Renin-angiotensin system antagonists in the perioperative setting: clinical consequences and recommendations for practice.

Renineangiotensin system antagonists in the
perioperative setting: clinical consequences and
recommendations for practice
Moises Auron,1,2 Brian Harte,1 Ajay Kumar,1 Franklin Michota1
ABSTRACT
There are no existing guidelines supporting the
withdrawal or continuation of
renineangiotensinealdosterone system (RAAS)
antagonists in the preoperative setting. RAAS
antagonists include ACE inhibitors, angiotensin II receptor
subtype 1 blockers and direct renin inhibitors (eg,
aliskiren), as well as the aldosterone antagonists. The
use of these agents before surgery has been associated
with a variable incidence of hypotension during the initial
30 min after induction of anaesthesia; however, these
hypotensive episodes have not been conclusively linked
to any significant postoperative complications, although
recent data suggest an increase in postoperative
morbidity and mortality in patients undergoing coronary
artery bypass grafting. Further studies are required to be
able to demonstrate if the organ-protective benefits of
RAAS antagonists justify their continuation in the
perioperative setting. Temporary withdrawal of RAAS
antagonists in these patients may prevent or attenuate
intraoperative hypotension and hypovolaemia.
Alternatively, the increase in RAAS activity and blood
pressure expected with cessation of RAAS antagonist
therapy may impair regional circulation secondary to an
increase in systemic vascular resistance. Full discussion
of the potential implications of perioperative RAAS
antagonist therapy with the surgical team is important,
and strategies to ensure careful monitoring and
maintenance of adequate intravenous volume before
induction of anaesthesia are essential.
INTRODUCTION
The renineangiotensinealdosterone system (RAAS)
antagonists include ACE inhibitors (ACEIs),
angiotensin II receptor subtype 1 blockers (ARBs)
and direct renin inhibitors (eg, aliskiren). The use of
these agents has increased substantially in the past
two decades, and they currently are among the
most commonly used and effective treatments for
hypertension,1 congestive heart failure,2 coronary
artery disease3 and diabetic nephropathy.4 5 As
a result, many contemporary surgical patients will
be using RAAS antagonists before their procedure,
and questions remain as to the potential risks and/
or benefits of continuing these agents in the
immediate perioperative period.
There have been several reports and small studies
suggesting that intraoperative hypotension after
the induction of anaesthesia is more common in
patients who receive RAAS antagonist therapy on
the day of surgery.6 Similar reports have linked
postoperative acute renal failure with RAAS
antagonist use before surgery, which is related
to both intraoperative hypotension and use of
inotropes.7 8 Although most of the existing litera-
ture has not associated the perioperative use of
these agents with an increase in short- or long-term
mortality, one recent analysis has found a higher
incidence of postoperative atrial fibrillation (POAF),
use of inotropes, and death with preoperative RAAS
antagonist therapy.8
The available literature on this topic is scant, and
no guidelines have yet been published on the
appropriate use of RAAS antagonists in the surgical
patient. In addition, the introduction of new agents
that modulate RAAS, such as the direct renin
inhibitor aliskiren, will add further complexity to
this important clinical question. The purpose of
this review is to compare and contrast the existing
literature supporting the use or cessation of
RAAS antagonists in both cardiac and non-cardiac
surgery patients, and to provide further insight
for the clinician caring for such patients in the
perioperative period.
PHARMACOLOGICAL PROPERTIES AND
PERIOPERATIVE IMPLICATIONS
The vasodilatory actions of RAAS antagonists
involve multiple mechanisms (tables 1 and 2).
These include direct sympathetic blockade,
increased bioavailability of vasodilators such as
bradykinin, nitric oxide and prostacyclins, inhibi-
tion of the direct and indirect vasoconstrictor
effects of angiotensin II, and reduced secretion of
aldosterone and antidiuretic hormone resulting in
a decrease in salt and water reabsorption by the
kidney.11 Given the wide distribution of ACE in
the body, the RAAS antagonists have wide-ranging
effects, inhibiting various angiotensin peptides as
well as both renin and pro-renin receptors with
subsequent endocrine, paracrine and intracrine
functions, which in turn regulate diverse physio-
logical functions (figure 1).12 13 There are well-
defined deleterious effects of chronic RAAS
stimulation such as upregulation of angiotensin 1
receptor, subsequent aldosterone release, and the
promotion of vascular hypertrophy, fibrosis and
proliferation. There are also novel components of
the RAAS that exert unclear effects, such as
a homologue of ACE called ACE 2, which mediates
the formation of the heptapeptide Ang1e7,
a peptide with both vasodilatory and vascular
endothelial anti-inflammatory properties.14 15 The
RAAS, along with sympathetic nervous system
activation and arginineevasopressin (AVP) release,
is a primary mechanism for the maintenance of
1Department of Hospital
Medicine, Cleveland Clinic,
Cleveland, Ohio, USA
2Center for Pediatric Hospital
Medicine, Children’s Hospital,
Cleveland Clinic, Cleveland,
Ohio, USA
Correspondence to
Moises Auron, Department of
Hospital Medicine, Cleveland
Clinic, 9500 Euclid Ave, M2
Annex, Cleveland, OH 44195,
USA; auronm@ccf.org
Received 28 October 2010
Accepted 21 February 2011
Auron M, Harte B, Kumar A, et al. Postgrad Med J (2011). doi:10.1136/pgmj.2010.112987 1 of 10
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venous return and systemic blood pressure (SBP) during periods
of acute haemodynamic stress such as the induction of anaes-
thesia. Angiotensin II is a potent direct vasoconstrictor and
physiological stimulus for AVP release, and counter-regulates the
usual hypotensive effect of anaesthetic agents on the sympa-
thetic nervous system (increased venous pooling of blood,
decreased cardiac output, and arterial hypotension). As a result,
patients chronically treated with RAAS antagonists are poten-
tially at higher risk of developing clinically significant hypo-
tension after the induction of anaesthesia because of the
decreased vascular resistance and associated decreased cardiac
filling.6 16 17 The withdrawal of these agents should reduce
the hypotensive episodes, but may also increase systemic
vascular resistance, which can compromise regional circulation
(splanchnic).
Because the RAAS interacts at multiple levels to maintain
intraoperative blood pressure (BP), the successful treatment of
intraoperative hypotension in the setting of RAAS blockade
includes adequate intravascular volume repletion, as well as the
use of AVP agonists (terlipressin, vasopressin) and adrenergic
agonists. In the USA, vasopressin is the only available AVP
agonist.18 AVP agonists potentiate the response to endogenous
catecholamines, which increases vascular resistance and venous
return and improves myocardial oxygen delivery and cardiac
contractility.19
Complicating matters further, recent pharmacogenomic
studies of the RAAS have demonstrated variable genetic
susceptibility to RAAS antagonists via single-nucleotide poly-
morphisms in the genes that encode angiotensinogen, angio-
tensin receptor 1 and angiotensin receptor 2.20 21 The most
comprehensively studied RAAS polymorphism is the ACE
insertion/deletion polymorphism; this is based on the presence
(I) or absence (D) of a 287 bp Alu repeat sequence within intron
16 of the ACE gene. The D allele has been associated with
increased ACE concentrations in plasma and at the tissue level,
and its expression (DD allele) has been postulated to offer
resistance to ACE inhibitors and cause increased adverse
cardiovascular and renal effects.22 23 Thus the haemodynamic
response to RAAS antagonists in the perioperative setting may
be further influenced by individual genetics.
EVIDENCE AGAINST RAAS ANTAGONISTS IN THE
PERIOPERATIVE SETTING
The current medication guideline used at the perioperative clinic
in our institution recommends that both ACEIs and ARBs be
discontinued on the morning of non-cardiac surgery.24 There are
no national or international guidelines that delineate a standard
of care in the use of these agents in the perioperative period.
The literature supporting this practice relates to the frequency
and degree of intraoperative hypotension observed with
concomitant use of RAAS antagonists.
Non-cardiac surgery
The following studies focused on the effect on BP after intuba-
tion in patients taking ACEIs before surgery.
McCarthy et al studied the effect of two doses of sublingual
captopril (12.5 mg and 25 mg) versus placebo administered
25 min before tracheal intubation in 40 patients. The patients
receiving captopril were more likely to develop hypotension
than those receiving placebo (p<0.05) within 3 min of intuba-
tion; however, there was no significant difference between the
two captopril doses.25 Coriat et al randomised 56 patients
undergoing non-cardiac surgery chronically treated for hyper-
tension with captopril (n¼36) or enalapril (n¼20) into two
groups, one in which the ACEIs were administered on the
morning of surgery and the other in which it was withdrawn. In
the former group, all of the patients who received enalapril and
64% of those who received captopril required ephedrine to treat
post-induction hypotension. The rate was significantly higher
than in the patients whose ACEIs were withdrawn (enalapril
100% vs 18%, p<0.005; captopril 64% vs 21%, p<0.05).26
The difference in haemodynamic response between ACEIs and
ARBs was demonstrated in a study by Brabant et al. Haemo-
dynamic responses were evaluated in patients treated with
b-adrenergic blockers (BBs) and/or calcium channel blockers
(CBs), ACEIs or ARBs after induction of anaesthesia. Hypoten-
sion was defined as an SBP decrease of >30% from the preop-
erative value or an absolute SBP decrease below 90 mm Hg.
Hypotension occurred in 100% of patients receiving ARBs (12
out of 12), compared with 60% of BB/CB-treated patients (27 of
45) or with 66% of ACEI-treated patients (18 of 27) (p#0.05).
After induction of anaesthesia, the lowest mean arterial pressure
(mm Hg) was 5466 in the ARB group, 66612 in the BB/CB
group, and 68610 in the ACEI group (p<0.001comparing ARB
with CC/BB or ACEI groups). The patients treated with ARBs
Table 1 Pharmacology of ACE inhibitors
Active
metabolite Zinc ligand Bioavailability (%) Half-life (h)
Route of
elimination
Captopril No Sulfhydryl 75e91 1.7 Kidney
Enalapril Yes Carboxyl 60 11 Kidney
Lisinopril No Carboxyl 6e60 12 Kidney
Benazepril Yes Carboxyl >37 10e11 Kidney
Quinapril Yes Carboxyl >60 1.9e2.5 (25 terminal) Kidney
Ramipril Yes Carboxyl 50e60 Triphasic 4, 9e18, >50 Kidney
Trandolapril Yes Carboxyl 70 15e24 Kidney, liver
Moexipirl Yes Carboxyl 13 2e9 Kidney
Fosinopril Yes Phosphinyl 36 12 Liver, kidney
Adapted from Brown and Vaughan.9
Table 2 Pharmacology of angiotensin receptor II type 1 blockers
Active
metabolite
Bioavailability
(%)
Half-life
(h)
Route of
elimination (%)
Kidney Liver
Losartan Yes 33 2 40 60
Valsartan No 25 9 15 85
Irbesartan No 70 11e15 20 80
Candesartan Yes 42 3.5e4 35 65
Telmisartan No 43 24 1 99
Eprosartan No 15 5e7 10 90
Olmesartan Yes 26 13 35e50 50e65
Adapted from Barreras and Gurk-Turner.10
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required higher doses of adrenergic agents (ephedrine, phenyl-
ephrine) (4 of 12) compared with the BB/CB group (0 of 45) or
the ACEI group (1 of 27); however, the hypotension was
responsive to vasopressin agonists.27
Several studies have focused on the time that RAAS antago-
nists should be withheld before surgery. Bertrand et al studied 37
patients receiving chronic therapy with ARBs; 18 had their ARBs
discontinued the day before surgery, and 19 received their ARB
dose 1 h before induction of anaesthesia. He found that the
administration of ARBs on the morning of surgery was associ-
ated with more frequent episodes of hypotension as well as
longer duration of hypotension than if ARBs was withheld. In
addition, the hypotensive episodes were refractory to initial
therapy with adrenergic agents, requiring the addition of terli-
pressin. This study also found that the timing of the RAAS
antagonist did play a role in the outcome. Patients that received
an ARB dose within 10 h of anaesthesia induction were more
likely to have hypotension than patients receiving the ARB dose
more than 10 h before the induction of anaesthesia. The authors
recommended discontinuing ARBs on the day before surgery.28
Comfere et al evaluated 267 patients receiving chronic anti-
hypertensive treatment with ACEIs/ARBs undergoing general
anaesthesia. The incidence of hypotension during the first
30 min after induction of anaesthesia was more common in
patients whose most recent ACEIs/ARBs was taken <10 h
compared with those who stopped it >10 h before induction
(60% vs 46%, OR 1.74 (95% CI 1.03 to 2.93), p¼0.04).29
Shirmer and Schurmann randomised 100 patients receiving
chronic antihypertensive therapy with ACEIs in a double-blind
study of ACEI discontinuation in non-cardiac surgery. Fifty
patients were allocated to receive ACEIs on the morning of
surgery and 50 to have it withdrawn. After induction of
anaesthesia, the BP and heart rate were significantly lower in the
group of patients receiving ACEIs than in the withdrawal group,
and the use of supportive adrenergic agonists was required more
often (17 of the 50 patients who took ACEIs versus five of the 50
patients in the withdrawal group, p<0.05). The authors
concluded that patients chronically treated with ACEIs should
receive the last dose on the day before surgery.30
The effect of sympathetic blockade of RAAS antagonists in
the perioperative setting was evaluated by Licker et al, who
compared in a prospective caseecontrol study, the heart rate
variability and baroreflex control before surgery and 30 min after
induction of anaesthesia in two groups of patients with
ischaemic heart disease undergoing non-cardiac surgery (16
receiving chronic ACEIs and 16 who did not) and found no
Figure 1 Renineangiotensinealdosterone system (RAAS) and site of action of the different RAAS antagonists. Note the pleiotropic effects of the
RAAS that can be indirectly affected by the use of RAAS antagonists given its activity. Ang III-angiotensin 2e8 heptapeptide has similar activity to Ang
II, as well as acts on angiotensin type 2 receptors. Ang IV-angiotensin 3e8 hexapeptide exerts its actions via insulin-regulated amino peptidase
receptors (IRAP) with subsequent expression of inflammatory and immune mediators. Ang 1e9 (angiotensin 1e9 nanopeptide) is a precursor of Ang 1e7
via ACE 2 (homologue of ACE). Ang 1e7 (angiotensin 1e7 heptapeptide) acts via Mas receptors. Adapted from: Fyhrquist F, Saijonmaa O.
Renineangiotensin system revisited. J Intern Med 2008;264:224e36. Varagic J, Trask AJ, Jessup JA, et al. New angiotensins. J Mol Med
2008;86:663e71. Ferrario CM. New physiological concepts of the renineangiotensin system from the investigation of precursors and products of
angiotensin I metabolism. Hypertension 2010;55:445e52. ARB, angiotensin receptor II type 1 blocker; ICAM, intracellular adhesion molecule; IL, interleukin;
MCP, monocyte chemoattractant protein; PAI, platelet activation inhibitor-1; SNS, sympathetic nervous system; TNF, tumour necrosis factor.
Auron M, Harte B, Kumar A, et al. Postgrad Med J (2011). doi:10.1136/pgmj.2010.112987 3 of 10
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significant effect of ACEIs on cardiac autonomic regulation as
measured by baroreflex sensitivity. All patients had normal
cardiac function. Anaesthesia-related hypotension was defined
by SBP <90 mm Hg. Baroreflex sensitivity was estimated after
BP changes induced by injections of phenylephrine and nitro-
glycerin. Anaesthesia-related hypotension occurred in nine
patients in the ACEI group versus only two controls, and
they found a diminished response to phenylephrine in the
ACEI group. The authors determined that anaesthetic-induced
hypotension is mainly an effect of decreased adrenergic vaso-
constrictive response.31
A systematic review with random-effects meta-analysis (five
studies; N¼434 patients) found a greater likelihood of hypo-
tension requiring vasopressors at or shortly after induction of
anaesthesia in the setting of preoperative RAAS antagonist
administration on the day of surgery (RR 1.50, 95% CI 1.15 to
1.96). Despite this, the incidence of perioperative myocardial
infarction was not significantly different between groups
continuing or stopping RAAS antagonists (RR 0.41, 95% CI 0.07
to 2.53). It should be noted that this analysis was not controlled
for cardiac risk factors, as data were insufficient for subgroup
comparisons.32 In a subsequent large prospective observational
study of 12 381 patients undergoing non-cardiac surgery, with
similar cardiovascular and pulmonary comorbidities controlled
by propensity score matching, the concomitant use of diuretics
along with RAAS antagonists increased both intraoperative
hypotension and requirement for vasopressors compared with
ACEIs alone or when used in combination with calcium-channel
blockers. It should be noted that all hypertensive patients were
excluded from the study. There were no statistically significant
differences in postoperative renal failure or myocardial ischaemia
between patients receiving RAAS alone versus RAAS and
diuretics.33
A recent study addressing the effect of RAAS blockade on
30-day mortality was conducted by Railton et al. They demon-
strated an increase in postoperative 30-day mortality in patients
using RAAS inhibitors before surgery in an observational cohort
study of 883 consecutive patients undergoing elective open
abdominal aortic aneurysm repair. RAAS blockers were used
before surgery by 359 patients compared with 524 who did not.
The overall 30-day mortality was 3.5% (31/883 patients).
Analysis of 261 propensity score-matched pairs showed a 30-day
mortality of 6.1% (16/261) in the patients with RAAS blockade
compared with 1.5% (4/261) in the unblocked patients (OR 5.0,
95% CI 1.4 to 27; p¼0.008).34
Cardiac surgery
Most of the negative outcomes related to the use of RAAS
antagonists before cardiac surgery (regardless of whether the
patients undergo cardiopulmonary bypass (CPB)) are believed to
be related to the development of intraoperative hypotension
requiring vasopressor support35e37; however, other potential
adverse outcomes include intraoperative reduction in cardiac
output,38 postoperative decline in renal function,7 atrial fibril-
lation, and even death.8 39
Vasoplegic syndrome is a form of vasodilatory shock that can
occur after CPB. In a prospective study of 145 patients undergoing
CPB, two independent predictors of development of vasodilatory
shock after discontinuation of CPB were identified: ejection
fraction (EF) <35% (OR 11.9, 95% CI 2.7 to 53.1; p¼0.003) and
ACEI use (OR 9.1, 95% CI 2.1 to 38.8; p¼0.001). These patients
responded well to AVP infusions.40 In a subsequent retrospective
study (2002e2006) of 2823 adult cardiac surgery cases, Levin et al
found that 577 (20.4%) developed post-CPB vasoplegic syndrome;
these patients had an increased inpatient mortality and length of
stay >10 days (OR 3.30; 95% CI 1.44 to 7.57; p<0.005). The
preoperative use of ACEIs was associated with a modest increase
in the risk of vasoplegia (OR 1.37, 95% CI 1.04 to 1.80;
p¼0.026).38
In a study of 249 patients who underwent aortic surgery,
Cittanova et al found that 61 developed postoperative renal
impairment, defined as a 20% decrease in baseline glomerular
filtration rate (GFR), 7 days after surgery. Chronic treatment
with ACEIs was the only factor significantly associated with
postoperative renal impairment even after exclusion of patients
with EF <35% (OR 2.01, 95% CI 1.05 to 3.83; p¼0.034).7
The association of hypotension with intraoperative decrease in
cardiac output was described by Colson et al, who studied 16
hypertensive patients (eight receiving ACEIs, and eight receiving
a combination of other antihypertensive agents) who underwent
coronary artery bypass grafting (CABG) or vascular surgery. In
ACEI-treated patients, the hypotension was associated with
a consistent decrease in pulmonary capillary wedge pressure
(�26.4%; p¼0.035) and cardiac index (�23.9%; p¼0.001),
suggesting that the post-induction hypotension in patients using
ACEIs is secondary to poor cardiac output during acute decreases
in ventricular volume. Although the sample size was small, this
study is important in that it was the first to address the effect of
ACEIs on intraoperative cardiac output and to have used the same
anaesthetic technique in all patients to avoid confusing variables.35
A prospective non-randomised study to address the utilisation
of vasopressor therapy in patients taking ACEIs on CPB was
carried out by Tuman et al. In 4301 adults undergoing elective
coronary artery and/or valve surgery, they identified 519 patients
taking ACEIs before surgery, and 3782 that were not. Preopera-
tive ACEI use was identified as an independent risk factor for
multiple (>2) vasoconstrictor infusions after extracorporeal CPB
to keep SBP >85 mm Hg (OR¼1.53, 95% CI 1.05 to 2.25;
p¼0.0301).36
Deakin et al studied 62 sequential adult patients undergoing
cardiac surgery requiring hypothermic (288C) CPB. Twenty-one
patients were receiving ACEIs before surgery. Preoperative ACEI
therapy was associated with a significant decrease in systemic
vascular resistance during the rewarming phase of CPB
(p¼0.006) and increases in post-CPB vasoactive drug require-
ments (RR 3.32, 95% CI 1.43 to 7.71; p¼0.01). This study is
unfortunately limited by its small size, non-randomised design,
and inability to identify whether the hypotension was linked to
low systemic vascular resistance or low cardiac output.37
The effects of preoperative ACEI use in patients undergoing
CABG without CPB (off pump) were studied by Lee et al. They
compared 43 patients treated with ACEIs for at least 4 weeks
before surgery with 37 patients who did not receive ACEIs.
There was greater utilisation of vasoconstrictors in the ACEI
group especially during anastomosis of the obtuse marginal
branch of the left circumflex artery. The study was limited by its
relatively small sample size, non-randomised design, and pres-
ence of other multiple confounding factors such as diabetes and
hypertension which can affect haemodynamic parameters.41
Boeken et al studied 240 patients undergoing cardiac surgery
(CABG or valvular) and divided them in a non-randomised
fashion into three groups: group A used pre- and post-operative
ACEIs; group B used preoperative ACEIs only; group C used no
ACEIs. They did find a significant increase in intra- and post-
operative catecholamine use in the patients using preoperative
ACE (p<0.05). In the ACEI groups, nine patients developed
systemic inflammatory response syndrome compared with only
two cases in group C, suggesting that the vasodilatory effect of
4 of 10 Auron M, Harte B, Kumar A, et al. Postgrad Med J (2011). doi:10.1136/pgmj.2010.112987
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RAAS inhibition may predispose to ‘post-perfusion syndrome’
and systemic inflammatory response syndrome. Interestingly,
four patients in group B (no postoperative ACEI use) had
postoperative disturbances of the intestinal microcirculation,
suggesting that the withdrawal of ACEIs in patients with
chronic use may further predispose to microcirculation
derangements.42
A best evidence topic review addressing whether preoperative
cessation of RAAS antagonists in cardiac surgery permits
avoidance of postoperative vasodilatation was performed by
Raja and Fida. They initially examined 421 articles and ulti-
mately selected three randomised controlled trials and seven
large cohort and caseecontrol studies. The authors concluded
that preoperative administration of ACEIs and ARBs in patients
undergoing cardiac surgery contributes to a postoperative
decrease in systemic vascular resistance and vasoplegia, and
that withholding ACEIs and ARBs before cardiac surgery is
reasonable to avoid postoperative vasodilatation; however, the
evidence supporting this decision is weak.43
Miceli et al performed a retrospective observational cohort
study (1996e2008) of 10 023 patients undergoing isolated
CABG. Of these, 3052 patients receiving preoperative ACEIs
were matched with a control group by propensity score analysis.
Patients receiving preoperative ACEIs were more likely to have
an EF <50% (32.8% vs 20.2%). They found that preoperative use
of ACEIs was an independent predictor of mortality (OR 2.83,
95% CI 1.03 to 7.8; p¼0.04), was associated with an increased
risk of postoperative renal dysfunction (OR 1.7, 95% CI 1.22 to
2.38; p¼0.0002), was an independent risk factor for POAF (OR
1.33, 95% CI 1.17 to 1.51; p¼0.0001), and was associated with
increased use of inotropic support (OR 1.17, 95% CI 1.07 to 1.29;
p¼0.0001). The overall mortality was 1%. Preoperative ACEIs
were associated with a doubling of the mortality risk (1.3% vs
0.7%; OR 2.00, 95% CI 1.17 to 3.42; p¼0.013). The main limi-
tations of this study are its retrospective nature, the inability to
distinguish between the use of ACEIs and ARBs, and the lack of
information with regard to drug dose and timing.8
Magee et al developed a predictive risk algorithm to determine
the possibility of developing postoperative atrial fibrillation
using a database of 19 083 patients who underwent CABG
(1995e2006). Among the risk factors, the preoperative use of
ACE inhibitors was associated with a modest increase in the
development of POAF (OR 1.123, 95% CI 1.045 to 1.205;
p<0.001). However, it should be mentioned that the algorithm
had modest validation scores (receiver operating characteristic
curve area of 0.72 and concordance between observed and
predicted of 72.3%).39
In a recent large observational study, Rader et al evaluated the
relationship of preoperative use of RAAS inhibition with ACEIs
or ARBs within 24 h of surgery and the development of POAF in
patients undergoing CABG. Preoperative RAAS inhibition
occurred in 4795 patients versus 5757 who did not. In the
patients receiving RAAS inhibition, 1725 (36%) developed POAF
compared with 1908 (33%) (OR 1.13, 95% CI 1.05 to 1.25;
p<0.01). However, after propensity score matching, there was
no significant association between preoperative RAAS inhibition
and POAF (OR 1.05, 95% CI 0.95 to 1.16; p¼0.38).44
Postoperative renal failure
As described in the previous section, multiple studies have found
a relationship between the preoperative use of RAAS antagonists
and the development of postoperative renal failure.7 8
The effect of the chronic RAAS inhibition on postoperative
renal function was addressed by Arora et al in a retrospective
cohort study (2001e2005) of 1358 patients who underwent
cardiac surgery. The authors confirmed by multiple regression
and propensity scores model a 27.6% higher risk of postoperative
acute kidney injury (AKI) associated with preoperative use of
ACEIs/ARBs.45
In a retrospective study (2000e2002) of 1209 adult patients
undergoing coronary artery bypass graft, valve or combined
procedures, Kincaid et al found an incidence of perioperative
acute renal failure of 3.5%, with a 48% incidence of mortality for
the patients that developed renal failure. The most significant
risk factor for development of acute renal failure was the
preoperative use of ACEIs along with the intraoperative use of
aprotinin (OR 2.9, 95% CI 1.4 to 5.8; p<0.0001). Interestingly,
the effect of either drug alone was not significant. The proposed
mechanism of this relationship is attributed to an aprotinin-
mediated vasoconstriction of the afferent arteriole with subse-
quent reduction of the glomerular perfusion pressure in the
setting of an ACEI-promoted vasodilatation of the efferent
arteriole.46
Neuraxial anaesthesia
The studies described in the previous section occurred in the
setting of general anaesthesia with standard pharmacological
protocols. The haemodynamic effects of neuraxial anaesthesia
are related to the spinal level of anaesthesia; for instance, in
thoracic epidural anaesthesia, hypotension results from attenu-
ation of efferent sympathetic drive.47
The evidence on the effects of RAAS blockade in neuraxial
anaesthesia is limited and contradictory. It has been shown that,
in patients with preoperative use of ACEIs, there are increased
concentrations of vasopressin and norepinephrine in the early
phases of spinal anaesthesia that appear to attenuate the
hypotensive effect of RAAS blockade.48e50 However, multiple
cases of significant hypotension and bradycardia following
spinal anaesthesia in patients chronically treated with ACEIs
have been reported.51e55
Until further randomised studies are carried out to further
clarify the best practice, it appears safe to stop RAAS blockade
before spinal anaesthesia.
EVIDENCE SUPPORTING RAAS ANTAGONISTS IN THE
PERIOPERATIVE SETTING
Although the basis for withholding RAAS antagonists on the
morning of surgery is to avoid the risk of initial hypotension
after the induction of anaesthesia, before the study by Miceli
et al
8 there had been no significant adverse effects (eg, mortality)
related to the use of these agents reported in the literature. It
was considered that, in certain cases, the preoperative use versus
discontinuation of these agents should be factored into the
overall riskebenefit equation, as certain groups of patients
may benefit from its continuation (eg, systolic dysfunction,
uncontrolled hypertension).
As part of their Physicians’ Information and Education
Resource, the American College of Physicians supports the
cautious continuation of RAAS antagonists on the morning of
surgery, with the caveat that euvolaemia should be maintained.56
Some authors suggest the continuation of ACEIs in patients
with congestive heart failure, as the benefit may outweigh
the risksdespecially since hypotensive episodes are usually
responsive to volume expansion and vasoconstrictors.17 57
The most important described beneficial effects of the peri-
operative use of RAAS antagonists include neuroprotection,
improved haemodynamic stability, decreased POAF, limited
ischaemiaereperfusion injury and renal protection.
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Neuroprotection
Tohmo et al described the use of preoperative enalapril as part of
balanced hypotensive anaesthesia for cerebrovascular surgery.58
This is a technique in which controlled hypotension is used to
minimise intraoperative bleeding and the need for transfusional
support.59 Enalapril was associated with a decrease in the
hypertensive response to intubation, lowered the requirements
for postoperative vasodilators, and provided for more stable BP
control compared with placebo.58 The authors theorised that
preoperative fasting may be a more significant contributor to
perioperative hypotension, and that the hypotension after
induction of anaesthesia might be prevented by ensuring proper
intravascular volume rather than withholding ACEIs before
surgery.60
Haemodynamic stability
Sear et al measured the haemodynamic response to anaesthesia
induction followed by laryngoscopy and intubation in 103
patients; 83 were already receiving one of four antihypertensive
agents: ACEIs, BBs, CCBs and diuretics. Twenty-three patients
were naïve to treatment. BP, cardiac output and stroke volume
were monitored during induction of anaesthesia, intubation and
maintenance of anaesthesia. Induction of anaesthesia caused
hypotension and a decrease in cardiac output in all groups. Heart
rate decreased in patients taking ACEIs and diuretics (p<0.01),
and systemic vascular resistance decreased in patients taking
ACEIs and b blockers (p<0.05). BP and heart rate increased in all
groups after laryngoscopy and intubation (p<0.01), as did the
systemic vascular resistance in patients taking ACEIs, BBs and
diuretics (p<0.02). In the group of untreated patients, the
changes were similar. Comparison over time of all haemody-
namic variables showed no differences between all groups.61
Pigott et al studied 40 patients undergoing CABG on chronic
ACEI therapy; 20 patients continued ACEIs and 20 had
ACEIs suspended before surgery. There was no significant
difference between the groups in the frequency of hypotension
during anaesthesia; however, the group in which ACEIs was
withheld had postoperative hypertension that required the use
of vasodilators.62
Some authors advocate preoperative ACEIs for all CAGB
patients. Although intraoperative hypotension may develop,
there is a concomitant postoperative increase in cardiac output
and index.63
Decreased POAF
Ozaydin et al studied the effect of preoperative administration
of ACEIs or ARBs on the development of POAF in patients
undergoing cardiac surgery. The study involved 128 consecutive
patients (ACEIs (n¼49), ACEIs plus candesartan (n¼49), control
(n¼30)). The rate of POAF was higher in the control group
(33.3%) than the ACEI (12.2% (RR 0.34, 95% CI 0.12 to 0.93;
p¼0.03)) or ACEI plus candesartan (10.2% (RR 0.28, 95% CI
0.09 to 0.83; p¼0.02)) group.64
White et al evaluated the impact of preoperative ACEI or ARB
use in the development of POAF after cardiac surgery (CABG or
valvular surgery) in a cohort of 338 patients (51.8%; N¼175
received preoperative ACEIs or ARBs). The authors did not find
an association between preoperative use of ACEIs/ARBs and
reduction in POAF (adjusted OR 0.71, 95% CI 0.42 to 1.20).
They proposed that a larger number of patients would be needed
to further evaluate the impact of preoperative ACEI or ARB use
and POAF.65
A recent meta-analysis of 23 randomised control trials with
87 048 patients showed that RAAS antagonists decreased the
OR for AF by 33% (p<0.00001), especially among patients with
heart failure and those with hypertension and left ventricular
hypertrophy. However, this meta-analysis was not designed in
the perioperative context.66
The anti-arrhythmogenic potential of RAAS antagonists may
be due to a sympatholytic effect or the attenuation of electrical
and/or structural remodelling. RAAS antagonists also have
antihypertensive properties with subsequent decrease in atrial
and left ventricular end diastolic pressure. In addition, RAAS
antagonists help prevent hypokalaemia.67
Protection against ischaemiaereperfusion injury
Boldt et al randomised 88 patients undergoing CABG into four
groups of 22 patients each, to receive intravenous enalapril,
enoximone (a phosphodiesterase inhibitor), clonidine or placebo
(normal saline). The patients who received enalapril after
induction of anaesthesia and before CPB had lower levels of
cardiac enzyme release, suggesting that RAAS antagonists may
have a cardioprotective effect against ischaemiaereperfusion
injury.68 A similar finding was obtained by Benedetto et al in
patients undergoing CABG with CPB. They compared 245
patients who received preoperative ACEIs with 236 patients
who did not; the patients receiving preoperative ACE inhibitors
had lower postoperative troponin I concentrations (1.6 ng/ml
(95% CI 1.05 to 3.4) vs 2.4 ng/ml (95% CI 1.13 to 6.10);
p¼0.0006). Although not significant, there was also a decreased
rate of postoperative myocardial infarction (2.0% vs 4.2%;
p¼0.25) in patients receiving perioperative ACEIs.69
Licker et al allocated 20 patients into two groups: 11 patients
received intravenous enalapril 50 mg/kg and nine patients
received normal saline at the time of anaesthesia induction for
aortic surgery. After infrarenal aortic cross-clamping, the inves-
tigators found that the preoperative administration of enalapril
was associated with enhanced systemic oxygen delivery,
improved splanchnic perfusion and improved GFR 24 h after
surgery.70
Renal protection
Temporary withdrawal of RAAS antagonists may be expected to
increase RAAS activity. The potential loss of BP control may be
at the expense of impaired regional circulation as demonstrated
by several studies that show the preservation and even
improvement of renal function in patients receiving ACEIs
before surgery.17
In a randomised double-blind study, Colson et al compared
short-term (2 days) preoperative treatment with captopril with
placebo in 18 patients undergoing CABG. Captopril-treated
patients had improved renal plasma flow and GFR during bypass
compared with placebo-treated patients.71
In a study of 536 patients by Benedetto et al, the effect of
preoperative ACEIs on AKI (defined as a postoperative decrease
in GFR of >50% from the preoperative value) was evaluated
after CABG with CPB. Of the 536 patients, 281 received ACEI
inhibitors before surgery. The incidence of AKI was 6.4% in the
ACEI group and 12.2% in the control group (p¼0.02). The
incidence of AKI requiring dialysis was 2.4% in the ACEI group
and 6.3% in the controls (p¼0.03). The authors found that
preoperative ACEIs was associated with a decreased incidence of
postoperative AKI (OR 0.48, 95% CI 0.23 to 0.77; p#0.04) after
on-pump CABG surgery.72
Adverse consequences of RAAS antagonist cessation
The benefit of ACEIs in patients with systolic heart failure is
well documented. Groban and Butterworth recommend that
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ACEIs should be continued before surgery in patients with heart
failure in both cardiac and non-cardiac surgery, as the benefits
outweigh the potential risks. Careful expansion of intravascular
volume should occur before induction of anaesthesia, and any
brief episodes of hypotension should be treated with sympa-
thomimetics.17 In the case of refractory hypotension either
during non-cardiac surgery or on weaning from CPB during
cardiac surgery, vasopressin or vasopressin antagonists can be
used.18 73 Careful selection of anaesthetic agents less likely to
cause hypotension (eg, etomidate) as well as sequential admin-
istration of the anaesthetic agents may prevent or attenuate the
hypotensive response to anaesthesia.17 An important consider-
ation in the heart failure patient is the concurrent use of
multiple drugs, including antiarrhythmics such as amiodarone.
Mackay et al reported two cases of refractory hypotension in
anaesthetised patients under CPB who received amiodarone in
combination with ACE.74
There is very limited evidence about the perioperative conse-
quences of withdrawing RAAS antagonists in the setting of
heart failure with preserved EF (diastolic heart failure). Careful
haemodynamic monitoring of these patients, including strict
BP control, is recommended. It is important to avoid hyper-
tensive crises which may precipitate the development of flash
pulmonary oedema.75e77
OTHER RAAS ANTAGONISTSdTHE DIRECT RENIN
INHIBITORS
Because renin controls the rate-limiting step in the RAAS
cascade, the blockage of its receptors is an optimal target for
RAAS suppression. Aliskiren is the first direct renin inhibitor
approved by the Food and Drug Administration for treating
hypertension. It has a long half-life (30e40 h), as well as an
increased renal vasodilatory effect compared with ACEIs and
ARBs. However, owing to its low oral bioavailability (up to 90%
excreted unchanged in faeces), its terminal half-life is 24 h. It is
a second-line agent and generally considered a weak antihyper-
tensive. It should preferably be used in combination with
natriuretic agents or ARBs.78e82 No long-term outcome data on
its use are available at this time. Consequently, there are no data
to guide its use in the perioperative setting. However, we
hypothesise that, given its pharmacological properties, the last
dose should be given at least 24 h before scheduled surgery,
and clinical trials should be pursued to address its effect on
perioperative BP control and outcomes.
OTHER RAAS ANTAGONISTSdTHE ALDOSTERONE
ANTAGONISTS
The final pathway in RAAS is the stimulation of aldosterone
production and release from the zona glomerulosa of the adrenal
cortex. This hormone is a mineralocorticoid that increases the
renal absorption of water and sodium and enhances renal
potassium excretion. Its final effect is an increase in circulating
blood volume. Elevated concentrations of aldosterone are asso-
ciated with increased mortality in heart failure. In patients with
cirrhosis and portal hypertension, elevated concentrations of
aldosterone are associated with the development of ascites. The
pathophysiological mechanisms of aldosterone in heart failure
and portal hypertension are beyond the scope of this review.
However, given its deleterious effect in heart failure, aldosterone
blockade has emerged as a mainstay of treatment in advanced
heart failure (New York Heart Association class III and IV). Also,
because of its hyperkaliuric properties, the use of aldosterone
blockers are commonly used as ‘potassium-sparing’ diuretics.
There are two known aldosterone antagonistsdspir-
onolactone and eplerenone. The first one is well known as
a diuretic agent,83 and the second is used in patients who
develop heart failure after myocardial infarction, but may also be
used in patients with heart failure of any aetiology who are
intolerant of spironolactone. The evidence supporting the use
or discontinuation of spironolactone or eplerenone in the
perioperative setting is scant except for the recommendation of
continuation of these agents in patients undergoing resection of
aldosterone-producing tumours.
Given their mineralocorticoid antagonist activity, as well as
the diuretic effect of spironolactone, we recommend with-
holding these agents before surgery to minimise intraoperative
hypotension as well as electrolyte derangement, especially
hyperkalaemia.
CONCLUSIONS AND RECOMMENDATIONS
The use of RAAS antagonists (ACEIs/ARBs) has been associated
with a variable incidence of intraoperative hypotension after
induction of anaesthesia; at the present time, there is growing
evidence linking the preoperative use of these agents with
postoperative adverse effects including worsening of renal
function and even death.
In certain cases (eg, uncontrolled hypertension, systolic
dysfunction), continuation of RAAS antagonists may be
Main messages
< The renineangiotensinealdosterone system (RAAS) antago-
nists include: ACE inhibitors (ACEIs), angiotensin 1 receptor
blockers (ARBs) and aliskiren (direct renin inhibitor), as well
as the aldosterone antagonists (spironolactone, eplerenone).
< The preoperative use of RAAS antagonists is associated with
significant hypotensive episodes after induction of anaes-
thesia requiring the use of systemic vasopressor drugs.
< Recently, increased morbidity and mortality have been shown
in patients undergoing coronary artery bypass grafting who
continue ACE inhibitors before surgery.
< In patients who are using RAAS antagonists and will undergo
surgery, RAAS should be withheld one half-life before
induction of anaesthesia.
< If it is not possible to withhold RAAS antagonists before
induction of anaesthesia (eg, emergency surgery), the
anaesthesiologist should maintain adequate intravenous
volume and perform careful haemodynamic monitoring.
Current research questions
< A large prospective randomised controlled trial comparing the
preoperative administration versus withdrawal of ACE
inhibitors, angiotensin II receptor subtype 1 blockers and
placebo is required to further clarify the safety of the
preoperative use of these agents.
< Further studies should include the direct renin inhibitor
aliskiren.
< New insights in pharmacogenomics suggest the study of the
preoperative use versus discontinuation of RAAS antagonists
in different populations.
Auron M, Harte B, Kumar A, et al. Postgrad Med J (2011). doi:10.1136/pgmj.2010.112987 7 of 10
Review
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considered after a full discussion with the anaesthesiologist and
surgeon, along with maintenance of careful intraoperative
haemodynamic monitoring and adequate intravenous volume
status before induction of anaesthesia.
Temporary withdrawal of RAAS antagonists may prevent or
attenuate intraoperative hypotension and hypovolaemia. The
current practice in our institution is to avoid the use of ACEIs
and ARBs on the morning of surgery.
MULTIPLE-CHOICE QUESTIONS (TRUE (T)/FALSE (F); ANSWERS
AFTER THE REFERENCES)
1. The drug aliskiren is a direct renin inhibitor.
2. The vasodilatory actions of RAAS antagonists involve:
A. sympathetic blockade
B. decreased bioavailability of bradykinin, nitric oxide and
prostacyclins
C. inhibition of the direct and indirect vasoconstrictor effects
of angiotensin II
D. increased secretion of aldosterone
E. increased secretion of antidiuretic hormone
3. The preoperative administration of captopril 25 mg increases
the likelihood of hypotension following induction of anaes-
thesia compared with a dose of 12.5 mg
4. The preoperative use of ARBs is associated with an increased
frequency of refractory intraoperative hypotension compared
with ACEIs
5. The use of RAAS antagonists in non-cardiac surgery:
A. is not associated with an increased need for post-
induction vasopressor agents
B. may require the use of vasopressin and its analogues to
respond to hypotension that is refractory to adrenergic
agents
C. is associated with increased risk of death
D. is not associated with postoperative renal failure
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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Auron M, Harte B, Kumar A, et al. Postgrad Med J (2011). doi:10.1136/pgmj.2010.112987 9 of 10
Review
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ANSWERS
1. (T)
The RAAS antagonists include ACE inhibitors, angiotensin II receptor subtype 1
blockers and direct renin inhibitors (eg, aliskiren).
2. A (T); B (F); C (T); D (F); E (F)
The vasodilatory actions of RAAS antagonists involve multiple mechanisms, which
include direct sympathetic blockade, increased bioavailability of vasodilators such
as bradykinin, nitric oxide and prostacyclins, inhibition of the direct and indirect
vasoconstrictor effects of angiotensin II, and reduced secretion of aldosterone and
antidiuretic hormone leading to a decrease in salt and water reabsorption by the
kidney. Given the wide distribution of ACE in the body, the RAAS antagonists have
wide-ranging effects, secondary to the inhibition of various angiotensin peptides
as well as both renin and pro-renin receptors with endocrine, paracrine and
intracrine functions, which in turn regulate diverse physiological functions
3. (F)
McCarthy et al studied the effect of two doses of sublingual captopril (12.5 mg
and 25 mg) versus placebo administered 25 min before tracheal intubation in 40
patients. The patients receiving captopril had increased hypotension compared
with those receiving placebo (p<0.05) within 3 min of intubation; however, there
was no significant difference between the two captopril doses.
4. (T)
The different haemodynamic response between ACEIs and ARBs was
demonstrated by Brabant comparing the responses between patients treated
with beta-adrenergic blockers (BBs) and/or calcium channel blockers (CBs), ACEIs
or ARBs after induction of anaesthesia. The administration of ARBs was
associated with more common and more severe hypotensive episodes compared
with ACEIs, BBs and CBs.
5. A (F); B (T); C (F); D (T)
The most common adverse effect of the preoperative administration (within 10 h
of surgery) of RAAS antagonists is a significant fall in BP after induction of
anaesthesia. This hypotension may not respond to volume resuscitation alone and
may require the use of vasopressor agents. The hypotensive episodes seen with
RAAS antagonists are often refractory to adrenergic agents and vasopressin
analogues should be used. To date, the observed increase in hypotension has not
been directly linked to major cardiovascular complications (myocardial ischaemia,
heart failure), stroke, renal failure, length of stay in the intensive care unit or
increased mortality.
10 of 10 Auron M, Harte B, Kumar A, et al. Postgrad Med J (2011). doi:10.1136/pgmj.2010.112987
Review
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doi: 10.1136/pgmj.2010.112987
published online March 25, 2011Postgrad Med J
 
Moises Auron, Brian Harte, Ajay Kumar, et al.
 
practice
consequences and recommendations for
the perioperative setting: clinical
angiotensin system antagonists in−Renin
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