant patients who are concomitantly on
ACEI therapy significantly increases their risk of
developing angioedema [46]. Incidence of angioedema is increased 24-fold in cardiac transplant recipients and 5-fold in renal transplant recipients who
were on concomitant ACEI therapy [46].
To date, there are no data of angioedema in
patients who are on triple combination therapy
(DPP-IV inhibitors, immunosuppressants, and
ACEI/ARB/DR); however, it is very plausible to
encounter such patients in the near future because
of an ever more complex clinical picture and the
advanced medical treatments available today. It is
very important to have in mind their increased risk
of angioedema, especially during the perioperative
period and airway manipulations. Airway trauma, in
particular during difficult intubation, may precipitate severe angioedema, and further worsen
airway compromise.
GENETIC FACTORS
When ACE is inhibited, Des-Arg9-Bradykinin inactivation is highly dependent on APP activity (Fig. 1).
The APP enzyme exists in two isoforms, the soluble/
cytosolic form and the membrane-bound form,
encoded by two different genes, XPNPEP1 and
XPNPEP2, respectively. In vivo, only membranebound APP enzyme is involved in Des-Arg9-Bradykinin metabolism. Genetic variants of the XPNPEP2
gene have been shown to decrease APP activity [47].
Single-nucleotide polymorphism C-2399A, located
in the enhancer region of the XPNPEP2 promoter, is
associated with increased risk of ACEI-induced
angioedema, especially in African–American men
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Renin–angiotensin system inhibitors and angioedema Stojiljkovic
Table 1. Risk factors for the development of RAAS inhibitor-induced angioedema
Genetic factors
Epidemiological factors
Pharmacological factors
XPNPEP2 gene polymorphisms (APP enzyme):
African-Americans
DPP-IV inhibitors (treatment of diabetes mellitus):
SNP C-2399A
Women
Promoter haplotype ATG
Age >65
Sitagliptin
Saxagliptin
Smoking
Vildagliptin
Airway trauma (intubation)
Immunosuppressants
APP, aminopeptidase P; DPP-IV, dipeptidyl peptidase IV; SNP, single-nucleotide polymorphism.
[48]. Recently, a functional XPNPEP2 promoter haplotype ATG (located in the potent transcriptional
enhancer region of the gene) was significantly
associated with ACEI-induced angioedema [49 ].
The authors suggest that the ATG haplotype may
be a useful biomarker for ACEI-induced angioedema
risk prediction [49 ].
during airway management and intubation may precipitate RAAS inhibitor-induced angioedema, especially if other risk factors are present [9,30].
Risk factors associated with RAAS inhibitorinduced angioedema are summarized in Table 1.
EPIDEMIOLOGICAL FACTORS
Angioedema can be classified according to clinical
presentation into three types; mild forms (type 1)
are the most common and are limited to face or lip
edema, with no or only anterior tongue involvement [52]. Extension to the base of the tongue, floor
of the mouth, soft palate or uvula could be classified
as moderate (type 2). In severe forms, angioedema
extends to supraglottic and laryngeal structures
(type 3). Characteristics of the three types of angioedema are summarized in Table 2. As supraglottic
edema may not always correlate with tongue edema,
flexible fiberoptic laryngeal examination is essential
to diagnose more severe forms [9,53 ]. In addition,
the degree and rapid progression of tissue swelling
are sensitive indicators for the necessity of intubation for airway protection [54]. Patients with mild
&&
&&
RAAS inhibitor-induced angioedema is three times
more prevalent in patients with African–American
ancestry, as compared to Caucasians [3 ,50].
African–Americans also tend to have more severe
symptoms associated with angioedema and are more
likely to require hospitalization and intubation for
airway protection. Lower endogenous Bradykinin
levels and increased sensitivity to Bradykinin in
African–Americans has been proposed [51].
Other risk factors include the female sex, a
history of smoking, advanced age (>65), and a
history of ACEI-induced cough [3 ,50].
The factors of special interest to anesthesiologists
are those that may increase the perioperative risk of
developing angioedema. Trauma to the upper airway
&
&
CLINICAL PRESENTATION AND
MANAGEMENT
&&
Table 2. Clinical presentation and management of RAAS inhibitors-induced angioedema
Type of angioedema
Clinical presentation
Management
Treatment
Mild (Type 1)
Face, lip, and anterior tongue edema
Observation in emergency room
or on regular ward
Corticosteroids and antihistamines
Moderate (Type 2)
Edema extension to base of the tongue,
floor of the mouth, soft palate, and uvula
ICU admission
Add s.c. or racemic epinephrine
if stridor is present
FFP
Icatibant
Severe (Type 3)
Edema involving supraglottic and
laryngeal structures
ICU admission
Drooling, odynophagia, hoarseness,
or dyspnea
As in type 1 and type 2
Fiberoptic endotracheal intubation
in airway compromise or rapid
progression of symptoms
FFP, fresh frozen plasma; s.c., subcutaneous.
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Anesthesia and medical disease
forms may be observed in the emergency department or hospitalized on the regular floor. Patients
with moderate and severe angioedema should be
observed in the intensive care unit. Patients with
rapid progression symptoms (drooling, odynophagia, hoarseness, and dyspnea) are at a high risk
of airway compromise and the airway should be
secured with elective fiberoptic intubation. Contrary to the previous reports, patients with RAAS
inhibitor-induced angioedema do not have a higher
incidence of intubations, compared to other types
of angioedema [55]. However, if RAAS-inhibitorinduced angioedema occurs after airway management during the perioperative period, intubation is
almost always required.
Angioedema is self-limiting and usually resolves
within a few days after discontinuation of the drug.
Standard treatment with corticosteroids and antihistamines is not very successful; however, it is still
widely used as a supportive measure [53 ,56]. Epinephrine injection or nebulized racemic epinephrine may be used in cases with stridor. Fresh-frozen
plasma has also been used to replete the enzymes in
more severe cases [57,58]. More recently, icatibant
(Firazyr), a B2 receptor blocker approved in the USA
in 2011 for the treatment of hereditary angioedema
[59], has been successfully used in the treatment of
ACEI-induced angioedema [60 ,61]. In one case
series, icatibant significantly shortened the resolution of edema in all patients, and none of the
patients required intubation for airway protection
[60 ]. Even though initial experiences with icatibant
are very promising, the efficacy and safety of its use
in RAAS inhibitor-induced angioedema need to be
established in large randomized clinical trials.
&&
&
&
CONCLUSION
Taken together, both environmental factors and
genetic predispositions play important and likely
synergistic roles in angioedema formation in
susceptible individuals. Prompt recognition and
timely intervention, including lifetime discontinuation of RAAS inhibitors, is of paramount importance. It is also important to keep in mind the high
recurrence rate with any of the drugs that act via the
RAAS/KKS pathway. As more data are emerging
regarding pathophysiological mechanisms, future
research should focus on new therapies targeting
inhibition of specific molecules and receptors
involved in the mechanism of the disease. One
of the new therapies may include NK-1 receptor
antagonists, which may inhibit substance P-mediated effects in angioedema formation [62 ]. Development of new therapeutics that inhibit the B1 receptor
may also prove beneficial. Pharmacogenomic tests
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may allow for screening of patients who are at risk. In
conclusion, there are exciting new avenues of
research that may help in the prevention, diagnosis,
and treatment of this potentially life-threatening
condition.
Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.
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READING
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&
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