Journal of Cardiothoracic and Vascular Anesthesia
Volume 22, Issue 2 , Pages 177-179, April 2008

Angiotensin Blockade and General Anesthesia: So Little Known, So Far to Go

Department of Anesthesiology and Critical Care, Cardiothoracic Section, University of Pennsylvania Medical Center, Philadelphia, PA

Article Outline

 

ANGIOTENSIN II IS A serum peptide that, as per its name, raises systemic blood pressure because of vasoconstriction. Its precursor angiotensinogen is cleaved by renin to form angiotensin I. Thereafter, angiotensin-converting enzyme (ACE) cleaves angiotensin I to form angiotensin II. Angiotensin II binds to a family of angiotensin receptors to increase systemic blood pressure both directly by vasoconstriction and also indirectly by stimulating secretion of vasopressin and aldosterone.

Currently, there are 2 drug classes in this pathway that have achieved therapeutic utility through angiotensin blockade: (1) ACE inhibitors (ACE-Is, the “prils”; eg, captopril and ramipril) and (2) angiotensin receptor blockers (ARBs, the “sartans”; eg valsartan and losartan). It follows from the physiology of the renin-angiotensin-aldosterone system that its blockade significantly alters the maintenance of systemic blood pressure, given its widespread direct and indirect effects. As a result for patients on ACE-I/ARB therapy, hemodynamic variables such as intravascular volume and sympathetic tone may have a larger role in blood pressure homeostasis.1 Furthermore, the guidelines from the seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure highlight the therapeutic value of ACE-I/ARB in combination with diuretic therapy, drugs that may be associated with a degree of hypovolemia.2

In the perioperative setting, significant hypotension may follow the induction of general anesthesia in patients with angiotensin blockade.3, 4 This hypotension may be refractory and require therapy with ephedrine, norepinephrine, and/or vasopressin agonists such as terlipressin.5, 6 Furthermore, this risk of hypotension is significantly reduced if angiotensin blockade with ACE-I/ARB is discontinued more than 10 hours before anesthetic induction.3, 7, 8 As a consequence, the American College of Physicians recommends that angiotensin blockade be discontinued on the day of surgery, as outlined in their physicians’ information and education resource (www.pier.acponline.org).

The cumulative studies to date about perioperative angiotensin blockade, however, have the following limitations:

1.They predominantly focus on hemodynamics at anesthetic induction and/or before surgical incision. It remains to be elucidated whether the hypotensive tendency associated with ACE-I/ARB persists after surgical incision, when sympathetic vascular tone is typically higher.

2.Their sample sizes are small (n range = 50-250). As a result, they are not powered to permit statistical identification of factors that with ACE-I/ARB are significantly associated with intraoperative hypotension.

Given the limitations in current understanding of perioperative angiotensin blockade, the lead study in this issue of the journal by Kheterpal and colleagues9 is timely. In this article, these investigators from Michigan and Baylor Universities present an important prospective observational study of intraoperative hemodynamics associated with chronic angiotensin blockade. This groundbreaking study has the following 3 advantages over previous studies in this field:

1.It examines hemodynamics through the entire intraoperative period (from time in the operating room to time out of the operating room).

2.The study cohort totals 45,291 subjects, making it by far the largest study on this topic. The cohort was divided by exposure to angiotensin blockade (ACE-I/ARB [yes] = 9,143; ACE-I/ARB [no] = 36,148). After propensity matching to account for baseline comorbidities, 2 clinically similar subgroups resulted as follows: ACE-I/ARB (yes) = 5,689 and ACE-I/ARB (no) = 6,693. Although almost homogeneous with respect to baseline comorbidity, these 2 subgroups remained clinically distinct in 2 aspects: (1) chronic diuretic therapy (ACE-I/ARB [yes] = 45%; ACE-I/ARB [no] = 29%; p < 0.001) and (2) chronic calcium-channel blocker therapy (ACE-I/ARB [yes] = 24%; ACE-I/ARB [no] = 22%; p = 0.002).

3.With the largest cohort size to date even after propensity matching (N = 5,689 + 6,693 = 12,382), subgroup correlations with intraoperative hypotension were subsequently controlled for the differences in diuretic and calcium-channel blocker exposure. Thus, possible synergistic interactions with concomitant ACE-I/ARB therapy could be assessed. It must be remembered that study patients had omitted ACE-I/ARB therapy the day of surgery, as per the guidelines of the American College of Physicians.

With these 3 important advantages in methodology over prior studies, the main finding from this landmark study is that, despite discontinuation on the day of surgery, chronic ACE-I/ARB and diuretic therapy together are significantly associated with hypotension and vasopressor therapy throughout the intraoperative period. This persistent intraoperative hypotensive tendency was, however, not significantly associated with perioperative myocardial infarction or renal failure.

What is the best explanation of this finding? As the authors point out in their discussion, the hypotensive effects of angiotensin blockade are exaggerated in the setting of hypovolemia.1, 10 Therefore, because patients on chronic diuretic therapy are more likely to be hypovolemic, it follows that their risk for intraoperative hypotension in association with ACE-I/ARB exposure would be higher. The question that remains to be clarified is why chronic calcium-channel blockade does not increase the intraoperative hypotensive risk caused by angiotensin blockade.

What future studies are indicated in this field in the wake of this seminal study? Although numerous studies will no doubt be undertaken, the following considerations apply to these subsequent investigations:

1.Prospective randomized trials are indicated to confirm this significant association between chronic angiotensin blockade and diuretic therapy. This group of trials should also explore whether extending the time period of preoperative discontinuation reduces the intraoperative hypotensive risk. Based on the study by Kheterpal and colleagues, there is a rationale to extend the preoperative abstention from angiotensin blockade and diuretic therapy to >24 hours.

2.Randomized trials should continue to test strategies to manage this risk of intraoperative hypotension caused by angiotensin blockade, especially in the ACE-I/ARB/diuretic group. Strategies to test include optimal induction technique, intraoperative volume expansion, and best intraoperative vasopressor management. With respect to induction technique, recent evidence highlights the hypotensive effect of propofol and the potential advantage of etomidate for induction in the setting of chronic angiotensin blockade.11, 12 Furthermore, current evidence suggests that the vagotonic effect of a propofol and narcotic induction in this setting may be responsible for a degree of the observed intraoperative hypotension. This aspect might be improved with supplementary vagolytic support with preinduction glycopyrrolate.13, 14

3.Future trials that assess intraoperative hemodynamics related to angiotensin blockade should assess and control for the impact of the following 3 confounders:
a.Genetic polymorphisms of the angiotensin system: functional variants of the angiotensinogen gene have recently been demonstrated to affect vasodilatory responses to therapy with ACE-I.15 Conceptually, this may apply to associated medication groups such as chronic diuretic therapy as well. These pharmacogenetic considerations deserve special focus in the future.

b.Cardiovascular autonomic neuropathy, both latent and apparent: cardiovascular autonomic dysfunction, as defined by traditional criteria, was recently shown to underestimate the incidence of intraoperative hypotension.16 Heart rate variability, as an indicator of autonomic dysfunction, was in the same study an independent predictor of intraoperative hypotension, even in subjects without apparent autonomic dysfunction (p < 0.001). As a result, intrinsic sympathetic vascular tone varies significantly in surgical patients and should be controlled for in future studies of risk factors for intraoperative hypotension.

c.The lack of a consensus definition of intraoperative hypotension: a recent study showed that the incidence of intraoperative hypotension varies from 5% to 99%, depending on definition.17 This study applied definitions of hypotension from the current anesthetic literature to a large adult cohort (N = 15,509) undergoing general anesthesia for noncardiac surgery. A generally accepted definition for the endpoint of intraoperative hypotension is a major requirement to place future studies in this area of investigation on a firmer foundation.


It is likely that angiotensin blockade will continue to be a significant perioperative consideration, given the novel indications for angiotensin blockade with ACE-I/ARB in common and important disease states such as atrial fibrillation, ischemic stroke, and Alzheimer’s disease.18, 19, 20 Furthermore, the overwhelming impact of hypertension should not be forgotten. Hypertension affects approximately 50 million individuals in the United Sates and approximately 1 billion individuals worldwide.21 Recent consensus guidelines, clinical trials, and expert opinion highlight the synergistic efficacy of combination therapy for hypertension such as ACE-I/ARB with diuretics.2, 22 As a result of all these developments, the perioperative hemodynamic considerations associated with angiotensin blockade and diuretic therapy will remain important because they are so common and they so profoundly affect the anesthetic plan.

In conclusion, Kheterpal and colleagues deserve congratulations for their groundbreaking study that advances the frontiers of understanding with respect to perioperative care for patients on chronic angiotensin blockade. We look forward to the future studies that will result from the inspiring work from this group of investigators.

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References 

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PII: S1053-0770(08)00003-7

doi:10.1053/j.jvca.2008.01.002

Journal of Cardiothoracic and Vascular Anesthesia
Volume 22, Issue 2 , Pages 177-179, April 2008

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