SHOULD THE ANGIOTENSIN II

ANTAGONISTS BE DISCONTINUED
BEFORE SURGERY?

A study from Anaethesia Analgesia Journal (Jan 2001)

Michèle Bertrand, MD, Gilles Godet, MD, Karolin

Meersschaert, MD, Luc Brun, MD, Eduardo Salcedo, MD,
and Pierre Coriat, MD.
 Angiotensin II antagonists (AIIA) are part of a new rational
treatment of hypertension (HT). AIIA interfere with the renin-
angiotensin system by inhibiting angiotensin II from binding to its
receptor, resulting in increased angiotensin II and normal bradykinin
plasma levels.

Brabant et al. found a more frequent incidence of hypotension

during induction of anesthesia in patients chronically treated with
AIIA, in comparison with matched patients receiving ß-adrenergic
blocking drugs, calcium-channel blockers, or ACEI. In these studies,
in contrast with other drugs, ACEI were discontinued by the
anesthesiologist on the day before the operation. Moreover, an
important result of this study was to clarify that the hypotension
observed in the patients treated with AIIA was less responsive to
conventional vasopressors such as ephedrine or phenylephrine.
 The aim of this prospective randomized study was to
compare hemodynamics during induction of anesthesia in
patients chronically treated with AIIA versus those of
patients not receiving this drug on the morning before
operation.

Our hypothesis is that the incidence and the severity

of hypotension during induction of anesthesia are less
when AIIA are discontinued on the day before the
anesthesia.
METHODS
Patients chronically treated with AIIA for HT during the
previous 3 months and scheduled for elective major vascular
surgery were included.

Thirty-seven patients were enrolled in this prospective

randomized study and gave informed consent after approval
of the study by the Ethic Committee .

Patients were randomly assigned to one of the study

groups .
 Patients were randomized in 2 groups as follows:
GroupI, AIIA discontinued on the day before surgery (n = 18);
and Group II, AIIA given 1 h before anesthesia (n = 19).

SURGICAL CHARACTERISTICS
Group I (AIIA Group II (AIIA
withdrawn) given)
Type of surgery
Carotid endarterectomy 9 10
Abdominal aortic repair 6 7
Infrainguinal 3 2
revascularization
P = not significant.
 Exclusion criteria : severe heart failure (stages III-IV of the
New York Heart Association), severe renal insufficiency (creatinine
plasma level more than 200 µmol/L), and patients chronically
treated with ACEI.

In all patients, premedication consisted of PO midazolam 5

mg. Patients received their cardiovascular medication on the
morning before the operation. A radial catheter was inserted before
induction and patients were monitored with continuous ST-T
analysis. After a 10 mL/kg crystalloid infusion and breathing 100%
oxygen, patients received sufentanil 0.4 µg/kg, propofol 1.5 mg/kg,
and atracurium 0.5 mg/kg IV.

Mechanical ventilation was performed using a mixture of

50% N2O in oxygen. Maintenance of anesthesia consist of
isoflurane administration. Boluses of sufentanil were administered
intraoperatively as needed.
 INDUCTION CHARACTERISTICS

Group I Group II
(AIIA withdrawn) (AIIA given)

Dose of propofol (mg) 110 ± 40 120 ± 40

Dose of sufentanil (µg) 33 ± 9 32 ± 10
Intravascular fluid volume 980 ± 220 840 ± 260
expansion (mL)

P = not significant.
 Hemodynamic variables were recorded each 1 min,
from 10 min before the induction of anesthesia, and during
at least the next 30 min. Hemodynamic study ended at
incision.

During the procedure, systolic blood pressure and

heart rate were maintained within 30% of baseline values
(defined as the average of three repeated measures on the
day before surgery), using IV fluid administration and
vasoconstrictors (e.g., ephedrine, phenylephrine, or
terlipressin).
HEMODYNAMIC EVENTS WERE DEFINED AS FOLLOWS:
• Hypotension: systolic blood pressure value less than 80 mm Hg lasting
more than 1 min,

• Hypertension: systolic blood pressure value more than 160 mm Hg lasting

more than 1 min,

• Tachycardia: heart rate (HR) value more than 90 bpm lasting more than 1
min,

• Bradycardia: HR value less than 40 bpm lasting more than 1 min.

• Refractory hypotension: SBP that did not remain more than 100 mm Hg
after the administration of either 6 mg of ephedrine until 24 mg (if HR less
than 60 bpm) and/or 100 µg of phenylephrine until 300 µg (if HR more than
60 bpm).

• Terlipressin, an agonist of the vasopressin system, is effective in rapidly

restoring arterial blood pressure in patients chronically treated with ACEI or
AIIA who presented with refractory hypotension after the induction of
anesthesia, without a detrimental effect in left ventricular function. A bolus of
1 mg of terlipressin is repeated once or twice as necessary.
 The number and duration of hemodynamic events were
collected, and total doses of vasoactive drugs were noted in each
group.

After surgery, patients were transferred to our recovery

room. Treatments for HT were orally continued in the
postoperative period. Hemodynamic events such as HT (more
than 130% of control value) were treated with a bolus of
nicardipine 1 mg or titrated esmolol when associated with
increased HR (more than 85 bpm) or clonidine.

Postoperative myocardial ischemia, defined as a ST

depression > 1 mm at 60 ms after the J point, was treated with
diltiazem, or nitrates in case of poor left ventricular function.
Postoperative analgesia included paracetamol administration and
morphine administered by patient-controlled analgesia.
Postoperative period ended at discharge.
Postoperative cardiac complications were defined as
follows:
Congestive heart failure, pulmonary edema, cardiac death, supraventricular
arrhythmia, ventricular arrhythmia, new Q-wave or ST-T depression longer
than 48 h on twice-daily 12-lead electrocardiogram, associated or not with
clinical findings such as circulatory failure with the need for catecholamines,
or a decrease in global or regional function on echography, or an increase of
cardiac troponin I (cTnI). cTnI was measured at recovery and on the first,
second, and third postoperative days, using an immunoenzymofluorometric
assay on a Stratus autoanalyzerTM . Normal values are 0–0.5 ng/mL.

Statistical analysis was performed by using NCSS 6.0TM software .

Hemodynamic variables were analyzed using analysis of variance and
paired-t-test; clinical characteristics of the patients, hemodynamic events,
and use of vasoactive drugs were analyzed using paired-t or K2 tests when
appropriate, and normality of the variables were checked by using the
Kolmogorov-Smirnov test.
RESULTS
The two groups were comparable in age, sex ratio, and
main preoperative characteristics.

CLINICAL CHARACTERISTICS OF THE PATIENTS

Sex ratio (male/female) 15/3 15/4 NS
Age (yr) (mean ± sd) 68 ± 11 68 ± 13 NS
Hypertension 18 19 NS
Coronary disease
Angina 1 1 NS
History of myocardial infarction 5 1 NS
Previous coronary 3 1 NS
revascularization
Congestive heart failure 1 0 NS
Chronic pulmonary disease 6 7 NS
Chronic renal diseasea 4 3 NS
Diabetes mellitus 6 4 NS
ASA physical status
II 12 16 NS
III 6 3 NS
Cardiovascular treatment
Calcium blockers 12 3 <0.01
Nitrates 7 1 <0.02
Diuretics 4 4 NS
ß-blockers 7 2 NS
CEI 0 0 NS
Other vasoactive 0 0 NS
Preoperative arterial
pressure (mm Hg) (mean ±
sd)
Systolic 145 ± 12 145 ± 22 NS
Diastolic 78 ± 11 77 ± 13 NS
AIIA = angiotensin II antagonists; NS = not significant; CEI = converting
enzyme inhibitors.
a
Creatinine plasma level between 120 and 200 µmol/L.
 There was an increased incidence of treatment with
calcium channel blockers and nitrates in the group in which AIIA
were withdrawn. Arterial blood pressure was identical between
both groups before the start of the study. Type of surgery and
doses of anesthetics used during the induction of anesthesia
were identical between both groups.

Systolic arterial pressure was significantly less in Group II

at 5, 15, and 23 min after the induction (*P < 0.05). In this group,
the decrease in systolic arterial pressure was associated with
more frequent episodes of hypotension (AIIA withdrawn: 1 ± 1;
AIIA given: 2 ± 1; P < 0.01), in more patients (AIIA withdrawn:
12; AIIA given: 19; P < 0.01), and a longer duration of episodes
of hypotension (AIIA withdrawn: 3 ± 4 min; AIIA given: 8 ± 7
min.; P < 0.01), and an increased need for vasoactive drugs (P <
0.02).
 HEMODYNAMIC EVENTS
Systolic blood pressure Group I Group II P value
Preinduction 159 ± 24 151 ± 26 NS
Postinduction 126 ± 33 109 ± 24 NS
Intubation 136 ± 34 121 ± 33 NS

Episodes of hypotension (No.) 1±1 2±1 <0.01

Patients with at least 1 episode (No.) 12 19 <0.01
Duration of episodes (min) 3±4 8±7 <0.01
Patients receiving ephedrine (No.) 12 17 NS
Dose of ephedrine (mg) 10 ± 10 15 ± 9 NS
Patients receiving neosynephrine 0 5 <0.02
Dose of neosynephrine (µg) 0±0 47 ± 86 <0.05
Patients receiving terlipressine 0 6 <0.01
Dose of terlipressine (mg) 0±0 0.3 ± 0.5 <0.01
Values expressed as mean ± sd.
HT = hypertension.
 During recovery, 8 of 18 patients with AIIA withdrawn
developed HT, as opposed to 5 of 19 patients when AIIA were
given. Terlipressin was administered in only 2 of these last 5
patients.

Only one patient in each group developed a

postoperative complication: one patient in Group I developed
during the postoperative period, a transient new chest pain
with ST-T abnormalities on electrocardiogram, but without
increased cTnI, necessitating a circumflex angioplasty on
postoperative day 3. One patient in Group II developed
transient ST-T abnormalities without pain nor increased cTnI
on postoperative day 1.
DISCUSSION
This study confirms that patients treated with AIIA until the
morning of surgery developed severe and more frequent
hypotensive episodes during the induction of anesthesia in
comparison with those in whom the AIIA was delayed on the
previous day. Patients treated with AIIA until the morning of surgery
have developed severe hypotensive episodes after the induction of
general anesthesia and required vasoconstrictor treatment.

Moreover, in these patients, hypotension refractory to

repeated epinephrine or phenylephrine occurred, requiring the use
of an agonist of the vasopressin system. No study patient developed
a severe postoperative complication such as stroke, myocardial
infarction, respiratory, or renal failure, or need for reoperation. The
incidence of HT during recovery was identical in both groups.
 AIIA acts by binding to specific membrane-bound receptors
that are coupled to one of several signal transduction pathways. The
AT 1 receptor mediates the major cardiovascular action of the renin
angiotensin system.

Losartan it is as effective in the treatment of essential HT,

and congestive heart failure, as ACEI. The key advantage AIIA
provide over ACEI is that they may avoid unwanted side effects that
are related to bradykinin potentiation with the latter drugs

Blockade of the renin-angiotensin system increases the

blood-pressure decreasing effect of anesthetic induction. A severe
hypotensive episode, requiring vasoconstrictor treatment, occurs
after the induction of general anesthesia in patients chronically
treated with AIIA. Recommendations to discontinue these drugs on
the day before the surgery may be justified.
CONCLUSION
We conclude that significant adverse effects occurred
during the induction of anesthesia in patients chronically
treated with AIIA when the drug was given before induction
in comparison with patients in whom AIIA were discontinued
on the day before operation.

These results suggest the need to discontinue the AIIA on

the day before operation.