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Update for Nurse Anesthetists
Pathophysiology and Management of AngiotensinConverting Enzyme Inhibitor–Associated Refractory Hypotension During the Perioperative Period
Andrea Thoma, CRNA, MS
Hypertension is a common chronic condition in many
patients requiring anesthesia. Pharmacologic therapy
is a mainstay of treatment for hypertension, with
angiotensin-converting enzyme (ACE) inhibitors being
a frequently prescribed class of drugs. The American
College of Cardiology and American Heart Association
2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery provide information on many drug classes used in the treatment
of hypertension; noticeably absent is a guideline for
ACE inhibitors. Literature demonstrates that practice
standards vary on whether ACE inhibitor regimens are
continued or withheld during the preoperative period.
When ACE inhibitor therapy is continued in patients
undergoing general anesthesia, varying degrees of
hypotension can be seen depending on confounding
Objectives
At the completion of this course, the reader should be
able to:
1.
Describe the factors that control short-term and
long-term blood pressure regulation.
2.Identify the therapeutic effects and side effects of
ACE inhibitors.
3.Understand the two types of hypotension associated with the preoperative use of ACE inhibitors.
4.Explain the pathophysiology of vasoplegic syndrome.
5.Discuss available treatment options for vasoplegic
syndrome.
Introduction
As many as 60 million Americans have been diagnosed
with hypertension (blood pressure ≥ 140/90 mm Hg).1
The prevalence of hypertension increases with advanced
patient variables and the type of surgical procedure.
In some instances, this hypotension can be refractory
to traditional interventions such as administration of a
fluid bolus, ephedrine, or phenylephrine. Vasopressin
and methylene blue have been found to be effective
treatments for ACE inhibitor–associated refractory
hypotension. With the prevalence of hypertension and
use of ACE inhibitors, anesthesia providers are likely
to encounter refractory hypotension of this nature. The
absence of guidelines regarding ACE inhibitors in the
perioperative period contributes to a lack of consistency in practice.
Keywords: Angiotensin-converting enzyme (ACE)
inhibitor, methylene blue, refractory hypotension,
vasoplegic syndrome, vasopressin.
age. There is often a delay in diagnosis and treatment
because of a lack of overt signs and symptoms associated with hypertension. The development of ischemic
heart disease, congestive heart failure, and atherosclerosis leading to stroke and renal failure can occur with
long-standing hypertension. Pharmacologic therapy with
various classes of antihypertensive drugs is a mainstay
of treatment when diet and exercise do not lower blood
pressure to acceptable values.
Angiotensin-converting enzyme (ACE) inhibitors are
commonly prescribed antihypertensives. This class of
drugs is advantageous for control of blood pressure
because of its many other therapeutic effects often of
value to patients with hypertension.2 When ACE inhibitors are taken within 8 to 24 hours of general anesthesia,
intraoperative hypotension is more likely.3 This hypotension can occur following the induction of anesthesia and
AANA Journal Course No. 33 (Part 1): AANA Journal course will consist of 6 successive articles, each with objectives for the
reader and sources for additional reading. At the conclusion of the 6-part series, a final examination will be published on the AANA
website and in the AANA Journal. This educational activity is being presented with the understanding that any conflict of interest
on behalf of the planners and presenters has been reported by the author(s). Also, there is no mention of off-label use for drugs
or products.
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can occasionally be refractory to standard treatments
such as administration of a fluid bolus, ephedrine, or
phenylephrine.3-7 In addition, continued preoperative
use of ACE inhibitors can be associated with a more
profound and persistent hypotension in surgical patients
undergoing cardiopulmonary bypass (CPB). This form of
ACE inhibitor–associated refractory hypotension is a type
of a vasodilatory shock known as vasoplegic syndrome
(VS).8-10 Vasopressin and methylene blue have emerged
as treatment options that are effective in the treatment of
VS.9,11-13 Bolus doses of vasopressin agonists have been
used successfully for the treatment of ACE inhibitor–associated hypotension following induction of anesthesia.4-7
Anesthesia providers are certain to encounter hypertensive patients being treated with ACE inhibitors.
Unfortunately, unequivocal guidelines regarding the preoperative administration of ACE inhibitors and perioperative management of ACE inhibitor–associated refractory
hypotension do not exist, most likely because of a paucity
of research and the variability with which ACE inhibitor–
associated refractory hypotension manifests, especially
as it relates to its incidence and severity. Owing to the
lack of definitive guidelines, anesthesia providers must
understand the pathophysiology of hypertension and the
implications related to ACE inhibitors and anesthesia.
Physiology of Short-term Blood Pressure
Regulation
Knowledge of mechanisms that contribute to hemodynamic stability is necessary to understand the dysfunction that occurs when hypertension exists. Regulation
of blood pressure is required to maintain homeostasis
and involves short- and long-term regulatory mechanisms. An area of the brain termed the vasomotor center
governs primary control of the cardiovascular system.
The vasomotor center regulates the autonomic nervous
system, thus influencing vasoconstriction and vasodilation.1 Short-term regulation involves neural reflexes and
hormones. These adaptations respond to acute decreases
in mean arterial pressure (MAP) and restore MAP to 50
to 120 mm Hg within 30 minutes.1
There are 6 types of reflexes that influence short-term
regulation of blood pressure: (1) atrial stretch reflex,
(2) baroreceptor reflex, (3) chemoreceptor reflexes,
(4) Cushing reflex, (5) celiac reflex, and (6) oculocardiac reflex. The atrial stretch reflex, also known as the
Bainbridge reflex, occurs when the atria are stretched in
response to hypervolemia.14 Reflex stimulation causes
vascular smooth muscle vasodilation, increased heart
rate, decreased systemic vascular resistance (SVR), and
decreased MAP.14 Associated with the atrial stretch reflex
is the release of atrial natriuretic factor, which causes
dilation of renal vasculature leading to increased glomerular filtration and decreased secretion of antidiuretic
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hormone (ADH), resulting in diuresis and a further decrease in MAP.1
Baroreceptors in the aortic arch and carotid sinus
also contribute to short-term regulation through activation or inhibition of neural impulses to the vasomotor
center in the presence of hypotension or hypertension
respectively.14 Over time, baroreceptors adapt to higher
blood pressures, making this reflex less effective in longterm regulation.1 In addition, the baroreceptor reflex is
blunted by the use of volatile anesthetics.1
Central chemoreceptors in the medulla and peripheral chemoreceptors in the carotid and aortic bodies
contribute mostly to respiratory system regulation, but
also have a lesser role in the short-term regulation of
MAP.15 Stimulation of central chemoreceptors is associated with increased levels of hydrogen ions in the
blood, and stimulation for peripheral chemoreceptors
is primarily due to hypoxia.15 The circulatory response
seen with stimulation of chemoreceptors is an increase
in sympathetic nervous system activity accounting for the
increase in MAP.15
The Cushing reflex is also a short-term regulatory
mechanism that occurs with increases in intracranial
pressure.1 With increased intracranial pressure, the sympathetic nervous system is stimulated, thereby increasing
MAP in an effort to maintain cerebral perfusion pressure.
Finally, the celiac and oculocardiac reflexes cause
hypotension and reflex bradycardia when traction is
applied to the thoracic or abdominal mesentery and extraocular muscles, respectively.1
Also contributing to short-term regulation are hormones, notably norepinephrine, epinephrine, ADH, and
angiotensin II. Although hormones have a slower onset
compared with the neural reflexes, they are still capable of
restoring MAP to normal limits within 30 minutes.1 The
central nervous system and adrenal medulla are responsible for releasing norepinephrine and epinephrine in response to sympathetic stimulation, resulting in vasoconstriction and increased MAP.1 Two additional hormones,
ADH and angiotensin II, further contribute to short- and
long-term regulation. As mentioned for its role in the
atrial stretch reflex, ADH is a potent hormone released
from the posterior pituitary gland that increases MAP
through vasoconstriction.1 The role of ADH in long-term
regulation is through water reabsorption in the collecting
ducts of the kidney, thus promoting fluid retention.16
Angiotensin II, a powerful vasoconstrictor, is part of
the renin-angiotensin-aldosterone system (RAAS), which
contributes to regulation of MAP and blood volume.16
Physiology of Long-term Blood Pressure
Regulation
The goal of long-term blood pressure regulation is
euvolemia.1 The kidneys are the predominant organ
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Figure 1. Renin-Angiotensin-Aldosterone System
Abbreviations: MAP, mean arterial pressure; Na+, sodium.
(Adapted from Cheung.17)
through which euvolemia is achieved, with the RAAS
being of utmost importance. When hypotension, sodium
depletion, or sympathetic nervous stimulation occurs, the
juxtaglomerular cells of the kidney secrete the enzyme
renin.16 Renin interacts with circulating angiotensinogen,
a serum glycoprotein produced by the liver, to form the
hormone angiotensin I.16 Angiotensin I is biologically
inactive, with the majority of angiotensin I converted to
angiotensin II in the lungs by ACE.16 Angiotensin II is not
only a potent vasoconstrictor, but also a stimulus for the
production and release of aldosterone from the adrenal
cortex.16 Aldosterone, the primary mineralocorticoid of
the body, promotes sodium reabsorption, water retention,
and potassium secretion in the distal tubules and collecting ducts of the kidney, thus increasing MAP16 (Figure 1).
The complex interactions of blood pressure regulation make identifying a specific dysfunction as the
primary cause of hypertension difficult. An immense
amount of intertwined physiology exists between and
within short- and long-term regulatory mechanisms.
Owing to this complexity, a variety of pharmacologic
agents with differing mechanisms of action can be used
to treat hypertension.
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ACE Inhibitor Pharmacology
Multiple classes of drugs exert their effects by inhibiting
a specific phase of the RAAS; ACE inhibitors are one of
these classes. The primary mechanism of action of ACE
inhibitors is competitive antagonism of the conversion of
angiotensin I to angiotensin II.17 Another proposed contributing mechanism of action is the inhibition of bradykinin catabolism.17 Bradykinin is a peptide that promotes
the release of nitric oxide (NO) from endothelial cells,
resulting in vasodilation of vascular smooth muscle and
thereby contributing to a decrease in MAP.17 The ending
“-pril” in the generic form makes drugs of this class easily
recognizable. With the exception of fosinopril, which
is metabolized by the liver, all other ACE inhibitors
undergo primary renal excretion.17 The average half-life
of commonly prescribed ACE inhibitors is approximately
10 hours, which explains why withholding ACE inhibitors for 8 to 24 hours preoperatively tends to decrease the
incidence of hypotension.3
The ACE inhibitors are commonly prescribed for
their many additional therapeutic effects, including
stabilization of atherosclerotic plaques, inhibition of
left ventricular hypertrophy, prevention of myocardial
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remodeling, decreased SVR, decreased platelet aggregation, decreased intraglomerular pressure, decreased
fluid retention, increased insulin sensitivity, and antiinflammatory properties.2 Another advantage of ACE inhibitors is the minimal development of tolerance to their
antihypertensive effect.18 Unlike other classes of antihypertensive drugs, ACE inhibitors do not cause orthostatic
hypotension, rebound hypertension with missed doses,
or insomnia.18
The ACE inhibitors are not without side effects, with
a persistent dry cough a common occurrence. The cause
of cough is proposed to be the result of increased levels
of bradykinin.19 Other side effects include hypotension,
especially with the first dose; angioedema; rash; leukopenia; renal impairment; and an altered sense of taste.17
It should be noted that upper airway angioedema can be
life threatening. Recognized drug interactions with ACE
inhibitors include hyperkalemia when combined with
a potassium-sparing diuretic, increased risk of renal
complications when combined with nonsteroidal antiinflammatory drugs, and decreased antihypertensive
effect when oral contraceptives are also prescribed.17
If a woman taking an ACE inhibitor becomes pregnant, an alternative class of antihypertensives that is
not teratogenic should be prescribed.17 ACE inhibitors
should be avoided in volume-depleted patients and in
the presence of decreased renal perfusion because of the
potential for renal complications.20 Anesthesia providers should recognize ACE inhibitors when they are part
of a patient’s medication regimen and inquire about the
timing of the last dose.
Postinduction ACE Inhibitor–Associated
Hypotension
Patients with hypertension have been observed to have an
increased incidence of hypotension and labile blood pressure during general anesthesia. It remains controversial
whether intraoperative hypotension is more frequently
observed in hypertensive patients treated with ACE inhibitors compared with other antihypertensive drugs.3,21
Two types of hypotension associated with the preoperative use of ACE inhibitors within 8 to 24 hours of
general anesthesia have been documented. They include
intraoperative hypotension following induction of anesthesia or a more profound and persistent hypotension
in patients undergoing surgery that requires CPB. Some
literature supports that hypotension is more likely to
occur after induction among patients who continue their
ACE inhibitor preoperatively and even more likely when
antihypertensives from multiple drug classes or diuretics
are taken.3,22 In some studies, ACE inhibitor–associated
hypotension following induction was refractory to standard treatments.3-7 After the 30-minute postinduction
phase, the incidence of intraoperative hypotension was
similar whether an ACE inhibitor was withheld or taken
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the day of surgery.3 The sympathetic nervous system,
the RAAS, and the vasopressin system are 3 endogenous
vasopressor systems in the body.4 When one of these
systems is inhibited, the body is able to compensate and
effectively prevent hypotension. The cause of ACE inhibitor–associated refractory hypotension is the inhibition
of the sympathetic nervous system by anesthetic agents
and also the blockade of the RAAS by ACE inhibitors.4
With 2 of the endogenous vasopressor systems inhibited,
the likelihood of hypotension increases and treatment of
hypotension can be more difficult. Since the vasopressin
system is the only functioning endogenous vasopressor
system, this explains why vasopressin and vasopressin
agonists are effective in treating ACE inhibitor–associated refractory hypotension.
The American College of Cardiology and American
Heart Association 2007 Guidelines on Perioperative
Cardiovascular Evaluation and Care for Noncardiac
Surgery detail specific guidelines for continuing or
withholding several classes of antihypertensives in the
perioperative period.23 Noticeably lacking is an unequivocal statement for the perioperative use of ACE
inhibitors. Some recommendations suggest withholding
ACE inhibitors the day of surgery and resuming therapy
once normal intravascular volume has been restored to
prevent renal dysfunction.23 Withholding of ACE inhibitors preoperatively remains controversial because not all
patients develop ACE inhibitor–associated hypotension
during anesthesia.21,24,25
Pathophysiology of Vasoplegic Syndrome
Refractory hypotension associated with ACE inhibitors
can be seen in patients undergoing surgery that requires
CPB, although this topic remains controversial in the
literature as well.25 Vasoplegic syndrome is a form of
vasodilatory shock characterized by hypotension and
decreased central venous pressure, decreased SVR, and
normal cardiac output after the discontinuation of CPB.13
A distinguishing characteristic of VS is the inability to
correct hypotension after adequate fluid resuscitation
and administration of vasopressors.10 The incidence of
VS following cardiac surgery is approximately 9% to
10%.13 Prolonged CPB times, inadequate left ventricular
function, and preoperative administration of ACE inhibitors, intravenous heparin, and calcium channel blockers
contribute to the development of VS.9,13 Specifically,
ACE inhibitors have been reported to increase the incidence of VS by up to 44%13
Three possible mechanisms have been theorized to
explain the pathophysiology of VS: (1) activation of
adenosine triphosphate–sensitive potassium channels,
(2) activation of the inducible form of NO synthase, and
(3) ADH deficiency.10 Adenosine triphosphate–sensitive
potassium channels in vascular smooth muscle are activated, making the cells more negative (hyperpolarized),
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thus preventing the entry of calcium into the cells.10
Without an influx of calcium, vascular smooth muscle
contraction cannot occur.
A second contributing factor to VS is activation of the
inducible form of NO synthase, the enzyme responsible
for catalyzing the reaction to form NO.10 When NO is
synthesized and released, the enzyme guanylate cyclase
is activated, thereby causing an increase in the second
messenger cyclic guanosine monophosphate.10 In turn,
cyclic guanosine monophosphate results in vasodilation
of vascular smooth muscle.
The third proposed mechanism for the hypotension
seen with VS is a deficiency of ADH.10 In the early stages
of VS, circulating levels of ADH are elevated.10 As the
condition progresses, ADH levels decrease, possibly due
to depleted hormone stores in the posterior pituitary
gland or as a result of prolonged baroreceptor reflex
stimulation.10
In addition, bradykinin contributes to ACE inhibitor–
associated hypotension when CPB is used. As previously
discussed, bradykinin results in vasodilation of vascular
smooth muscle. Circulating levels of bradykinin are elevated with the use of ACE inhibitors and are further increased during CPB because the lungs are not functional
and therefore are unable to break down the peptide.13
Treatment of ACE Inhibitor–Associated
Refractory Hypotension
Vasopressin and methylene blue have been documented
as treatment options for VS. An endogenous stress
hormone, vasopressin, also known as arginine vasopressin or ADH, is secreted from the posterior pituitary
gland in response to decreased MAP, decreased plasma
volume, and increased plasma osmolality.26 Vasopressin
receptors (V1, V2, and V3) have the specific functions
of vasoconstriction, osmoregulation via insertion of
aquaporin channels in the kidney, and hypothalamic
secretion of adrenocorticotropic hormone, the precursor
to vasopressin, respectively.26 Vasopressin is most commonly administered as a continuous infusion because of
its short plasma half-life of 4 to 20 minutes.26 A study
reported in 2010 showed improved hemodynamics after
coronary artery bypass grafting when a low-dose vasopressin infusion of 0.03 U/min was used during the
perioperative period in patients with ejection fractions
of 30% to 40% and who also continued taking their ACE
inhibitors.9 Should VS develop after CPB, 0.01 to 0.1 U/
min of vasopressin can be given as a continuous infusion
with minimal side effects.9
Unfortunately, literature regarding the use of intravenous bolus doses of vasopressin for the treatment
of ACE inhibitor–associated refractory hypotension is
limited. Several articles document the use of 1-mg
intravenous bolus doses of terlipressin, a vasopressin
agonist not available in the United States, as effective in
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treating intraoperative ACE inhibitor–associated refractory hypotension.4-7 The administration of terlipressin in
combination with ephedrine has been shown to correct
hypotension more rapidly than when either drug is
administered alone.4 Similarly, bolus doses of terlipressin more rapidly corrected hypotension compared with
an infusion of norepinephrine.7 Guidelines for treating
ACE inhibitor–associated refractory hypotension with
intravenous bolus doses of vasopressin agonist that are
available in the United States are lacking. Side effects of
vasopressin and vasopressin agonists are dose-dependent
and include decreased organ perfusion, especially to the
kidneys, liver, and mesentery due to increased SVR.6,26
Myocardial ischemia and cardiac arrest with higher doses
can occur due to increases in SVR resulting in decreased
cardiac output, decreased myocardial oxygen delivery,
and increased myocardial oxygen demand.6,26
Methylene blue has been documented as effectively
treating VS in the postoperative period and when given
preoperatively for patients at high risk for VS.11-13 The
use of methylene blue for treating ACE inhibitor–associated hypotension following the induction of anesthesia
that is refractory to standard treatments has not been
documented. The mechanism of action for methylene
blue involves competition with NO for binding sites on
guanylate cyclase.13 When methylene blue binds to guanylate cyclase, cyclic guanosine monophosphate levels
do not increase and vascular smooth muscle vasodilation
is inhibited.13 Methylene blue can be given as an intravenous infusion of 2 mg/kg infused over 20 minutes.13
It has been documented that this dose has reversed VS
in approximately 2 hours.13 Research is limited on the
use of methylene blue as a continuous infusion. Like
vasopressin, side effects of methylene blue are dose-dependent. Transient arrhythmias and angina can occur, as
can decreased cardiac output, decreased perfusion to the
kidneys and mesentery, and increased pulmonary vascular resistance.13 Discoloration of the urine and skin can
occur but is usually self-limiting.13 The administration of
methylene blue causes interference with the light emission necessary for accurate pulse oximetry readings,13
and falsely low readings will be observed. Use of methylene blue is contraindicated in patients with severe renal
insufficiency and should be used cautiously in patients
with a deficiency of glucose-6-phosphate dehydrogenase
because of the risk of hemolytic anemia.13
Conclusion
The number of patients with hypertension undergoing surgery continues to increase. Patients are often
prescribed 1 or more antihypertensive medications;
therefore, anesthesia providers must be aware of the interactions between anesthesia and specific drug classes
of antihypertensives. Unlike other classes of antihypertensive drugs, an unequivocal guideline for continuing
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Figure 2. Postinduction ACE Inhibitor–Associated Refractory Hypotension Treatment Algorithm
Abbreviation: ACE, angiotensin-converting enzyme.
a Insufficient evidence to provide specific dosing guidelines for use of vasopressin or methylene blue for the use of ACE inhibitor–
associated postinduction refractory hypotension.
Figure 3. VS Treatment Algorithm
Abbreviations: ACE, angiotensin-converting enzyme; VS, vasoplegic syndrome; CPB, cardiopulmonary bypass.
a Insufficient evidence to support the use of intravenous bolus doses of vasopressin for treatment of VS.
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or withholding ACE inhibitors in the preoperative period
has not been established, contributing to a potential lack
of consistency and uncertainty in clinical management.
The continued use of ACE inhibitors within 8 to
24 hours of general anesthesia can result in 2 types of
hypotension: (1) intraoperative hypotension following
the induction of anesthesia or (2) a more profound and
persistent hypotension in surgical patients undergoing
CPB. These 2 types of hypotension can be refractory to
standard treatments. A continuous infusion of vasopressin has been used successfully in the treatment of VS, and
intravenous bolus doses of terlipressin have been used
successfully in treating intraoperative refractory hypotension following induction. Terlipressin is not available
in the United States, and comparative doses of available
vasopressin agonists for this purpose have not yet been
documented. Methylene blue has been used successfully
in the treatment of VS in the postoperative period and
preoperatively for patients at high risk for developing VS.
The literature is lacking on the use of methylene blue for
the treatment of intraoperative ACE inhibitor–associated
refractory hypotension following induction.
Guidelines have not been established for vasopressin
and methylene blue as treatment options for either type
of ACE inhibitor–associated refractory hypotension, although several studies show their effectiveness. Without
guidelines, managing ACE inhibitor–associated refractory hypotension is also lacking consistency and contributing to uncertainty in clinical practice. To promote
consistency and evidence-based practice, a potential
treatment algorithm for managing ACE inhibitor–associated refractory hypotension is proposed based on the
current literature (Figures 2 and 3).
7. Boccara G, Ouattara A, Godet G, et al. Terlipressin versus norepinephrine to correct refractory arterial hypotension after general anesthesia
in patients chronically treated with renin-angiotensin system inhibitors. Anesthesiology. 2003;98(6):1338-1344. doi:10.1097/00000542200306000-00007.
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AANA Journal
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April 2013

Vol. 81, No. 2
AUTHOR
Andrea Thoma, CRNA, MS, is a staff nurse anesthetist at Loyola University Medical Center, Maywood, Illinois. At the time this article was
written, she was a student at Rosalind Franklin University of Medicine
and Science, Nurse Anesthesia Program, North Chicago, Illinois. Email:
[email protected].
ACKNOWLEDGMENTS
I thank Susan McMullan, CRNA, MSN, for being a mentor during my
work on this project. A special thank you to Jennifer Garcia Wojtczak,
MD, for helping develop my interest in the topic of this article. To Sandra
L. Larson, CRNA, PhD, APN, thank you for your ongoing support and
encouragement during my anesthesia training.
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