Case Synopsis
A 95-kg, 70-year-old man is scheduled to have a left internal carotid endarterectomy. He takes amlodipine (5 mg/day) and irbesartan (150 mg/day), an angiotensin II receptor antagonist, for hypertension. He took his usual doses of both medications on the morning of surgery. Preoperative tests included a transthoracic echocardiogram that showed normal left ventricular systolic function and septal hypertrophy. Blood pressure and heart rate immediately before induction of anesthesia were 150/70 mm Hg and 56 beats per minute, respectively. After receiving 900 mL of crystalloid, he was induced with sufentanil (10 μg), propofol (150 mg), and rocuronium (50 mg), with subsequent endotracheal intubation and anesthetic maintenance with oxygen and air (40:60) and desflurane (0.7 minimum alveolar concentration [MAC]). Two minutes after induction, his blood pressure fell to 80/44 mm Hg. Despite repeated intravenous blouses of ephedrine (50 mg total), his blood pressure was 47/30 mm Hg 4 minutes after induction.
Problem Analysis
Definition and Recognition
Renin-angiotensin system (RAS) antagonists include both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists. These drugs are used to treat hypertension and heart failure in selected patients. ACE inhibitors and angiotensin II receptor antagonists cause a blockage of the RAS that can adversely affect hemodynamics during anesthesia and surgery. Although anesthesia is not invariably associated with hemodynamic instability in RAS-blocked patients, unexpected episodes of refractory hypotension have been reported. Also, RAS antagonists, specifically ACE inhibitors, have been associated with potentially life-threatening angioedema of the head and neck.
The RAS plays an essential role in the regulation of vascular tone and extracellular fluid volume. As shown in Fig. 8.1 , sympathetic stimulation via β 1 -adrenergic receptors, renal artery hypotension, and decreased sodium delivery to the distal tubules stimulate the release of renin by the kidney. Renin is a proteolytic enzyme that cleaves to the circulating substrate angiotensinogen to form angiotensin I, which has little intrinsic pharmacologic activity. Angiotensin I is converted immediately to angiotensin II via a reaction catalyzed by ACE, which is present in vascular endothelium and lung tissue.
In the short term (i.e., intraoperatively), angiotensin II contributes to vascular homeostasis by increasing vascular (especially arteriolar) tone. It acts directly on angiotensin II receptors and indirectly by enhancing sympathetic adrenergic function to increase vascular tone, which is necessary to maintain adequate perfusion pressure in patients with hypovolemia or reduced cardiac output. In the longer term (e.g., hours to days), angiotensin II contributes to vascular homeostasis by its effect on extracellular fluid volume. It causes the adrenal cortex to release aldosterone, a hormone that acts on the kidneys to increase sodium and fluid retention. Angiotensin II also stimulates the release of vasopressin (i.e., antidiuretic hormone) from the posterior pituitary, which causes the kidneys to increase fluid retention. Blocking angiotensin II–mediated increased vascular tone and relative reduction of intravascular volume in patients receiving RAS antagonists chronically may cause refractory hypotension after induction of anesthesia.
Angioedema of the oropharynx or larynx has been recognized as an unusual complication of ACE inhibitor therapy. ACE inhibitor–induced angioedema usually manifests spontaneously within hours to days of initiation of treatment and has been described in association with anesthesia and endotracheal intubation. Edema of the tongue is commonly the presenting symptom, with involvement of the face, lips, floor of the mouth, pharynx, glottis, or larynx frequently observed.
The precise mechanism of angioedema formation is uncertain. Because it is likely mediated by the kallikrein-bradykinin system, it is probably a biochemical rather than an immunologic phenomenon. Bradykinin is a potent vasodilator that increases vascular permeability and produces tissue edema. Kinase II (which is identical to ACE) is the major tissue enzyme responsible for the breakdown of bradykinin. ACE inhibitors inhibit kinase II to prevent bradykinin breakdown. Angioedema associated with ACE inhibitor therapy may therefore be a result of inhibition of bradykinin inactivation by kinase II.
Recognition
Hypotension
Recognition of RAS antagonist therapy as a contributor to hypotension relies on the exclusion of other intraoperative events that may produce hypotension. A heightened index of suspicion in patients chronically treated with these drugs, especially in those with left ventricular diastolic dysfunction, is justified. The temporal relationship between cardiovascular instability and induction of anesthesia in patients chronically treated with RAS antagonists, along with the failure of ephedrine or phenylephrine in usual doses to resolve the hypotension, makes RAS antagonists a likely cause of hypotension.
Angioedema
Recognition of ACE inhibition as the cause of angioedema relies on the exclusion of other perioperative events associated with swelling of the head and neck (e.g., allergy, anaphylaxis), as well as the knowledge that angioedema can occur (though infrequently) with ACE inhibitors. When it does occur, angioedema is usually temporally related to the initiation of ACE inhibitor therapy.
Risk Assessment
Hypotension
A number of patient factors modify the risk of severe hypotension with the induction of anesthesia in those treated with RAS antagonists. Patients treated with other antihypertensive agents in combination with an RAS antagonist are more likely to have refractory hypotension on induction. Likewise, the combination of RAS antagonists and other vasodilator drugs (e.g., amiodarone) increases the risk of hypotension. Patients with “complete” RAS blockade, which is associated with high doses and recent administration, are more likely to be unstable on induction. Patients with a history of severe hypertension, especially those with left ventricular diastolic dysfunction (which amplifies the dependence of cardiac output on preload), are also at increased risk for refractory hypotension. Short-term preoperative RAS inhibition (1 to 2 days) in normotensive or mildly hypertensive subjects is less likely to result in refractory hypotension on induction. Patients who continue therapy until the day of surgery are also at increased risk. One review found that the incidence of hypotension on induction of anesthesia in patients with a history of severe hypertension was 75% to 100% when ACE inhibitors were continued until the day of surgery.
Angioedema
Angioedema involving the oropharynx or larynx is an unusual complication of ACE inhibitor therapy, occurring on average in 0.1% of patients taking captopril, lisinopril, or enalopril; the incidence in patients taking enalapril may be slightly higher (0.2%) than in those taking the other two drugs. Patients are at highest risk within the first week of starting an ACE inhibitor; a retrospective study of 36,000 patients receiving enalapril showed that 60% to 70% of cases of angioedema occurred within this period. However, angioedema has occurred suddenly after months to years of therapy, and about 20% of known cases of angioedema occurring in this context may involve severe symptoms (e.g., dyspnea, stridor, laryngospasm). Unfortunately, there are no characteristics to predict which patients will progress to life-threatening airway compromise.
Implications
Concerning the risk for refractory hypotension on induction of anesthesia in patients taking RAS antagonists, there is no consensus on continuing or discontinuing the drug in the immediate preoperative period. For this class of drugs, the elimination half-life does not necessarily predict the duration of action, making recommendations with respect to perioperative dosing difficult.
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