Post on 12-Nov-2014
description
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.
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.
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.
• 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.
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