Anesthesia Experts

Angiotensin Axis Blocking Drugs In the Perioperative Period

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Alan Smeltz, MD

Resident-CA 2
University of North Carolina
Chapel Hill, North Carolina

 

Priya A. Kumar, MD

Professor of Anesthesiology
University of North Carolina
Chapel Hill, North Carolina
Introduction

Drugs causing angiotensin axis blockade (AAB) include angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) agents. Due to the current trend of an aging population combined with an ever-increasing complexity of procedures, it is inevitable that these medications will be commonly encountered in the perioperative patient.

The long-term use of AAB has been shown to reduce vascular disease–related morbidity and mortality in patients with hypertension, coronary artery disease, congestive heart failure, diabetes, and chronic kidney disease.1 However, in short-term situations of physiologic extremis, such as surgery and anesthesia, there is controversy regarding the best practice for the perioperative management of AAB therapy. Currently, there are no universal guidelines for the management of refractory hypotension associated with these drugs in the perioperative setting. In this review, we hope to explore this area with the goal of identifying the best evidence to aid perioperative decision making regarding patients on chronic AAB.

Controversies in Current Practice

Exaggerated hypotension in patients on AAB has been well described in those undergoing elective noncardiac surgery,2-5 vascular surgery,6,7 and cardiac surgery.8,9 This decrease in blood pressure, usually within 30 minutes of induction of anesthesia,10 has classically been more difficult to manage than typical general anesthesia–associated hypotension. As a result, there has been an ongoing controversy as to whether AAB should be withheld or continued prior to elective surgery. Whereas holding these medications may decrease hypotensive episodes intraoperatively,10 some argue that it could lead to a loss of their established long-term benefits1 as well as the theoretical risk for precipitating a withdrawal hypertensive crisis on the day of surgery.

To add to the controversy, 3 large cohort studies that evaluated long-term outcomes in patients on AAB undergoing anesthesia arrived at remarkably conflicting conclusions. Railton et al11 found increased mortality in vascular surgery patients with the perioperative continuation of AAB. Toppin et al12reported decreased mortality with the continuation of these drugs in noncardiac surgical patients, whereas Turan et al13 found no difference in 30-day mortality in this population.

Additionally, there has been inconsistency regarding the association between perioperative AAB and the development of end-organ damage. The incidence of acute kidney injury (AKI) in patients on perioperative AAB undergoing vascular surgery,14 thoracic surgery,15 and orthopedic surgery16 has been shown to be increased. However, the incidence of AKI in the same population following cardiac surgery has been shown in certain studies to be increased,17-19unchanged,20 and even decreased.21,22

Likewise, there has been a discrepancy in the reported perioperative mortality of patients on AAB. In different studies, mortality has been shown to be increased,18,20,22 not different,13 or even decreased.23 Similarly, the development of atrial fibrillation in post–cardiopulmonary bypass (CPB) patients on perioperative AAB has been shown to be increased.20,24 However, the evidence for these associated complications, overall, is weak and based primarily on observational data.

Other well-known side effects of AAB include hyperkalemia and airway complications. Potassium levels rise after initiation of AAB therapy to varying degrees in up to 10% of patients, affecting patients with chronic kidney disease the most.25 In this subset of patients, preoperative assessment of potassium levels as a part of the routine laboratory workup might help prevent electrolyte-associated cardiac dysrhythmias.

ACEI-associated airway issues such as cough, bronchospasm, and angioedema have also been described. In some cases, these airway complications have been reported to occur years after the initiation of an ACEI regimen.26 However, a large, retrospective propensity-matched study did not identify a difference in the rate of airway complications in patients on chronic ACEI therapy undergoing noncardiac surgery.13

Pharmacology

The effects of AAB occur systemically as well as at the tissue level. An understanding of the renin-angiotensin-aldosterone system (RAAS), pathways regulating vascular tone, and half-lives of antihypertensive agents is important for management decisions regarding AAB and associated intraoperative hypotension.

The complex pharmacology of AAB is summarized as a schematic in the Figure. Sympathetic stimulation results in a release of renin from the juxtaglomerular apparatus of the kidneys.10 Renin cleaves angiotensinogen to angiotensin I (AT-I), which is then converted to AT-II by angiotensin-converting enzyme (ACE). AT-II then acts at several sites. This chain of events, functioning to regulate blood pressure and maintain fluid and electrolyte balance, is known as the RAAS.

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; AT-I, angiotensin I; AT-II,angiotensin II; AVP, arginine vasopressin; BP, blood pressure; JGA, juxtaglomerular apparatus; SNS, sympathetic nervous system

ARBs prevent AT-II from binding the vasoconstricting AT1 receptors, thereby lowering blood pressure. Acting mechanistically upstream of ARBs, ACEIs prevent both the conversion of AT-I to AT-II and the inactivation of vasodilatory bradykinin. The accumulation of bradykinin itself is vasodilatory and therefore has a blood pressure–lowering effect.

Guidelines

Many authors have attempted to consolidate the literature to offer advice regarding perioperative AAB.27-29 Most providers would consider withholding the regimen on the day of surgery, especially if there is anticipated hemodynamic instability based on either patient- or surgery-related factors. The duration of holding the ACEI or ARB preoperatively would depend on the agent’s unique half-life and duration of antihypertensive effect (Table 1).30-33 The time to restart the medication is based on when the patient is hemodynamically stable postoperatively.

Table 1. Half-life and Duration of Antihypertensive Effect of Commonly Used ACEIs and ARBs
ACEI t1/2, ha,b Duration of Antihypertensive Effect, hc,d
Captopril 1.7 6-10
Enalapril 11 18-30
Lisinopril 12 18-30
Ramipril 4-18 24-60
ARB    
Candesartan 6-13 12
Losartan 1-3 11
Telmisartan 21-38 10
Valsartan 6-10 13
a Brown and Vaughan, 1998.

b Williams et al, 1988.

c Israili, 2000.

d Nishimura et al, 2005.

t1/2, half-life; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker

On the other side of the argument, there has been concern that withholding AAB might precipitate withdrawal hypertension on the day of surgery that might itself lead to problems, such as case cancellations and end-organ damage related to a hypertensive crisis. Although studies investigating reasons for case cancellations on the day of surgery34,35 list hypertension as one of the major medical reasons (medical reasons comprising 11% of case cancellation reasons), there have not been any studies linking case-cancelling hypertension to the withholding of AAB. A randomized trial of ambulatory patients that either withheld or continued their AAB the day of surgery36 demonstrated no difference in preoperative rate of hypertension, number of cases cancelled due to hypertension, postoperative hypertension, hospital length of stay, or other adverse events.

In light of the concerns regarding exaggerated perioperative hypotension in patients on AAB, the American College of Physicians initially had recommended stopping ACEIs on the day of surgery. This recommendation has since evolved to “uncertain, although they are usually continued.”37-39

The European Society of Cardiology and European Society of Anaesthesiology 2014 guidelines on perioperative AAB40 recommend initiating AAB therapy in heart failure patients not currently on AAB therapy at least 7 days in advance of surgery, and continuing therapy on the day of surgery with close monitoring.

In patients on AAB for the management of hypertension, with documented episodes of hypotension, the societies recommend considering holding the ACEI or ARB on the day of surgery. Even more vague, the latest American College of Cardiology and American Heart Association guidelines pertaining to perioperative ACEI/ARBs41 state their continuation on the day of surgery is “reasonable” (level of evidence B), and that if held they should be restarted as soon as “clinically feasible” (level of evidence C). There is, however, no published statement of recommendations by the American Society of Anesthesiologists.

Management of Hypotension

Hemodynamics are maintained by complex interactions between the cardiovascular system (preload, afterload, contractility), the autonomic nervous system, renin-angiotensin system, and arginine vasopressin system. Pharmacologic blunting of one or more of the vasoregulatory systems results in compensation by the intact systems, in order to maintain stability.

Induction of general anesthesia causes hemodynamic alterations by its effect on the sympathetic nervous system. It results in a decrease in circulating catecholamines, reduced vascular tone, and blunting of the reflex sympathetic activity in response to hypotension.

The body compensates for general anesthesia–associated hypotension via the RAAS, the sympathetic nervous system (SNS), and the vasopressinergic system.24 Thus, as anesthesia impairs the SNS in a patient with AAB, treatment with a vasopressin analog should theoretically overcome hypotension otherwise refractory to traditional means of support, such as volume, ephedrine, and phenylephrine. Multiple prospective cohort and randomized studies have corroborated this concept in the setting of vascular and cardiac surgery.42-47

In AAB-associated post-induction refractory hypotension, vasopressin analog boluses and norepinephrine infusions have been shown to be effective in raising blood pressure, with vasopressin analogs having a more rapid effect than norepinephrine.46 Prophylactic vasopressin analogs were shown to be effective in lowering post-CPB vasopressor requirement and shortening subsequent intensive care durations of care.45 However, laser Doppler of gastric mucosal perfusion suggested that perfusion was decreased more with vasopressin analogs than with norepinephrine, indicating that it might be more prone to compromising gastrointestinal microcirculation.47

Table 2. Effects of Angiotensin Axis Blockade
Decreased reflex tachycardia in response to hypotension
Decreased responsiveness to exogenous catecholamines
Lower circulating levels of:

·                   angiotensin II

·                   aldosterone

·                   arginine vasopressin

Patients on AAB are in a predominantly parasympathomimetic state with a blunting of reflex tachycardia response to hypotension.48 They have a decreased responsiveness to exogenous catecholamines and lower levels of circulating arginine vasopressin and aldosterone.49Patients on ACEI also have decreased levels of AT-II. Hemodynamic effects of AAB are summarized in Table 2.

Regardless of whether AAB medications have been withheld on the day of surgery (depending on their half-lives), the perioperative physician will likely be faced with the problem of exaggerated hypotension. This is a result of persistent tissue-based activity of these powerful drugs.7 The perioperative care of these patients should be individualized accordingly. A low threshold for invasive monitoring where indicated and adequate volume loading may help prevent refractory hypotension with induction of anesthesia. Cautious titration of induction drugs is important, with ready availability of conventional and second-line pressor agents.

Pharmacologic agents considered as first-line medications, such as phenylephrine and ephedrine, have varying efficacy in the treatment of AAB-associated hypotension.2,4,7 In most cases, these agents may be needed in higher than usual doses or might be ineffective, necessitating a switch to an alternate therapy.

Vasopressin is a peptide released in response to hypotension, and changes in serum osmolality act via V1 receptors, which cause vasoconstriction; V2 receptors, which result in antidiuresis in the kidneys; and V3, which results in release of cortisol, angiotensin, and natriuretic peptide. Synthetic vasopressin, with a half-life of 4 to 20 minutes, has been described as a second-line agent to treat refractory hypotension in AAB.

Catecholamines such as epinephrine, norepinephrine, and dopamine have been efficacious in the treatment of exaggerated hypotension. Studies have suggested that norepinephrine may be better at preserving the heart rate by avoiding reflex bradycardia.46,47

Anticholinergics such as atropine and glycopyrrolate have been described as second-line agents used in conjunction with other agents to counter the parasympathomimetic state.

Methylene blue, a competitive nitric oxide antagonist, has a half-life of 40 minutes. It decreases the levels of vasodilatory cGMP with a reported efficacy in situations of refractory hypotension.

Conclusion

Despite all the questions that have been investigated about perioperative use of ACEIs/ARBs, there remains much to learn. In the absence of a randomized controlled trial, the risks associated with continuing or discontinuing AAB on the day of surgery are still unclear, leaving conflicting data and much speculation:

  • Are there specific patient or surgical variables that might help tease out who might benefit most from withholding versus continuing perioperative AABs?
  • Are there benefits to maintaining AAB therapy throughout the perioperative period analogous to those described with β-blockers and statin medications?
  • Should we be initiating AAB therapy in heart failure patients with a known scheduled surgery in the near future?

It would seem that members of the American Society of Anesthesiologists would benefit from the publication of a practice advisory or guideline based on a thorough discussion addressing this topic. In the meantime, we must remain mindful of the potential issues one might encounter in practice and strive to do what is best in the context of our individual patients. Until further evidence is available, the authors believe that:

  1. It is reasonable and less confusing for most patients to continue AAB up to the day of surgery.
  2. Regardless of whether AAB has been withheld on the day of surgery, the perioperative physician must be prepared to face the problem of refractory hypotension. Depending on the individual situation, the physician should perhaps maintain a lower threshold for the placement of invasive monitors such as arterial catheters.
  3. Euvolemia must be ensured by adequate preloading prior to the induction of anesthesia.
  4. Gradual titration of induction agents such as propofol, or preferential use of relatively hemodynamically stable induction agents such as etomidate, may be justified in these cases.
  5. The choice of inhalational anesthetic is unlikely to make a difference; however, desflurane has the theoretical advantage of stimulating greater sympathetic activity compared with isoflurane or sevoflurane.
  6. Higher doses of first-line agents (phenylephrine, ephedrine, or glycopyrrolate) for the treatment of perioperative hypotension may be necessary in patients on AAB.
  7. For refractory hypotension, additional therapy such as vasopressin, norepinephrine, epinephrine, and anticholinergics may be necessary.
  8. Methylene blue (1-2 mg/kg), a competitive nitric oxide antagonist, may be considered as a last resort.

References

  1. Werner C, Baumhakel M, Teo KK, et al. RAS blockade with ARB and ACE inhibitors: current perspective on rationale and patient selection.Clin Res Cardiol. 2008;97(7):418-431.
  2. Bertrand M, Godet G, Meersschaert K, et al. Should the angiotensin II antagonists be discontinued before surgery?Anesth Analg. 2001;92(1):26-30.
  3. Colson P, Saussine M, Seguin JR, et al. Hemodynamic effects of anesthesia in patients chronically treated with angiotensin-converting enzyme inhibitors.Anesth Analg. 1992;74(6):805-808.
  4. Comfere T, Sprung J, Kumar MM, et al. Angiotensin system inhibitors in a general surgical population.Anesth Analg.2005;100(3):636-644.
  5. Rajgopal R, Rajan S, Sapru K, et al. Effect of pre-operative discontinuation of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists on intra-operative arterial pressures after induction of general anesthesia.Anesth Essays Res. 2014;8(1):32-35.
  6. Kataja JH, Kaukinen S, Viinamäki O, et al. Hemodynamic and hormonal changes in patients pretreated with captopril for surgery of the abdominal aorta.J Cardiothorac Anesth. 1989;3(4):425-432.
  7. Coriat P, Richer C, Douraki T, et al. Influence of chronic angiotensin-converting enzyme inhibition on anesthetic induction. 1994;81(2):299-307.
  8. Tuman KJ, McCarthy RJ, O’Connor CJ, et al. Angiotensin-converting enzyme inhibitors increase vasoconstrictor requirements after cardiopulmonary bypass.Anesth Analg. 1995;80(3):473-479.
  9. Oh YJ, Lee JH, Nam SB, et al. Effects of chronic angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitor treatments on neurohormonal levels and haemodynamics during cardiopulmonary bypass.Br J Anaesth. 2006;97(6):792-798.
  10. Mets B. Management of hypotension associated with angiotensin-axis blockade and general anesthesia administration.J Cardiothorac Vasc Anesth. 2013;27(1):156-167.
  11. Railton CJ, Wolpin J, Lam-McCulloch J, et al. Renin-angiotensin blockade is associated with increased mortality after vascular surgery.Can J Anaesth. 2010;57(8):736-744.
  12. Toppin J, Naughton F, Wijeysundera D, et al. ACE inhibitors reduce 30 day mortality after non-cardiac surgery. Presented at the annual meeting of the Society of Cardiovascular Anesthesiologists; April 30-May 4, 2011; Savannah, GA. Abstract 64.
  13. Turan A, You J, Shiba A, et al.Angiotensin converting enzyme inhibitors are not associated with respiratory complications or mortality after noncardiac surgery. Anesth Analg. 2012;114(3):552-560.
  14. Cittanova ML, Zubicki A, Savu C, et al. The chronic inhibition of angiotensin-converting enzyme impairs postoperative renal function.Anesth Analg. 2001;93(5):1111-1115.
  15. Ishikawa S, Griesdale DEG, Lohser J. Acute kidney injury after lung resection surgery: incidence and perioperative risk factors.Anesth Analg. 2012;114(6):1256-1262.
  16. Nielson E, Hennrikus E, Lehman E, et al. Angiotensin axis blockade, hypotension, and acute kidney injury in elective major orthopedic surgery.J Hosp Med. 2014;9(5):283-288.
  17. Arora P, Rajagopalam S, Ranjan R, et al. Preoperative use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers is associated with increased risk for acute kidney injury after cardiovascular surgery.Clin J Am Soc Nephrol. 2008;3(5):1266-1273.
  18. Yacoub R, Patel N, Lohr JW, et al. Acute kidney injury and death associated with renin angiotensin system blockade in cardiothoracic surgery: a meta-analysis of observational studies.Am J Kidney Dis. 2013;62(6):1077-1086.
  19. Coca SG, Garg AX, Swaminathan M, et al.Preoperative angiotensin-converting enzyme inhibitors and angiotensin receptor blocker use and acute kidney injury in patients undergoing cardiac surgery.Nephrol Dial Transplant. 2013;28(11):2787-2799.
  20. Miceli A, Capoun R, Fino C, et al. Effects of angiotensin-converting enzyme inhibitor therapy on clinical outcome in patients undergoing coronary artery bypass grafting.J Am Coll Cardiol.2009;54(19):1778-1784.
  21. Benedetto U, Sciaretta S, Roscitano A, et al. Preoperative angiotensin-converting enzyme inhibitors and acute kidney injury after coronary artery bypass grafting.Ann Thorac Surg. 2008(4);86:1160-1165.
  22. Shi P, Li Z, Young N, et al. The effects of preoperative renin-angiotensin system inhibitors on outcomes in patients undergoing cardiac surgery.J Cardiothorac Vasc Anesth. 2013;27(4):703-709.
  23. Johnston K, Stephens S. Effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on risk of atrial fibrillation before coronary artery bypass grafting.Ann Pharmacother.2012;46(9):1239-1244.
  24. Lange M, Van Aken H, Westphal M, et al. Role of vasopressinergic V1 receptor agonists in the treatment of perioperative catecholamine-refractory arterial hypotension.Best Pract Res Clin Anaesthesiol. 2008;22(2):369-381.
  25. Raebel MA. Hyperkalemia associated with use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.Cardiovasc Ther. 2012;30(3):e156-e166.
  26. Marques A, Retroz-Marques C, Mota S, et al. Postanesthetic severe oral angioedema in patient taking angiotensin-converting enzyme inhibitor.Case Rep Anesthesiol. 2014;2014:693191.
  27. Chopra V, Wijeysundera DN. The right time and ‘Pl ACE’: optimal management of perioperative angiotensin-converting enzyme inhibitors.J Hosp Med. 2014;9(5):334-336.
  28. Sear JW. Perioperative renin-angiotensin blockade: to continue or discontinue, that is the question!Anesth Analg.2014;118(5):909-911.
  29. Mets B. To stop or not?Anesth Analg. 2015;120(6):1413-1419.
  30. Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors.Circulation 1998;97(14):1411-1420.
  31. Williams GH. Converting-enzyme inhibitors in the treatment of hypertension.N Engl J Med.1988;319(23):1517-1525.
  32. Israili ZH. Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension.J Hum Hypertens. 2000;14 Suppl 1:S73-S86.
  33. Nishimura T, Hashimoto J, Ohkubo T, et al. Efficacy and duration of action of the four selective angiotensin II subtype 1 receptor blockers, losartan, candesartan, valsartan and telmisartan, in patients with essential hypertension determined by home blood pressure measurements.Clin Exp Hypertens. 2005;27:477-489.
  34. Kumar R, Gandhi R. Reasons for cancellation of operation on the day of intended surgery in a multidisciplinary 500 bedded hospital.J Anaesthesiol Clin Pharmacol. 2012;28(1):66-69.
  35. Garg R, Bhalotra AR, Bhadoria P, et al. Reasons for cancellation of cases on the day of surgery–a prospective study.Indian J Anaesth. 2009;53(1):35-39.
  36. Twersky RS, Goel V, Narayan P, et al. The risk of hypertension after preoperative discontinuation of angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists in ambulatory and same-day admission patients.Anesth Analg. 2014;118(5):938-944.
  37. Augoustides JG. Angiotensin blockade and general anesthesia: so little known, so far to go.J Cardiothorac Vasc Anesth. 2008;22(2):177-179.
  38. Kheterpal S, Khodaparast O, Shanks A, et al. Chronic angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy combined with diuretic therapy is associated with increased episodes of hypotension in noncardiac surgery.J Cardiothorac Vasc Anesth. 2008;22(2):180-186.
  39. Cohn S. Perioperative cardiovascular medication management: ACP PIER: perioperative medication management.http://pier.acponline.org/​physicians/​diseases/​d835/​d835.html
  40. Kristensen, SD, Knuuti J, Saraste A, et al. 2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management: The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA).Eur J Anaesthesiol. 2014;31(10):517-573.
  41. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.Circulation. 2014;130(24):e278-e333.
  42. Brabant SM, Bertrand M, Eyraud D, et al. The hemodynamic effects of anesthetic induction in vascular surgical patients chronically treated with angiotensin II receptor antagonists.Anesth Analg.1999;89(6):1388-1392.
  43. Eyraud D, Brabant S, Nathalie D, et al. Treatment of intraoperative refractory hypotension with terlipressin in patients chronically treated with an antagonist of the renin-angiotensin system.Anesth Analg. 1999;88(5):980-984.
  44. Meersschaert K, Brun L, Gourdin M, et al. Terlipressin-ephedrine versus ephedrine to treat hypotension at the induction of anesthesia in patients chronically treated with angiotensin converting-enzyme inhibitors: a prospective, randomized, double-blinded, crossover study.Anesth Analg. 2002;94(4):835-840.
  45. Morales DL, Garrido MJ, Madigan JD, et al. A double-blind randomized trial: prophylactic vasopressin reduces hypotension after cardiopulmonary bypass.Ann Thorac Surg. 2003;75(3):926-930.
  46. Boccara G, Ouattara A, Godet G, et al. Terlipressin versus norepinephrine to correct refractory arterial hypotension after general anesthesia in patients chronically treated with renin-angiotensin system inhibitors. 2003;98(6):1338-1344.
  47. Morelli A, Tritapepe L, Rocco M, et al. Terlipressin versus norepinephrine to counteract anesthesia-induced hypotension in patients treated with renin-angiotensin system inhibitors: effects on systemic and regional hemodynamics. 2005;102(1):12-19.
  48. Ajayi AA, Campbell BC, Howie CA, et al. Acute and chronic effects of the converting enzyme inhibitors enalapril and lisinopril on reflex control of heart rate in normotensive man.J Hypertens. 1985;3(1):47-53.
  49. Licker M, Neidhart P, Lustenberger S, et al. Long-term angiotensin-converting enzyme inhibitor treatment attenuates adrenergic responsiveness without altering hemodynamic control in patients undergoing cardiac surgery. 1996;84(4):789-800.

ARBs prevent AT-II from binding the vasoconstricting AT1 receptors, thereby lowering blood pressure. Acting mechanistically upstream of ARBs, ACEIs prevent both the conversion of AT-I to AT-II and the inactivation of vasodilatory bradykinin. The accumulation of bradykinin itself is vasodilatory and therefore has a blood pressure–lowering effect.

Guidelines

Many authors have attempted to consolidate the literature to offer advice regarding perioperative AAB.27-29 Most providers would consider withholding the regimen on the day of surgery, especially if there is anticipated hemodynamic instability based on either patient- or surgery-related factors. The duration of holding the ACEI or ARB preoperatively would depend on the agent’s unique half-life and duration of antihypertensive effect (Table 1).30-33 The time to restart the medication is based on when the patient is hemodynamically stable postoperatively.

Table 1. Half-life and Duration of Antihypertensive Effect of Commonly Used ACEIs and ARBs
ACEI t1/2, ha,b Duration of Antihypertensive Effect, hc,d
Captopril 1.7 6-10
Enalapril 11 18-30
Lisinopril 12 18-30
Ramipril 4-18 24-60
ARB    
Candesartan 6-13 12
Losartan 1-3 11
Telmisartan 21-38 10
Valsartan 6-10 13
a Brown and Vaughan, 1998.

b Williams et al, 1988.

c Israili, 2000.

d Nishimura et al, 2005.

t1/2, half-life; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker

On the other side of the argument, there has been concern that withholding AAB might precipitate withdrawal hypertension on the day of surgery that might itself lead to problems, such as case cancellations and end-organ damage related to a hypertensive crisis. Although studies investigating reasons for case cancellations on the day of surgery34,35 list hypertension as one of the major medical reasons (medical reasons comprising 11% of case cancellation reasons), there have not been any studies linking case-cancelling hypertension to the withholding of AAB. A randomized trial of ambulatory patients that either withheld or continued their AAB the day of surgery36 demonstrated no difference in preoperative rate of hypertension, number of cases cancelled due to hypertension, postoperative hypertension, hospital length of stay, or other adverse events.

In light of the concerns regarding exaggerated perioperative hypotension in patients on AAB, the American College of Physicians initially had recommended stopping ACEIs on the day of surgery. This recommendation has since evolved to “uncertain, although they are usually continued.”37-39

The European Society of Cardiology and European Society of Anaesthesiology 2014 guidelines on perioperative AAB40 recommend initiating AAB therapy in heart failure patients not currently on AAB therapy at least 7 days in advance of surgery, and continuing therapy on the day of surgery with close monitoring.

In patients on AAB for the management of hypertension, with documented episodes of hypotension, the societies recommend considering holding the ACEI or ARB on the day of surgery. Even more vague, the latest American College of Cardiology and American Heart Association guidelines pertaining to perioperative ACEI/ARBs41 state their continuation on the day of surgery is “reasonable” (level of evidence B), and that if held they should be restarted as soon as “clinically feasible” (level of evidence C). There is, however, no published statement of recommendations by the American Society of Anesthesiologists.

Management of Hypotension

Hemodynamics are maintained by complex interactions between the cardiovascular system (preload, afterload, contractility), the autonomic nervous system, renin-angiotensin system, and arginine vasopressin system. Pharmacologic blunting of one or more of the vasoregulatory systems results in compensation by the intact systems, in order to maintain stability.

Induction of general anesthesia causes hemodynamic alterations by its effect on the sympathetic nervous system. It results in a decrease in circulating catecholamines, reduced vascular tone, and blunting of the reflex sympathetic activity in response to hypotension.

The body compensates for general anesthesia–associated hypotension via the RAAS, the sympathetic nervous system (SNS), and the vasopressinergic system.24 Thus, as anesthesia impairs the SNS in a patient with AAB, treatment with a vasopressin analog should theoretically overcome hypotension otherwise refractory to traditional means of support, such as volume, ephedrine, and phenylephrine. Multiple prospective cohort and randomized studies have corroborated this concept in the setting of vascular and cardiac surgery.42-47

In AAB-associated post-induction refractory hypotension, vasopressin analog boluses and norepinephrine infusions have been shown to be effective in raising blood pressure, with vasopressin analogs having a more rapid effect than norepinephrine.46 Prophylactic vasopressin analogs were shown to be effective in lowering post-CPB vasopressor requirement and shortening subsequent intensive care durations of care.45 However, laser Doppler of gastric mucosal perfusion suggested that perfusion was decreased more with vasopressin analogs than with norepinephrine, indicating that it might be more prone to compromising gastrointestinal microcirculation.47

Table 2. Effects of Angiotensin Axis Blockade
Decreased reflex tachycardia in response to hypotension
Decreased responsiveness to exogenous catecholamines
Lower circulating levels of:

·                   angiotensin II

·                   aldosterone

·                   arginine vasopressin

Patients on AAB are in a predominantly parasympathomimetic state with a blunting of reflex tachycardia response to hypotension.48 They have a decreased responsiveness to exogenous catecholamines and lower levels of circulating arginine vasopressin and aldosterone.49Patients on ACEI also have decreased levels of AT-II. Hemodynamic effects of AAB are summarized in Table 2.

Regardless of whether AAB medications have been withheld on the day of surgery (depending on their half-lives), the perioperative physician will likely be faced with the problem of exaggerated hypotension. This is a result of persistent tissue-based activity of these powerful drugs.7 The perioperative care of these patients should be individualized accordingly. A low threshold for invasive monitoring where indicated and adequate volume loading may help prevent refractory hypotension with induction of anesthesia. Cautious titration of induction drugs is important, with ready availability of conventional and second-line pressor agents.

Pharmacologic agents considered as first-line medications, such as phenylephrine and ephedrine, have varying efficacy in the treatment of AAB-associated hypotension.2,4,7 In most cases, these agents may be needed in higher than usual doses or might be ineffective, necessitating a switch to an alternate therapy.

Vasopressin is a peptide released in response to hypotension, and changes in serum osmolality act via V1 receptors, which cause vasoconstriction; V2 receptors, which result in antidiuresis in the kidneys; and V3, which results in release of cortisol, angiotensin, and natriuretic peptide. Synthetic vasopressin, with a half-life of 4 to 20 minutes, has been described as a second-line agent to treat refractory hypotension in AAB.

Catecholamines such as epinephrine, norepinephrine, and dopamine have been efficacious in the treatment of exaggerated hypotension. Studies have suggested that norepinephrine may be better at preserving the heart rate by avoiding reflex bradycardia.46,47

Anticholinergics such as atropine and glycopyrrolate have been described as second-line agents used in conjunction with other agents to counter the parasympathomimetic state.

Methylene blue, a competitive nitric oxide antagonist, has a half-life of 40 minutes. It decreases the levels of vasodilatory cGMP with a reported efficacy in situations of refractory hypotension.

Conclusion

Despite all the questions that have been investigated about perioperative use of ACEIs/ARBs, there remains much to learn. In the absence of a randomized controlled trial, the risks associated with continuing or discontinuing AAB on the day of surgery are still unclear, leaving conflicting data and much speculation:

  • Are there specific patient or surgical variables that might help tease out who might benefit most from withholding versus continuing perioperative AABs?
  • Are there benefits to maintaining AAB therapy throughout the perioperative period analogous to those described with β-blockers and statin medications?
  • Should we be initiating AAB therapy in heart failure patients with a known scheduled surgery in the near future?

It would seem that members of the American Society of Anesthesiologists would benefit from the publication of a practice advisory or guideline based on a thorough discussion addressing this topic. In the meantime, we must remain mindful of the potential issues one might encounter in practice and strive to do what is best in the context of our individual patients. Until further evidence is available, the authors believe that:

  1. It is reasonable and less confusing for most patients to continue AAB up to the day of surgery.
  2. Regardless of whether AAB has been withheld on the day of surgery, the perioperative physician must be prepared to face the problem of refractory hypotension. Depending on the individual situation, the physician should perhaps maintain a lower threshold for the placement of invasive monitors such as arterial catheters.
  3. Euvolemia must be ensured by adequate preloading prior to the induction of anesthesia.
  4. Gradual titration of induction agents such as propofol, or preferential use of relatively hemodynamically stable induction agents such as etomidate, may be justified in these cases.
  5. The choice of inhalational anesthetic is unlikely to make a difference; however, desflurane has the theoretical advantage of stimulating greater sympathetic activity compared with isoflurane or sevoflurane.
  6. Higher doses of first-line agents (phenylephrine, ephedrine, or glycopyrrolate) for the treatment of perioperative hypotension may be necessary in patients on AAB.
  7. For refractory hypotension, additional therapy such as vasopressin, norepinephrine, epinephrine, and anticholinergics may be necessary.
  8. Methylene blue (1-2 mg/kg), a competitive nitric oxide antagonist, may be considered as a last resort.

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