Perioperative use of RAAS Perioperative use of RAAS Antagonists: Evidence and Antagonists: Evidence and

ControversyControversy

Moises Auron MD, FAAPMoises Auron MD, FAAP

Department of Hospital MedicineDepartment of Hospital Medicine

Cleveland ClinicCleveland Clinic

Objectives

• Appraise the evidence supporting the current perioperative management of Renin-Angiotensin-Aldosterone system (RAAS) antagonists in non-cardiac surgery.

• Appraise the existence of newer RAAS antagonists such as Aliskiren (direct renin inhibitor) and its management in the perioperative setting.

Introduction

• The renin-angiotensin-aldosterone system (RAAS) antagonists (RAAS-antagonists) include: – Angiotensin-converting enzyme inhibitors

(ACEI) – Angiotensin II receptor subtype 1 blockers

(ARB)– Direct renin inhibitors (Aliskiren)– Aldosterone antagonists (Spironolactone,

Eplerenone)

RAAS antagonists: indications

• Hypertension

• Congestive heart failure

• Coronary artery disease

• Diabetic nephropathy

• Prevention of progression of chronic renal failure

Ann Intern Med. 2008 Jan 1;148(1):16-29. J Card Fail. 2008 Apr;14(3):181-8. J Gen Intern Med. 2006 Dec;21(12):1242-7. Lancet. 2005 Dec 10;366(9502):2026-33. Curr Pharm Des. 2007;13(13):1335-45.

RAAS antagonists and surgery

• Intra-operative hypotension after induction of anesthesia

• Post-operative acute renal failure

• Not associated with increased mortality

• All based on small studies

Anesth Analg. 1999 Nov;89(5):1143-55.Anesth Analg. 2001 Nov;93(5):1111-5.

J Intern Med. 2008 Sep;264(3):224-36.

J Intern Med. 2008 Sep;264(3):224-36.

Pharmacology of RAAS antagonists: perioperative implications

• Sympathetic blockade• Increase in the bioavailability of the vasodilatory agents:

– Bradykinin– Nitric oxide – Prostacyclines

• Inhibition of the vasoconstrictor effects of angiotensin II• Reduction in the secretion of aldosterone and ADH

– Decrease in renal salt and water reabsorption.

• Pleiotropic effects – inhibition of the different angiotensin peptides as well as both

renin and pro-renin receptors

Circulation. 2000 Jul 18;102(3):351-6.J Intern Med. 2008 Sep;264(3):224-36.

Effects of anesthesia on the BP

• Increased venous pooling of blood

• Decreased cardiac output

• Arterial hypotension.

Curr Pharm Des. 2003;9(9):763-76

Intra-operative BP

• Maintained by:– RAAS– Sympathetic nervous system – Arginine-vasopressine (AVP)

• Secretion stimulated as well by Angiotensin II

Curr Pharm Des. 2003;9(9):763-76

Intra-operative BP

• Multilevel effect for maintenance of intra-operative BP – Adequate hydration– Sympathomimetics– AVP agonists (terlipressin)

Pharmacogenomics of RAAS

• Genetic susceptibility to the RAAS-antagonists affected by single nucleotide polymorphism (SNP) mutations in:– Angiotensinogen– Angiotensin receptor 1– Angiotensin receptor 2.

• Affects intraoperative hemodynamic response to RAAS-antagonists.

Circulation. 2007 Feb 13;115(6):725-32. J Mol Med. 2008 Jun;86(6):637-41.

ACEI

Am J Health Syst Pharm. 2004 May 1;61(9):899-912.

ARB

Circulation 2001;103;904-912.

EVIDENCE AGAINST

RAAS-ANTAGONISTS

Cleveland Clinic: IMPACT

• Current practice: discontinue both ACEI and ARB on the morning of surgery.

• Based on several small, controlled, randomized studies which found an increased frequency of refractory hypotension requiring intensive intravenous fluids and vasopressors after the induction of anesthesia when RAAS-antagonists were not discontinued preoperatively.

Cleve Clin J Med. 2006 Mar;73 Suppl 1:S82-7.

• Sublingual captopril (12.5 mg and 25 mg) vs. placebo 25 minutes before ETI

• N = 40

• Captopril - increased ↓BP (P <0.05) within 3 minutes after ETI– No significant difference between both doses.

Anaesthesia. 1990 Mar;45(3):243-5.

McCarthy

Coriat

• HTN patients on chronic ACEI - randomized 2 groups, - administration of ACEI in AM of surgery vs. withdrawn.

• Requirement of ephedrine:– Captopril (n = 36) 64% vs. 12% (P<0.05) – Enalapril (n = 20) 100% vs. 18% (P<0.005)

Anesthesiology. 1994 Aug;81(2):299-307.

Brabant• Hemodynamic response to induction between

ARB, beta-blockers (BB), Ca channel blockers (CB) and ACEI.

• ↓BP : SBP ↓ of > 30% from the preoperative value or an absolute SBP < 90 mm Hg. – ARB (12 of 12)– BB/CB-treated patients (27 of 45)– ACEI (18 of 27) (P< 0.05).

• ARB group – increased refractory to adrenergic agents (4 of 12) vs. BB/CB group (0 of 45) vs. ACEI (1 of 27).

• ↓BP - responsive to a vasopressin agonist.

Anesth Analg. 1999 Dec;89(6):1388-92.

Bertrand

• Patients on chronic therapy with ARB (N = 37)• 18 D/C ARB the day before sx vs. 19 received

ARB 1 h prior to induction.• ARB in AM of surgery - > frequent episodes and

longer duration of ↓BP.– ↓BP - refractory to adrenergic agents, requiring

terlipressin. – ARB dose < 10 hours of induction - > frequent

hypotensive episodes.

Anesth Analg. 2001 Jan;92(1):26-30.

Comfere

• Patients on chronic anti-HTN treatment with ACEI/ARB (N = 267)

• Incidence of ↓BP during the first 30 minutes after induction of anesthesia was more frequent in patients whose most recent ACEI/ARB was taken < 10 h. (60% vs. 46%, O.R. 1.74 (95% C.I. 1.03 to 2.93, P = 0.04)

Anesth Analg. 2005 Mar;100(3):636-44.

Shirmer

• Patients on chronic antiHTN with ACEI (N = 100) RCT.

• 50 received ACEI in AM of surgery vs. 50 who didn’t.

• BP and HR were significantly lower in the ACEI group requiring supportive adrenergic agonists – 17 of 50 in the ACEI vs. 5 of 50 in the

withdrawal group. Anaesthesist. 2007 Jun;56(6):557-61.

Licker

• Pts with CAD undergoing non-cardiac surgery • N = 32; 16 receiving chronic ACEI and 16 didn’t.• Induction-related ↓BP: 9 (ACEI) vs. 2 (control).

– Diminished response to phenylephrine in the ACEI group.

– Decreased -adrenergic vasoconstrictive response?

Can J Anaesth. 2000 May;47(5):433-40.

Kheterpal• Prospective observational study: N=

12,381 • Diuretics + ACEI/ARB increased ↓BP and

requirement for vasopressors vs. ACEI alone or when combination with Ca-vs.

• Propensity score matching and ROC curve analysis was done to control for comorbidities that may acquaint for hemodynamic variations between groups.

J Cardiothorac Vasc Anesth. 2008 Apr;22(2):180-6.

Rosenman

• Systematic review • Random-effects meta-analysis (incorporates

within-study and between-study variability)• 5 studies; N = 434 • Preoperative RAAS-antagonists on the day of

surgery – increased likelihood of ↓BP requiring vasopressors after induction (RR 1.50, 95% CI 1.15 to 1.96).

• No difference noted in incidence of peri-operative MI between groups (RR 0.41, 95% CI 0.07 to 2.53).

J Hosp Med. 2008 Jul;3(4):319-25.

Metaanalysis: Hypotension

J Hosp Med. 2008;3:319–325

Metaanalysis: AMI

J Hosp Med. 2008;3:319–325

EVIDENCE SUPPORTING RAAS-ANTAGONISTS

• None of the studies showed any significant difference in postoperative complications.

• No proof of association between ↓BP and:– Major CV complications – Stroke– Renal failure– ICU LOS– Increased mortality

• Heropoulos– Assessment of hemodynamic and hormonal responses to:

• ETI• Incision• Limb-tourniquet inflation

– RCT; N = 30 patients undergoing limb surgery – Enalaprilat vs. placebo.

• - 1.25 mg IV 20 min prior to induction vs. 0.625 mg IV at the onset of tourniquet-associated hypertension.

– Venous blood samples for PRA and catecholamine (pre-intubation, 3 min post-intubation, 3 min post-incision, at onset of tourniquet hypertension, 3 min post-extubation and 1 hr postoperatively)

• No significant differences in catecholamine levels.

Anesth Analg. 1995 Mar;80(3):583-90.Drugs. 2007;67(7):1053-76.

• Pre-operative enalapril in balanced hypotensive anesthesia for cerebrovascular surgery.

• Controlled ↓BP - minimize intraoperative bleeding. RCT vs. placebo.

• Enalapril ↓ HTN response to ETI, ↓ postoperative vasodilators, more stable BP control.

• “Preoperative fasting may be the contributor to peri-operative ↓BP - improper fluid balance and Na2+ depletion - prevented by ensuring proper intravascular volume status”

J Neurosurg Anesthesiol. 1993 Jan;5(1):13-21.Acta Anaesthesiol Scand. 1996 Jan;40(1):132-3.

Tohmo and Karanko

ACE and Atrial Fibrillation

• Non surgical patients - ACEI - 50% reduction in the risk of developing new-onset atrial fibrillation (AF)

• White– Preop ACEI or ARB and postop AF following cardiac

surgery (CABG or valvular surgery) – N = 338 patients (175 (51.8%) received preoperative

ACEI or ARB). – No association found between preop ACEI/ARB and

reduction in postop AF (adjusted OR 0.71, 95% CI 0.42 to 1.20).

– Larger number of patients is needed.

Eur J Cardiothorac Surg. 2007 May;31(5):817-20.

Boldt

• RCT (N = 88)• CABG • 4 groups of 22 patients each

– intravenous enalapril– enoximone (phosphodiesterase inhibitor)– clonidine – placebo (normal saline).

• Enalapril - following induction of anesthesia - lower levels of cardiac enzyme release– Cardioprotective effect of RAAS-antagonists against

ischemia/reperfusion injury

Heart. 1996 Sep;76(3):207-13.

Pigott

• N = 40 patients undergoing CABG • All patients were on chronic ACEI

– 20 continued – 20 suspended

• No significant difference between the groups in the frequency of hypotension during anesthesia.

• The group that withheld ACEI had postoperative hypertension that required vasodilators

Br J Anaesth. 1999 Nov;83(5):715-20.

PERI-OPERATIVE RAAS-ANTAGONISTS AND RENAL FUNCTION

Colson

• RCT (N = 18)

• Short-term (2 days) pre-op captopril vs. placebo in CABG

• Captopril - better preserved RPF and GFR during CPB vs. placebo treated patients.

Anesthesiology. 1990 Jan;72(1):23-7.

Licker

– RCT (N = 20)– 11 – i.v. enalapril 50 mcg/kg; 9 – NS 0.9% at

induction of anesthesia for aortic surgery. – After infra-renal aortic cross

• Enalapril - ↑ DO2, ↑ splachnic perfusion, ↑GFR @ 24 h post-op. (43)

Br J Anaesth. 1996 May;76(5):632-9.

Benedetto• RCT (N= 536)

• Effect of pre-op ACEI on AKI (↓GFR > 50%) – CABG.

• Preop ACEI (N = 281) - ↓ post-op AKI (O.R. 0.48; 95% CI, 0.23 to 0.77; P < 0.04)

• Incidence of AKI requiring dialysis:– 2.4% in ACEI group vs. 6.3% in controls (P =

0.03). (44)

Ann Thorac Surg. 2008 Oct;86(4):1160-5.

Cittanova

• Prospective study (N = 249) - aortic surgery

• Chronic treatment with ACEI (withheld in AM) - only factor associated with significative postoperative renal impairment (O.R. 2.01 95% C.I. 1.05 to 3.83)

Anesth Analg. 2001 Nov;93(5):1111-5.

Kincaid

• Retrospective (N= 1209) – CABG

• Preop ACEI along with intra-op aprotinin – ARF (OR 2.9, 95% CI 1.4 to 5.8, P < 0.0001).

Ann Thorac Surg. 2005 Oct;80(4):1388-93

RAAS-ANTAGONISTS IN NEURAXIAL ANESTHESIA

• Thoracic epidural anesthesia – resultant ↓BP from attenuation of efferent sympathetic drive– ↑ vasopressin concentrations – renin activity remains unchanged.

Eur J Anaesthesiol. 1992 Jan;9(1):63-9.Anesthesiology. 1994 May;80(5):992-9.

• Hohne– Assessment of the initial (first 20 minutes)

hemodynamic effect of ACEI in spinal anesthesia for lower body procedures.

– RCT (21 on chronic ACEI vs. 21 control)– Decrease in BP was similar.– Plasma vasopressin and norepinephrine

levels increased.

Acta Anaesthesiol Scand. 2003 Aug;47(7):891-6.

Aliskiren

• Direct renin inhibitor

• Long half life (30 - 40h)

• Increased renal vasodilatory effect vs. ACEI and ARB. (59)

• Low oral bioavailability– Terminal half life is 24 hrs.

• Weak antihypertensive (second-line agent)

J Am Coll Cardiol. 2008 Feb 5;51(5):519-28.Circulation. 2008 Aug 12;118(7):773-84.Am J Health Syst Pharm. 2008 Jul 15;65(14):1323-32.

Conclusions

• RAAS-antagonists - associated with a variable incidence of hypotension during the initial 30 minutes after induction of anesthesia in non-cardiac surgery

• These hypotensive episodes have not been linked to any significant postoperative complications.

• The ACEI/ARB should be held at least 10 hours or for one dose before the induction of anesthesia.

Conclusions (cont.)

• Careful hemodynamic monitoring

• Prevention of hypovolemia

• When to continue RAAS-antagonists?– Complicated hypertensive patient– Chronic heart failure of ischemic heart

disease– Cardiac surgery– Requires discussion with anesthesiologist