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Angiotensin Axis Blocking Drugs

In the Perioperative Period
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A
PRIYA A. KUMAR, MD

Resident-CA 2
University of North Carolina
Chapel Hill, North Carolina

Professor of Anesthesiology
University of North Carolina
Chapel Hill, North Carolina

Creative Commons schematic by A.Rad.

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ALAN SMELTZ, MD

The authors reported no relevant financial disclosures.

Introduction

rugs causing angiotensin axis blockade (AAB) include

d.

angiotensin-converting enzyme inhibitor (ACEI) and

angiotensin receptor blocker (ARB) agents. Due to the current

trend of an aging population combined with an ever-increasing

complexity of procedures, it is inevitable that these medications will be
commonly encountered in the perioperative patient.

A N E ST H E S I O LO GY N E WS F E B R UA RY 2 0 1 6

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The long-term use of AAB has been shown to reduce

vascular diseaserelated morbidity and mortality in
patients with hypertension, coronary artery disease,
congestive heart failure, diabetes, and chronic kidney
disease.1 However, in short-term situations of physiologic extremis, such as surgery and anesthesia, there
is controversy regarding the best practice for the perioperative management of AAB therapy. Currently,
there are no universal guidelines for the management
of refractory hypotension associated with these drugs
in the perioperative setting. In this review, we hope to
explore this area with the goal of identifying the best
evidence to aid perioperative decision making regarding patients on chronic AAB.

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a withdrawal hypertensive crisis on the day of surgery.

To add to the controversy, 3 large cohort studies
that evaluated long-term outcomes in patients on AAB
undergoing anesthesia arrived at remarkably conflicting
conclusions. Railton et al11 found increased mortality in
vascular surgery patients with the perioperative continuation of AAB. Toppin et al12 reported decreased mortality with the continuation of these drugs in noncardiac
surgical patients, whereas Turan et al13 found no difference in 30-day mortality in this population.
Additionally, there has been inconsistency regarding the association between perioperative AAB and
the development of end-organ damage. The incidence
of acute kidney injury (AKI) in patients on perioperative AAB undergoing vascular surgery,14 thoracic surgery,15 and orthopedic surgery16 has been shown to be
increased. However, the incidence of AKI in the same
population following cardiac surgery has been shown
in certain studies to be increased,17-19 unchanged,20 and
even decreased.21,22
Likewise, there has been a discrepancy in the
reported perioperative mortality of patients on AAB.
In different studies, mortality has been shown to be
increased,18,20,22 not different,13 or even decreased.23
Similarly, the development of atrial fibrillation in post
cardiopulmonary bypass (CPB) patients on perioperative AAB has been shown to be increased.20,24 However,
the evidence for these associated complications, overall, is weak and based primarily on observational data.

Controversies in Current Practice

Exaggerated hypotension in patients on AAB has

been well described in those undergoing elective noncardiac surgery,2-5 vascular surgery,6,7 and cardiac surgery.8,9 This decrease in blood pressure, usually within
30 minutes of induction of anesthesia,10 has classically
been more difficult to manage than typical general
anesthesiaassociated hypotension. As a result, there
has been an ongoing controversy as to whether AAB
should be withheld or continued prior to elective surgery. Whereas holding these medications may decrease
hypotensive episodes intraoperatively,10 some argue
that it could lead to a loss of their established long-term
benefits1 as well as the theoretical risk for precipitating

SNS, LBP, Lsodium

Renal JGA

Vasodilatory
bradykinin

ACEIs

Renin

Angiotensinogen

ARBs

Inactive

AT-I receptor: vasoconstriction, KAVP

ACE

AT-I

AT-II

AT-II receptor: less well understood

Posterior pituitary: KAVP

Adrenal cortex: Kaldosterone

Adrenal medulla: Kcatecholamines

d.

Inhibit cardiac vagal response

Enhanced response to circulating catecholamines

Figure. Renin-angiotensin-aldosterone system and mechanism of action of

angiotensin-converting enzyme inhibitors and angiotensin receptor blockers
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; AT-I, angiotensin I; AT-II, angiotensin II;
AVP, arginine vasopressin; BP, blood pressure; JGA, juxtaglomerular apparatus; SNS, sympathetic nervous system

A N E ST H E S I O LO GY N E WS .CO M

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Other well-known side effects of AAB include hyperkalemia and airway complications. Potassium levels rise
after initiation of AAB therapy to varying degrees in up
to 10% of patients, affecting patients with chronic kidney disease the most.25 In this subset of patients, preoperative assessment of potassium levels as a part of the
routine laboratory workup might help prevent electrolyte-associated cardiac dysrhythmias.
ACEI-associated airway issues such as cough, bronchospasm, and angioedema have also been described.
In some cases, these airway complications have been
reported to occur years after the initiation of an ACEI
regimen.26 However, a large, retrospective propensitymatched study did not identify a difference in the rate
of airway complications in patients on chronic ACEI
therapy undergoing noncardiac surgery.13

to AT-II by angiotensin-converting enzyme (ACE). AT-II

then acts at several sites. This chain of events, functioning to regulate blood pressure and maintain fluid and
electrolyte balance, is known as the RAAS.
ARBs prevent AT-II from binding the vasoconstricting AT1 receptors, thereby lowering blood pressure. Acting mechanistically upstream of ARBs, ACEIs prevent
both the conversion of AT-I to AT-II and the inactivation
of vasodilatory bradykinin. The accumulation of bradykinin itself is vasodilatory and therefore has a blood
pressurelowering effect.

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Guidelines

Pharmacology

The effects of AAB occur systemically as well as at

the tissue level. An understanding of the renin-angiotensin-aldosterone system (RAAS), pathways regulating vascular tone, and half-lives of antihypertensive
agents is important for management decisions regarding AAB and associated intraoperative hypotension.
The complex pharmacology of AAB is summarized
as a schematic in the Figure. Sympathetic stimulation
results in a release of renin from the juxtaglomerular
apparatus of the kidneys.10 Renin cleaves angiotensinogen to angiotensin I (AT-I), which is then converted

Many authors have attempted to consolidate the literature to offer advice regarding perioperative AAB.27-29
Most providers would consider withholding the regimen
on the day of surgery, especially if there is anticipated
hemodynamic instability based on either patient- or
surgery-related factors. The duration of holding the
ACEI or ARB preoperatively would depend on the
agents unique half-life and duration of antihypertensive effect (Table 1).30-33 The time to restart the medication is based on when the patient is hemodynamically
stable postoperatively.
On the other side of the argument, there has been
concern that withholding AAB might precipitate withdrawal hypertension on the day of surgery that might
itself lead to problems, such as case cancellations and
end-organ damage related to a hypertensive crisis.

Table 1. Half-life and Duration of Antihypertensive Effect of

Commonly Used ACEIs and ARBs

Duration of Antihypertensive Effect, hc,d

Captopril

1.7

6-10

Enalapril

11

18-30

Lisinopril

12

18-30

Ramipril

4-18

24-60

Candesartan

6-13

12

Losartan

1-3

11

Telmisartan

21-38

10

Valsartan

6-10

13

ARB

d.

t1/2, ha,b

ACEI

Brown and Vaughan, 1998.

Williams et al, 1988.

Israili, 2000.

Nishimura et al, 2005.

t1/2, half-life; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker

A N E ST H E S I O LO GY N E WS F E B R UA RY 2 0 1 6

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Although studies investigating reasons for case cancellations on the day of surgery34,35 list hypertension
as one of the major medical reasons (medical reasons
comprising 11% of case cancellation reasons), there have
not been any studies linking case-cancelling hypertension to the withholding of AAB. A randomized trial of
ambulatory patients that either withheld or continued
their AAB the day of surgery36 demonstrated no difference in preoperative rate of hypertension, number
of cases cancelled due to hypertension, postoperative
hypertension, hospital length of stay, or other adverse
events.
In light of the concerns regarding exaggerated perioperative hypotension in patients on AAB, the American College of Physicians initially had recommended
stopping ACEIs on the day of surgery. This recommendation has since evolved to uncertain, although they
are usually continued.37-39
The European Society of Cardiology and European
Society of Anaesthesiology 2014 guidelines on perioperative AAB40 recommend initiating AAB therapy in
heart failure patients not currently on AAB therapy at
least 7 days in advance of surgery, and continuing therapy on the day of surgery with close monitoring.
In patients on AAB for the management of hypertension, with documented episodes of hypotension,
the societies recommend considering holding the ACEI
or ARB on the day of surgery. Even more vague, the
latest American College of Cardiology and American
Heart Association guidelines pertaining to perioperative ACEI/ARBs41 state their continuation on the day of
surgery is reasonable (level of evidence B), and that if
held they should be restarted as soon as clinically feasible (level of evidence C). There is, however, no published statement of recommendations by the American
Society of Anesthesiologists.

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renin-angiotensin system, and arginine vasopressin

system. Pharmacologic blunting of one or more of the
vasoregulatory systems results in compensation by the
intact systems, in order to maintain stability.
Induction of general anesthesia causes hemodynamic
alterations by its effect on the sympathetic nervous
system. It results in a decrease in circulating catecholamines, reduced vascular tone, and blunting of the
reflex sympathetic activity in response to hypotension.
The body compensates for general anesthesiaassociated hypotension via the RAAS, the sympathetic nervous system (SNS), and the vasopressinergic system.24
Thus, as anesthesia impairs the SNS in a patient with
AAB, treatment with a vasopressin analog should theoretically overcome hypotension otherwise refractory to
traditional means of support, such as volume, ephedrine, and phenylephrine. Multiple prospective cohort
and randomized studies have corroborated this concept in the setting of vascular and cardiac surgery.42-47
In AAB-associated post-induction refractory hypotension, vasopressin analog boluses and norepinephrine infusions have been shown to be effective in raising
blood pressure, with vasopressin analogs having a more
rapid effect than norepinephrine.46 Prophylactic vasopressin analogs were shown to be effective in lowering post-CPB vasopressor requirement and shortening
subsequent intensive care durations of care.45 However,
laser Doppler of gastric mucosal perfusion suggested
that perfusion was decreased more with vasopressin
analogs than with norepinephrine, indicating that it
might be more prone to compromising gastrointestinal
microcirculation.47
Patients on AAB are in a predominantly parasympathomimetic state with a blunting of reflex
tachycardia response to hypotension.48 They have a
decreased responsiveness to exogenous catecholamines and lower levels of circulating arginine vasopressin and aldosterone.49 Patients on ACEI also have
decreased levels of AT-II. Hemodynamic effects of AAB
are summarized in Table 2.
Regardless of whether AAB medications have been
withheld on the day of surgery (depending on their halflives), the perioperative physician will likely be faced
with the problem of exaggerated hypotension. This is a
result of persistent tissue-based activity of these powerful drugs.7 The perioperative care of these patients
should be individualized accordingly. A low threshold
for invasive monitoring where indicated and adequate
volume loading may help prevent refractory hypotension with induction of anesthesia. Cautious titration of
induction drugs is important, with ready availability of
conventional and second-line pressor agents.
Pharmacologic agents considered as first-line
medications, such as phenylephrine and ephedrine,
have varying efficacy in the treatment of AAB-associated hypotension.2,4,7 In most cases, these agents
may be needed in higher than usual doses or might

Management of Hypotension

Hemodynamics are maintained by complex interactions between the cardiovascular system (preload,
afterload, contractility), the autonomic nervous system,

Table 2. Effects of Angiotensin Axis

Blockade

Decreased responsiveness to exogenous

catecholamines
Lower circulating levels of:
angiotensin II
aldosterone
arginine vasopressin

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Decreased reflex tachycardia in response to

hypotension

It would seem that members of the American Society

of Anesthesiologists would benefit from the publication
of a practice advisory or guideline based on a thorough
discussion addressing this topic. In the meantime, we
must remain mindful of the potential issues one might
encounter in practice and strive to do what is best in the
context of our individual patients. Until further evidence
is available, the authors believe that:
1. It is reasonable and less confusing for most patients
to continue AAB up to the day of surgery.
2. Regardless of whether AAB has been withheld on
the day of surgery, the perioperative physician
must be prepared to face the problem of refractory hypotension. Depending on the individual
situation, the physician should perhaps maintain
a lower threshold for the placement of invasive
monitors such as arterial catheters.
3. Euvolemia must be ensured by adequate preloading prior to the induction of anesthesia.
4. Gradual titration of induction agents such as propofol, or preferential use of relatively hemodynamically stable induction agents such as etomidate,
may be justified in these cases.
5. The choice of inhalational anesthetic is unlikely to
make a difference; however, desflurane has the
theoretical advantage of stimulating greater
sympathetic activity compared with isoflurane or
sevoflurane.
6. Higher doses of first-line agents (phenylephrine,
ephedrine, or glycopyrrolate) for the treatment
of perioperative hypotension may be necessary
in patients on AAB.
7. For refractory hypotension, additional therapy such
as vasopressin, norepinephrine, epinephrine, and
anticholinergics may be necessary.
8. Methylene blue (1-2 mg/kg), a competitive nitric
oxide antagonist, may be considered as a last
resort.

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be ineffective, necessitating a switch to an alternate

therapy.
Vasopressin is a peptide released in response to
hypotension, and changes in serum osmolality act via
V1 receptors, which cause vasoconstriction; V2 receptors, which result in antidiuresis in the kidneys; and V3,
which results in release of cortisol, angiotensin, and
natriuretic peptide. Synthetic vasopressin, with a halflife of 4 to 20 minutes, has been described as a secondline agent to treat refractory hypotension in AAB.
Catecholamines such as epinephrine, norepinephrine,
and dopamine have been efficacious in the treatment of
exaggerated hypotension. Studies have suggested that
norepinephrine may be better at preserving the heart
rate by avoiding reflex bradycardia.46,47
Anticholinergics such as atropine and glycopyrrolate
have been described as second-line agents used in conjunction with other agents to counter the parasympathomimetic state.
Methylene blue, a competitive nitric oxide antagonist, has a half-life of 40 minutes. It decreases the levels
of vasodilatory cGMP with a reported efficacy in situations of refractory hypotension.

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Conclusion

Despite all the questions that have been investigated

about perioperative use of ACEIs/ARBs, there remains
much to learn. In the absence of a randomized controlled trial, the risks associated with continuing or discontinuing AAB on the day of surgery are still unclear,
leaving conflicting data and much speculation:
Are there specific patient or surgical variables that
might help tease out who might benefit most from
withholding versus continuing perioperative AABs?
Are there benefits to maintaining AAB therapy throughout the perioperative period analogous to those
described with -blockers and statin medications?
Should we be initiating AAB therapy in heart failure
patients with a known scheduled surgery in the near
future?

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