perioperative use of renin-angiotensin-aldosterone system antagonists
DESCRIPTION
The clinician find a difficulty in deciding whether to continue or not the Renin-Angiotensin-Aldosterone Antagonists perioperatively. The evidence supporting and against its use is presented.The clinician is advised about considering Aliskiren in the same context of RAAS antagonists.TRANSCRIPT
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.
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.
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