1. Journal Club Britni Fabacher Hebert, PGY 4

2. Angiotensin Blockade in the Perioperative Period  Case Presentation  Brief Review of Angiotensin Blockage  Medications implicated  Is there increased risk of hypotension perioperatively?  When would we hold which agents and in whom?  What are the possible downfalls of missed doses preoperatively  Discussion

3. Case Presentation  55 yo F with HTN and degenerative joint disease of the spine is scheduled for elective cervical fusion. She is on losartan 75 mg daily. Within minutes of induction, her systolic blood pressure drops below 70 mmHg. IV fluids, ephedrine, norepinephrine and epinephrine are unsuccessful. After 30 minutes, systolic blood pressure normalizes.  Should her losartan have been held prior to surgery?

4. Brief Review of Angiotensin Effects and Blockade

7. Is there increased risk for hypotension?

8. Background  Early 1990s  Established that blood pressure control intraoperatively is beneficial  Established that beta blockers and calcium channel blockers safely stabilize blood pressure during induction  Case reports question safety of ACEI/ARBs at induction  Reports of severe refractory hypotension

9. Coriat et al, 1994  Randomized, control, non-blinded trial  Inclusion criteria:  Scheduled for peripheral vascular surgery lasting < 2hours  chronic enalapril or captopril prior to peripheral vascular surgery  Admitted at least 3 days prior to surgery  Exclusion Criteria  Treatment with ACEI for diagnosis other than HTN  SBP > 170 at enrollment  Beta blocker or clonidine use  Recent myocardial infarction, unstable angina or IHD on nitrates

10. Design  Randomized to one of two groups  Continuation of ACEI through the morning of the surgery  Discontinuation of ACEI the day prior to surgery  Induction Sequence was protocoled  Blood pressure, heart rate monitored by radial arterial line  Free of surgical stimulation for 10 minutes after induction  Protocol to administer fluids and ephedrine for SBP < 90 Coriat et al, 1994

11. Parameters  Blood Pressure  Heart Rate  At 3-5 days preoperatively & Preinduction:  ACEI plasma levels  Plasma renin activity  Plasma converting-enzyme activity  Catecholamine levels were assessed at pre- & postinduction, 2 minutes after ventilation and during any hypotensive episodes Coriat et al, 1994

12. Results Coriat et al, 1994

13. Results Coriat et al, 1994

14. Results Coriat et al, 1994

15. Results Coriat et al, 1994

16. Discussion  Not blinded  Single center study  Very low patient numbers  Not powered to detect potentially large outcomes, including clinically significant hypertensive episodes  Did not assess longer term outcomes of concern: neurologic sequelae, renal insufficiency, myocardial infarction  Did not show the refractory nature of said hypotension discussed in the literature (all episodes responded to ephedrine) Coriat et al, 1994

17. Rosenman et al  Meta- Analysis by the Mayo Clinic in 2008  Searched 7 major databases for articles from 1981 – 2006  Inclusion Criteria:  Prospective cohort or controlled trials  Enrolling adults > 18 years old for nonemergent surgery  Chronic use of ACEI or ARB  Clinically significant outcomes asessed  Random effects model used and I 2 calculated

18. Results Rosenman et al

19. Results Rosenman et al

20. Results Rosenman et al

21. Results Rosenman et al

22. Limitations  Significant variability between studies  I 2 59%  Possibility of publication bias is very real  Very small numbers preclude assessment of clinically important outcomes  Though reported, the studies were not designed to assess MI as outcome

23. Schirmer & Schurmann, 2007  Excluded by dates from the Meta-analysis  Article in German, only reviews available in English  Randomized, Double Blinded, Control study of 100 patients on chronic ACEI

24. Results Schirmer & Schurmann, 2007

25. Results Schirmer & Schurmann, 2007

26. Auron et al  In depth review of the available evidence in noncardiac surgery  Notable Study findings  Bertrand et al & Comfere et al: A cutoff of 10 hours for ARB withdrawal seemed significant  Bertrand et al: ARB use has similar, if not more profound/frequent episodes of hypotension at induction compared to ACEI  Rosenman et al: Studied ACEI/ARB in combination with other antihypertensive agents. Only the group with ACEI/ARB + diuretics showed significant hypotension

27. Downfalls of Withdrawal?  Neuroprotective Effect of RAAS Antagonism  Decrease in POAF  Renoprotective?

28. Conclusion  Data quality is moderate at best  There does seem to be increased risk of hypotension, possibly refractory, with continuation of ACEI/ARBs prior to noncardiac surgery  Effect on clinically relevant outcomes is unclear  Target populations : + dehydration and/or use of diuretics  Continue in those with systolic heart failure as indication for ACEI  Cessation of drug at least one half life prior to induction is goal

29. Discussion & Questions

30. Resources  Auron M, Harte B, Kumar A, et al. Renin angiotensin system antagonists in the perioperative setting: clinical consequences and recommendations for practice. Postgrad Med J (2011). doi:10.1136/pgmj.2010.112987  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;89:1388e92.  Bertrand M, Godet G, Meersschaert K, et al. Should the angiotensin II antagonists be discontinued before surgery? Anesth Analg 2001;92:26e30.  Coriat P, Richer C, Douraki T, et al. Influence of chronic angiotensin-converting enzyme inhibition on anesthetic induction. Anesthesiology 1994;81:299e307.  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;22:180e6.  McCarthy GJ, Hainsworth M, Lindsay K, et al. Pressor responses to tracheal intubation after sublingual captopril. A pilot study. Anaesthesia 1990;45:243e5.  Rosenman DJ, McDonald FS, Ebbert JO, et al. Clinical consequences of withholding versus administering renin-angiotensin- aldosterone system antagonists in the preoperative period. J Hosp Med 2008;3:319e25.  Schirmer U, Schurmann W. Preoperative administration of angiotensin-converting enzyme inhibitors. Anaesthesist 2007;56:557e61.