The Hemodynamic Effects of Anesthetic Induction in Vascular Surgical Patients Chronically Treated with Angiotensin II Receptor Antagonists : Anesthesia & Analgesia

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The Hemodynamic Effects of Anesthetic Induction in Vascular Surgical Patients Chronically Treated with Angiotensin II Receptor Antagonists

Brabant, Steven M. MD; Bertrand, Michèle MD; Eyraud, Daniel MD; Darmon, Pierre-Louis MD; Coriat, Pierre MD

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Anesthesia & Analgesia 89(6):p 1388, December 1999. | DOI: 10.1213/00000539-199912000-00011
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The use of angiotensin II receptor subtype-1 antagonists (ARA), recently introduced as antihypertensive drugs, is becoming more prevalent. We studied the prevalence and severity of hypotension after the induction of general anesthesia in 12 patients treated with ARA until the morning of surgery. The hemodynamic response to induction was compared with that of patients treated with β-adrenergic blockers (BB) and/or calcium channel blockers (CB) (BB/CB group, n = 45) and angiotensin-converting enzyme inhibitors (ACEI) (ACEI group, n = 27). A standardized anesthesia induction protocol was followed for all patients. Hypotension occurred significantly (p ≤ 0.05) more often in ARA-treated patients (12 of 12) compared with BB/CB-treated patients (27 of 45) or with ACEI-treated patients (18 of 27). There was a significantly (P ≤ 0.001) increased ephedrine requirement in the ARA group (21 ± 3 mg) compared with the BB/CB group (10 ± 6 mg) or the ACEI group (7 ± 4 mg). Hypotension refractory to repeated ephedrine or phenylephrine administration occurred significantly (P ≤ 0.05) more in the ARA group (4 of 12) compared with the BB/CB group (0 of 45) or the ACEI group (1 of 27), but it was treated successfully by using a vasopressin system agonist. Treatment with angiotensin II antagonism until the day of surgery is associated with severe hypotension after the induction of anesthesia, which, in some cases, can only be treated with an agonist of the vasopressin system.


Hypotensive episodes occur more frequently after anesthetic induction in patients receiving Angiotensin II receptor subtype-1 antagonists under anesthesia than with other hypotensive drugs. They are less responsive to the vasopressors ephedrine and phenylephrine. The use of a vasopressin system agonist was effective in restoring blood pressure when hypotension was refractory to conventional therapy.

An increasing number of hypertensive patients scheduled for vascular surgery are chronically treated with angiotensin II (AII) receptor subtype antagonists (ARA), such as losartan and valsartan (1). These drugs interfere with the renin-angiotensin system (RAS) by inhibiting AII from binding to its receptor, resulting in increased AII and normal bradykinin plasma levels (1–4). In contrast, inhibition of the AII synthesis by Angiotensin-converting enzyme inhibitors (ACEI) is associated with lower AII and high bradykinin plasma levels (3). The potential therapeutic interest of ARA, compared with ACEI, is twofold. First, they produce less bradykinin-related side effects, such as cough. Second, because they competitively and selectively block AII receptors, they should better suppress AII vasoconstrictive effects (1,2,5).

The blood pressure-lowering effect of anesthetic induction is increased in patients chronically treated with ACEIs until the morning of surgery (6,7). This emphasizes the pivotal role of the RAS in the maintenance of intraoperative arterial blood pressure (BP) stability (8,9). The BP response to anesthetic induction has not been investigated in patients chronically treated with ARA. Therefore, we conducted a study to determine the occurrence and magnitude of hypotension and the associated vasoconstrictor requirements after the induction of anesthesia in patients chronically treated with ARA undergoing vascular surgery.


After approval of our committee for safety in human studies, 12 consecutive vascular surgical patients chronically treated with ARA were prospectively included in the ARA group (n = 12). During the study, 203 hypertensive patients were scheduled for elective vascular surgery, but only those patients (n = 72) of a similar age and with a minimum of two clinical characteristics (coronary artery disease, previous myocardial revascularization, previous vascular surgery, smoking, dyslipidemia, diabetes) similar to those of the patients in the ARA group were studied. Patients chronically treated with β-adrenergic blocker (BB) and/or calcium channel blockers (CB) were included in the BB/CB group (n = 45). Patients chronically treated with ACEI were included in the ACEI group (n = 27). We compared the hemodynamic response until 30 min after the induction of anesthesia in these three groups. Exclusion criteria were renal insufficiency and heart failure.

ARA, BB, and CB were given until the morning of surgery, whereas the last administration of ACEI and diuretics was 24 h before surgery.

The three anesthesiologists involved in the study were aware of the preoperative treatment, but, as part of the protocol, a standardized anesthetic technique was strictly followed in all patients. Similarly, the treatment of hypotensive episodes was prospectively defined. The anesthesiologists were involved to an equal extent in each of the three categories of patients studies. Patients were premedicated with oral midazolam (5 mg). A radial artery catheter was inserted under local anesthesia, and all patients received 10 mL/kg lactated Ringer’s solution before the induction of general anesthesia. Anesthesia was slowly induced with sufentanil (0.5 mg/kg) and propofol (1.5 mg/kg). Four minutes after atracurium administration (0.5 mg/kg), the trachea was intubated. Patients were maintained free of surgical incision, and anesthesia was maintained with O2/N2O 50% and isoflurane (end-tidal concentration 0.3%–0.5%) until 30 min after the induction of anesthesia. Heart rate (HR), BP, 5-lead electrocardiogram (ECG), and ST-segment analysis were continuously recorded (Solar 7000; Marquette, Milwaukee, WI). Using this monitor, end-tidal concentrations of CO2 and isoflurane were determined. A 12-lead ECG was obtained before anesthetic induction, immediately postoperatively, and on the first and the third postoperative days. Troponin I plasma levels were determined 6 and 24 h after surgery. Hypotension was defined as a systolic BP (SAP) decrease of >30% less the preoperative value or a SAP decrease <90 mm Hg. Hypotension was treated with IV boluses of 3 mg of ephedrine (if HR ≤75 bpm) or 50 μg of phenylephrine (if HR >75 bpm), which were repeated until SAP was restored. Refractory hypotension was defined as a persistent SAP decrease despite repeated ephedrine administration (minimum 18 mg, i.e., six boluses) or repeated phenylephrine administration (minimum 300 μg, i.e., six boluses). Refractory hypotension was treated with a vasopressin system (VPS) agonist—1-mg bolus of terlipressin (Glypressine®; Ferring, Malmö, Sweden) and was repeated until SAP was restored.

Patient characteristics and the incidence of hypotension were analyzed by using a χ2 test. Hemodynamic data were analyzed by using a two-way analysis of variance for repeated measures associated with the Student-Neuman-Keuls test. Data are presented as the number of patients or as means ± SD. A P value ≤0.05 was considered significant.


We studied 84 hypertensive patients scheduled for vascular surgery. As of a result of appropriate matching of the BB/CB group and ACEI group to the ARA group, preoperative demographic data, preoperative mean BP (MAP), and HR were comparable among all groups (Tables 1 and 2). All patients in the ARA group developed hypotension after the induction of anesthesia (Table 2), which was significantly (P ≤ 0.05) more compared with both other groups. The magnitude of hypotension (indicated as lowest MAP value in Table 2) was significantly (P ≤ 0.001) greater in the ARA group compared with the other groups. Hypotension occurred immediately (6 ± 2 min) after anesthetic induction in all patients in the ARA group, in 27 patients in the BB/CB group, and in 18 patients in the ACEI group. Despite the administration of ephedrine or phenylephrine, hypotension either could not be successfully treated or occurred a second time during the 30 min after the induction of anesthesia in all patients in the ARA group (16 ± 7 min) but in only 3 patients (12 ± 3 min) in the BB/CB group and in 2 patients (14 ± 4 min) in the ACEI group. During the study period, the highest observed MAP value was comparable among the groups and did not differ by more than 30% from the preoperative value. HR was comparable among all groups (Table 2). The amount of ephedrine, but not phenylephrine, required to restore BP was significantly (P ≤ 0.001) higher in the ARA group compared with both other groups (Table 3). After the induction of anesthesia, hypotension refractory to ephedrine or phenylephrine was noted significantly (P ≤ 0.001) more in the ARA group (Table 2). Terlipressin was given to four (30%) patients in the ARA group and to one (3.7%) patient in the ACEI group (Table 3). Its administration was repeated in two of five patients. After terlipressin administration, BP remained stable during the whole anesthesia period. Similar hemodynamic data and vasoconstrictor requirements were noted between the BB/CB and ACEI groups.

Table 1:
Patient Preoperative Characteristics
Table 2:
Hemodynamic Data until 30 Minutes After the Induction of Anesthesia
Table 3:
Vasoconstrictor Requirements until 30 Minutes After the Induction of Anesthesia

No ST-segment change was noted in the ARA group, and the postoperative ECG and troponin blood level were normal. Two patients in the BB/CB group and one patient in the ACEI group had intraoperative ST-segment changes. Postoperative infarction (ECG changes and troponin Ic >1 ng/mL) occurred in three patients in the BB/CB group and in one patient in the ACEI group, who all experienced severe intraoperative bleeding.


This study confirms that blockade of the RAS increases the BP-lowering effect of anesthetic induction. All patients in the study who were treated with ARA until the morning of surgery developed severe hypotensive episodes requiring vasoconstrictor treatment after the induction of general anesthesia. The increased need for ephedrine in those patients, compared with the patients in the other groups, reflects the magnitude and severity of the decrease in BP. In addition, in 30% of the patients in the ARA group, hypotension was refractory to repeated ephedrine or phenylephrine administration. These cases of refractory hypotension were successfully treated with an agonist of the VPS.

Treatment of hypertensive patients with ARA until the morning of surgery is a major factor influencing the BP-lowering effect of anesthesia. Similar observations were reported in patients chronically treated with ACEI until the morning of surgery (6,7). However, the increased incidence of hypotension that was constant in the study, and the major decrease in BP in the ARA group may also be explained by the different bradykinin and AII plasma levels and by the stronger inhibition of the RAS compared with ACEI (1,4). In addition, during ACEI treatment, there may still be an AII formation via alternative pathways (11); therefore, ARA are considered to be more selective in the inhibition of RAS (20). Selective inhibition of the AII subtype-1 receptor by ARA is associated with increased AII plasma levels, which result in an excessive stimulation of the AII subtype-2 receptor (1). Acute BP control depends on the interplay among the orthosympathetic system, the RAS, and the VPS (8–10). These three physiological neurohumoral systems are activated to maintain BP in the case of hypotension (10). Patients with a chronic blockade of the RAS who are also undergoing anesthesia are more at risk of developing hypotension because of the decreased vascular resistance and associated decreased cardiac filling (6,7,9). Hypotension can be treated by activating one of the two unblocked systems or by overstimulating the blocked system (RAS) (12). Although the larger ephedrine dose required to restore BP in the ARA group relies on the magnitude of the decrease in BP, it may also be consistent with Licker et al.’s (13) observation of a decreased vasopressor effect of norepinephrine in patients with inhibited RAS undergoing anesthesia. The RAS is selectively and effectively inhibited in patients chronically treated with ARA, which probably explains both the magnitude of hypotension observed immediately after anesthetic induction and the occurrence of a second hypotensive episode. In four patients in the ARA group and in one patient in the ACEI group, neither ephedrine nor phenylephrine could restore BP during severe hypotension.

Chronic RAS inhibition and inappropriate activation of the sympathetic system and the VPS may explain the occurrence of refractory hypotension in those patients (12,14). The inability of an agonist of the sympathetic system to restore BP in some patients led us to consider the use of a VPS agonist (terlipressin) to treat refractory hypotension (15). Terlipressin, or triglycylvasopressin, is a synthetic vasopressin analog that is slowly converted to lysine-vasopressin, resulting in a prolonged arterial and venous vasoconstriction without impairing left ventricular function (16). Terlipressin administration has a long-lasting effect (>45 min) and potentiates the increase in BP in response to endogenous catecholamines (16). A high sensitivity to a small dose of other VPS agonists, such as pitressin (19) and vasopressin (14), to restore BP has been demonstrated in patients with vasodilatory hypotension. Terlipressin restored BP in all cases, and its administration was not associated with myocardial ischemia or renal dysfunction. Terlipressin seems to be a promising vasopressor (18); however, further investigations are required to evaluate its hemodynamic effects and to confirm its effectiveness in treating refractory hypotension.

A limitation of our study is the small number of ARA-treated patients who could be included during the study period; thus, we did not compare the hemodynamic effects of withdrawal or continuation of ARA treatment until the morning of surgery. This is why we compared the data collected for these patients with those of a selected group of patients by matching them as to age and clinical characteristics.

We conclude that severe hypotensive episodes requiring vasoconstrictor treatment are particularly frequent after the induction of general anesthesia in patients chronically treated with ARA. Such episodes more often in these patients than in those receiving other antihypertensives. The hypotension was less responsive to conventional vasopressors such as ephedrine or phenylephrine. In some patients, hypotension may be refractory to classical vasoconstrictor therapy; in that case, a VPS agonist is effective to restore BP. Recommendations to continue hypertensive treatment until the day of surgery are justified for BB and CB but cannot be extrapolated to ARA chronically administered to hypertensive patients. Further investigations are required to evaluate the BP response to induction if ARA are withdrawn on the morning of surgery.


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© 1999 International Anesthesia Research Society