Perioperative Use Of RAAS Antagonists
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Perioperative Use Of RAAS Antagonists

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A review of the existing evidence that supports the current practice in perioperative medicine regarding Renin-angiotensin-aldosterone system antagonists, mainly ACE inhibitors and Angiotensin type 1 ...

A review of the existing evidence that supports the current practice in perioperative medicine regarding Renin-angiotensin-aldosterone system antagonists, mainly ACE inhibitors and Angiotensin type 1 receptor blockers (ARB's).
Presented as the Cleveland Clinic Hospital Medicine Grand Rounds on April 1, 2009. CME AMA Category 1 - 1 hour.

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Perioperative Use Of RAAS Antagonists Perioperative Use Of RAAS Antagonists Presentation Transcript

  • Perioperative use of RAAS Antagonists: Evidence and Controversy Moises Auron MD, FAAP Department of Hospital Medicine Cleveland 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.
    McCarthy Anaesthesia. 1990 Mar;45(3):243-5.
  • 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 Na 2+ depletion - prevented by ensuring proper intravascular volume status”
    Tohmo and Karanko J Neurosurg Anesthesiol. 1993 Jan;5(1):13-21. Acta Anaesthesiol Scand. 1996 Jan;40(1):132-3.
  • 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 - ↑ DO 2 , ↑ 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