Angiotensin II antagonists (AIIA) are part of a new rational treatment of hypertension (HT) (1). 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. Adverse circulatory effects during anesthesia are well known in patients chronically treated with angiotensin-converting enzyme inhibitors (ACEI), leading to the recommendation to discontinue them at least 24 hrs before anesthesia and surgery (2–4). Similarly, a case of refractory hypotension was reported after induction of anesthesia in a patient chronically treated with AIIA (5). Brabant et al. (6) found a more frequent incidence of hypotension during induction of anesthesia in patients chronically treated with AIIA, in comparison with matched patients receiving β-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.
There are no data concerning AIIA administration in patients scheduled for vascular surgery performed under general anesthesia. 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.
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 for Human Research of our Institution. Patients were randomly assigned to one of the study groups by a computer-generated list compiled before the start of the study.
Patients were randomized in 2 groups as follows: Group I, AIIA discontinued on the day before surgery (n = 18); and Group II, AIIA given 1 h before anesthesia (n = 19).
Exclusion criteria were the following: 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 (Marquette, Milwaukee). After a 10 mL/kg crystalloid infusion and breathing a 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 consisted of isoflurane administration. Boluses of sufentanil were administered intraoperatively as needed.
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). Previously, treatment of refractory hypotension was angiotensin that is no longer commercially available (7,8). As previously described (9), 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 autoanalyzer™ (Dade-Behring, Deerfield, IL). Normal values are 0–0.5 ng/mL.
Statistical analysis was performed by using NCSS 6.0™ software (Statistical Solutions, Cork, Ireland). 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.
The two groups were comparable in age, sex ratio, and main preoperative characteristics (Table 1). 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 (Tables 2,3).
Systolic arterial pressure was significantly less in Group II at 5, 15, and 23 min after the induction (Fig. 1) (*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) (Table 4).
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 it 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.
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.
Adverse circulatory effects during anesthesia are well known in patients chronically treated with ACEI, leading to the recommendation to discontinue them at least 24 hours before the induction of anesthesia. Similarly, a case of refractory hypotension was reported after the induction of anesthesia in a patient chronically treated with AIIA (5,6).
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, the leader in this field, is a selective AT1 receptor antagonist that was demonstrated to be an effective antagonist of many angiotensin II-induced actions and an effective antihypertensive drug in many animal models of HT (10). Clinical studies have confirmed the AIIA action of losartan and suggest that 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 (10–13).
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.
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.
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© 2001 International Anesthesia Research Society
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