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Three Part Question

In [patients prior to cardiac surgery] should [angiotensin converting enzyme inhibitors/angiotensin II receptor antagonists] be omitted to avoid [postoperative vasodilation]?

Clinical Scenario

You are clerking a patient who has been admitted for elective coronary artery bypass grafting (CABG) the next day. The responsible consultant asks you to omit the morning dose of ACE inhibitor for this patient. When you ask him ‘why?’ he replies that patients who get a morning dose of ACE inhibitor before surgery need more vasoconstrictors and inotropes postoperatively. Although you omit the morning dose of ACE inhibitor for this patient, however, you are confused as none of the other consultants in the unit practice this strategy. To resolve this issue you decide to carry out a literature search.

Search Strategy

The English language scientific literature was reviewed primarily by searching Medline from 1950 through November 2007 using Ovid interface.

[Angiotensin converting enzyme inhibitors.mp OR exp ACE inhibitors OR Angiotensin II receptor blockers.mp OR exp Angiotensin II type 1 receptor blockers] AND [CABG.mp OR exp Thoracic surgery/OR Coronary art$ bypass.mp OR Cardiopulmonary bypass.mp OR exp Cardiovascular surgical procedures/OR exp Thoracic surgical procedures/OR exp Coronary artery bypass] AND [Vasodilation.mp OR exp vascular resistance.mp OR vasoplegi$.mp].

Search Outcome

The ‘related articles’ function was used to broaden the search and all abstracts, studies, and citations scanned were reviewed. The reference lists of articles found through these searches were also reviewed for relevant articles.
A total of 421 papers were found using the search strategy. Eleven papers including three RCTs were deemed to represent the best evidence on the topic and are summarised in the Table

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Lee et al, 2005, Korea	80 OPCAB patients divided into ACEI group (n=43) and control group (n=37)	Case control study (level 3b)	Haemodynamic parameters measured at 5 points after pericardiotomy (T1), 10 min after the application of stabiliser to perform anastomoses of LAD (T2), OM (T3), and RCA (T4), and after pericardial suturing (T5)	No significant difference in the haemodynamic parameters measured were detected between the two groups, except for cardiac output, which was found to be significantly greater in the control group (P<0.05)	Small sample size Non-randomised design Multiple confounding factors such as diabetes, hypertension which can affect haemodynamic parameters
			Volume of noradrenaline infused during T2	Control group: 22.7±28.9 µg vs. ACEI group: 35.8±54.8 µg (P=ns)
			Volume of noradrenaline infused during T3	Control group: 39.8±47.3 µg vs. ACEI group: 73.7±92.8 µg (P<0.05)
			Volume of noradrenaline infused during T4	Control group: 39.8±41.8 µg vs. ACEI group: 63.2±87.3 µg (P=ns)
			Total volume of noradrenaline infused	Control group: 92.1±95.5 µg vs. ACEI group: 198.8±237.0 µg (P<0.05)
Devbhandari et al, 2004, UK	Survey of 167 practicing UK cardiac surgeons. 105 responded	National Survey (level 5)	% age who felt benefit of stoppage of ACEI prior to cardiac surgery	39%	63% response rate Only UK surgeons surveyed
			% age who felt that the use of ACEI leads to vasodilation resulting in increased usage of fluids, inotropes and vasoconstrictors	63%
			% age who felt it was harmful to stop ACEI prior to cardiac surgery	38%
			% age that actually practiced stoppage of ACEI prior to cardiac surgery made no difference	20%
			% age that actually practiced stoppage of ACEI prior to cardiac surgery	39%
Bertrand et al, 2001, France	37 patients chronically treated with AIIA for hypertension undergoing major vascular surgery were randomly assigned to two groups Group I: AIIA discontinued on the day before surgery (n=18) Group II: AIIA given 1 hr before anaesthesia (n=19)	RCT (level 1b)	Haemodynamic variables during induction of anaesthesia	Systolic arterial pressure was significantly decreased in Group II at 5, 15 and 23 mins after induction of anaesthesia (P<0.05)	Haemodynamic study ended at incision
			Episodes of hypotension	AIIA withdrawn: 1 ± 1; AIIA given: 2±1 (P<0.01)
			Patients developing at least 1 episode of hypertension	AIIA withdrawn: 12; AIIA given: 19 (P<0.01)
			Duration of an episode of hypotension	AIIA withdrawn: 3 ± 4 min: AIIA given: 8 ± 7 min (P<0.01)
			Dose of ephedrine (mg)	AIIA withdrawn: 10 ± 10; AIIA given 15 ± 9 (P=NS)
			Dose of neosynephrine (ug)	AIIA withdrawn 0 ± 0; AIIA given: 47 ± 86 (P<0.05)
			Dose of terlipressin (mg)	AIIA withdrawn: 0 ± 0; AIIA given: 0.3 ± 0.5 (P<0.01)
Mekontso-Dessap et al, 2001, France	36 patients undergoing CABG who developed vasoplegic shock (VS) were compared with 72 control patients without post-CPB cardiogenic or VS	Case control study (level 3b)	Multivariate logistic regression analysis to identify predisposing factors for the development of VS after CPB independent of ventricular function	Preoperative ACEI and IV heparin were independent predictors for post-CPB VS (relative risk of 2.26 and 2.78 respectively)	Small sample size Non-randomised design
Carrel et al, 2000, Switzerland	800 consecutive patients undergoing elective CABG and/or valve replacement	Cohort study (level 2b)	Incidence of postoperative low SVR	21.8%	Non-randomised design
			Multivariate logistic regression analysis to identify predisposing factors for the development of postoperative low SVR after CPB	Temperature and duration of CPB, total cardioplegic volume infused, reduced left ventricular function, and preoperative treatment with ACEI were predictive factors for early postoperative vasoplegia
Piggott et al, 1999, UK	40 patients with good left ventricular function undergoing CABG, allocated randomly to continue ACE inhibitor medication before surgery (Group 1: n=20) or omit (Group 2: n=20)	RCT (level 1a)	Haemodynamic measurements of heart rate and arterial pressure were made at the following times: on the ward before surgery; before and after induction of anaesthesia; after intubation; before and after sternotomy; before cannulation of the aorta; after weaning from CPB; at skin closure; on admission to cardiac recovery; and hourly for the first 2 h in the cardiac recovery unit	Arterial pressure measured in the ward before surgery before surgery (before omitting ACE inhibitors) was similar in both groups (P=NS), but patients in group 2 had a significantly greater mean arterial pressure over the whole study compared to patients in group 1 (P<0.05)	Small sample size Only patients with good left ventricular function were recruited
			Measurements of cardiac output, CVP, SVR, and PAWP were first performed after induction of anaesthesia and before commencement of surgery and thereafter at the same intervals as above	There was no sig difference between groups in heart rate, CVP or PAWP There was an overall increase in SVR in group 2, particularly noticeable after CPB (P<0.05)
			No of patients needing metaraminol after induction	Group 1: 3; group 2: 1 (P=ns)
			No of patients needing epinephrine after CPB	Group 1: 2; group 2: 1 (P=ns)
			No of patients needing norepinephrine after CPB	Group 1: 2; group 2: 1 (P=ns)
			No of patients needing GTN after CPB	Group 1: 7; group 2: 16 (P<0.05)
			GTN total (mg)	Group 1: 10.7±3.6; group 2: 21.6±13.0 (P<0.05)
			Metaraminol total (mg)	Group 1: 8.6±3.7; group 2: 5.2±1.9 (P<0.05)
Boeken et al, 1999, Germany	240 patients undergoing CABG or valve surgery were divided into 3 matched groups (group A: pre and postoperative ACEI; group B:ACEI only pre-, not postoperatively; group C: no ACEI)	Case control study (level 3b)	The need for catecholamines	Intraop. A: 35%, B: 35%, C: 15%; postop. A: 21.2%, B: 16.2%, C: 10% (P<0.05)	Non-randomised design Patients with post-operative ACEI therapy also included
			The incidence of a 'post-perfusion syndrome' or systemic inflammatory response syndrome (SIRS)	In the ACEI groups (A and B) there were 9 patients with a postoperative SIRS, only 2 cases in group C
			The incidence of impaired intestinal microcirculation	4 patients of group B
Webb et al, 1998, UK	96 patients undergoing CABG were randomised to quinapril 20 mg (n=47) once daily or placebo (n=49) in double-blind fashion, continued for up to 6 weeks prior to operation	RCT (level 1b)	Measurement of Left Ventricular function at the start of the study	Quinapril group: 54.9 (13.8)% vs. Placebo group: 55.6 (13.2)% (P=ns)	Small sample sizeOther anti-anginal drugs with varying mechanisms of action not discontinued
			Measurement of Left Ventricular function 3 months following surgery, after recommencement of pre-surgery anti-anginal therapy for 1 week	Quinapril group: 58.1 (13.6)% vs. Placebo group: 56.9 (12.6)% (P=ns)
			Effects on systematic vascular resistance (SVR) during bypass were calculated from perfusion records and vasoconstrictor use	The intra-operative BP and the SVR during bypass in the two treatment groups were not significantly different (Ps0.94)
			The safety of the addition of quinapril to the anti-anginal regimen was assessed by measurement of systemic blood pressure (BP) after the first dose of study medication, measurement of intra-operative BP, administration of inotropes and any intra-operative complications	No first dose hypotension 42 patients in the placebo group and 40 patients in the quinapril group required inotropes (P=ns)
Deakin et al, 1998, UK	62 patients undergoing CABG divided into two groups: ACEI group (n=21) and control (n=41)	Case control study (level 3b)	SVR was calculated at 1 min intervals during the rewarming phase of hypothermic CPB	Mean SVR in the ACE group was 978 dyne/s per cm5 and in the control group was 1194 dyne/s per cm5 (Ps0.006)	Small sample size Non-randomised design The study did not distinguish whether the observed hypotension was a result of low SVR or low cardiac output
			Mean arterial pressure	Mean arterial pressure was 48.8 mmHg in the ACE group and 56.3 mmHg in the control group (Ps0.004)
			The use of vasoactive drugs during and immediately after termination of CPB was recorded	There was a significant difference in vasoactive drug requirements between the groups (P-0.01)
Licker et al, 1996, Switzerland	Patients with preserved left ventricular function undergoing mitral valve replacement or CABG were divided into two groups according to preoperative drug therapy: patients receiving ACE inhibitors for at least 3 months ACEI group, (n=22) and those receiving analysis other cardiovascular drug therapy control group (n=19)	Case control study (level 3b)	Systemic haemodynamic variables were recorded before surgery, after anaesthesia induction, during sternotomy, after aortic cross clamping, after aortic unclamping, as well as after separation from CPB and during skin closure	At no time did the systemic haemodynamics and the need for vasopressor support differ between the two treatment groups	Small sample size Non-randomised study design
			Dose of fentanyl and midazolam needed for induction	Significantly less fentanyl and midazolam were given in the ACEI group (P-0.05)
			Blood was sampled repeatedly up to 24 h after surgery for hormone analysis	Plasma renin activity was significantly greater in the ACEI group throughout the whole 24 hours study period Plasma concentrations of angiotensin II did not differ between the two groups Similar changes in catecholamines angiotensin II, and plasma renin activity were found in the two groups in response to surgery and CPB The pressor and constrictor effects of norepinephrine infusion were attenuated markedly in the ACEI group: the dose-response curves were shifted to the right and the slopes were decreased at the two study periods
			Determination of PD (20) of norepinephrine during hypothermic CPB	ACEI group: 0.08 µ/kg vs. control group: 0.03 µ/kg (P-0.05)
			Determination of PD (20) of norepinephrine after separation from CPB	ACEI group: 0.52 µ/kg vs. control group: 0.1 µ/kg (P-0.05) In both groups, PD (20) was significantly less during hypothermic CPB than in the period immediately after CPB
Turman et al, 1995, USA	4301 patients undergoing elective CABG and/or valve surgery divided into two groups:ACEI group (n=512) and control group (n=3782)	Case-control study (level 3b)	Influence of chronic preoperative ACE inhibitor use and other perioperative factors on the incidence of vasoconstrictor therapy required to maintain systolic blood pressure at more than 85 mmHg despite a normal cardiac output after CPB	At least two vasoconstrictor infusions (phenylephrine, norepinephrine, or dopamine) were required for low perfusion pressure despite adequate cardiac output after CPB in 7.7% of 519 ACE-inhibited patients and 4.0% of 3782 patients not receiving ACE inhibitors (P=0.0001). In the first 4 h after arrival in the ITU, the need for vasoconstrictor infusions to treat hypotension with adequate cardiac output did not differ. In the first 4 h after arrival in the ITU, more ACE inhibited patients (6.4%) exhibited low values of SVR (<600 dyne.s.cm5) than patients not receiving ACE inhibitors (2.8%; P=0.0002)	Large sample size Non-randomised design Interaction between opioid anaesthesia and ACE inhibitors may enhance the vasodilator response
			Logistic regression analysis to determine risk factors requiring 2 vasoconstrictor infusions after CPB	Preoperative ACE inhibitor use, congestive heart failure, poor left ventricular function, duration of CPB, reoperative surgery, age, and opioid anaesthesia

Comment(s)

Lee et al.in a case-control study showed that pre-operative ACEI therapy significantly increased the amount of vasoconstrictor necessary to maintain the target blood pressure during obtuse marginal anastomosis during off-pump CABG.

Devbhandari et al. published the results of a UK national survey to address the issue whether it is beneficial or not to stop ACEI before cardiac surgery. Questionnaires were sent to 167 currently practicing UK cardiac surgeons, out of which 105 (62%) replied back. Analysis of their responses revealed that majority (63%) were of the opinion that the use of ACEI leads to vasodilatation resulting in increased usage of fluids, inotropes and vasoconstrictors. However, there was no agreement on the issue of stopping it prior to surgery. Forty-one (39%) felt it was beneficial to stop the ACEI prior to surgery whereas 40 (38%) of them thought it was harmful to stop it. Twenty-one (20%) were of the opinion that it made no difference. Thirty-nine per cent of respondents practiced stopping the drug prior to planned operation.

Bertrand et al. [4] in a small RCT recruiting 37 patients, randomized to Group I: AIIA discontinued on the day before surgery (n=18); Group II: AIIA given 1 h before anaesthesia (n=19), showed that more severe hypotensive episodes (P<0.01), requiring vasoconstrictor treatment, occur after induction of general anaesthesia in patients chronically treated with AIIA and receiving this drug on the morning before operation, in comparison with those in whom AIIA were discontinued on the day before operation.

Mekontso-Dessap et al. in a 2:1 case-control study, comparing 36 patients undergoing CABG who developed vasoplegia with 72 control patients without vasoplegia, and Carrel et al. in a large prospective cohort study of 800 consecutive CABG patients, in which 115 patients developed a mild vasoplegia, and 60 patients suffered from severe vasoplegia, showed by logistic regression analysis that preoperative use of ACEI was an independent predictor for postoperative low SVR.

Piggot et al. in their RCT, randomizing 40 patients with good left ventricular function to omit or continue ACEI before surgery, showed that there was no difference in hypotension on induction of anaesthesia or in the use of vasoconstrictors after CPB. Similar findings were reported by Webb et al.in their double-blind RCT randomising 96 CABG patients to receive 20 mg quinapril or placebo administered for six weeks preoperatively, with the final day of treatment being the morning of surgery.

On the other hand, Boeken et al. in their study of 240 patients undergoing CABG or valve surgery, divided into three matched groups (group A: pre- and postoperative ACEI; group B: ACEI only pre-, not postoperatively; group C: no ACEI), reported that there were significant differences in the intra- and postoperative need for catecholamines in groups A and B compared to C (intraop. A: 35%, B: 35%, C: 15%; postop. A: 21.2%, B: 16.2%, C: 10%) (P<0.05). In the ACEI groups (A and B) there were nine patients with a postoperative low SVR, only two cases in group C.

Deakin et al.in their case-control study of 62 CABG patients also showed that preoperative ACEI therapy decreased SVR during the rewarming phase of CPB (P=0.006) and increased post-bypass vasoactive drug requirements (P<0.01). Licker et al. in their case-control study of 41 patients failed to show alteration in haemodynamic stability during cardiac surgery in patients on ACEI therapy. However, the pressor and constrictor effects of norepinephrine infusion were attenuated markedly in the ACEI group. Tuman et al. in their case-control study of 4301 patients showed that more patients on ACEI therapy exhibited low values of SVR (P=0.0002) and required at least two vasoconstrictor infusions (phenylephrine, norepinephrine, or dopamine) (P=0.0001) postoperatively.

Editor Comment

AIIA, angiotensin II receptor blockers; ACEI, angiotensin converting enzyme inhibitors; CVP, central venous pressure; PAWP, pulmonary artery wedge pressure; GTN, glyceryl trinitrate; PD(20), the dose of norepinephrine required to increase mean arterial pressure by 20%; ns, not significant

Clinical Bottom Line

We conclude that preoperative administration of ACEI/AIIA in patients undergoing cardiac surgery contributes to lowering of SVR/vasoplegia postoperatively thereby making omission of ACEI/AIIA before cardiac surgery a rational strategy to avoid postoperative vasodilation. However, the current available evidence to support this strategy is weak.

References

1. Lee YK, Na SW, Kwak YL, Nam SB. Effect of pre-operative angiotensin-converting enzyme inhibitors on haemodynamic parameters and vasoconstrictor requirements in patients undergoing off-pump coronary artery bypass surgery. J Int Med Res 2005;33:693–702.
2. Devbhandari MP, Balasubramanian SK, Codispoti M, Nzewi OC, Prasad SU. Preoperative angiotensin-converting enzyme inhibition can cause severe post CPB vasodilation – current UK opinion. Asian Cardiovasc Thorac Ann 2004;12:346–349.
3. Bertrand M, Godet G, Meersschaert K, Brun L, Salcedo E, Coriat P. Should the angiotensin II antagonists be discontinued before surgery? Anesth Analg 2001;92:26–30.
4. Mekontso-Dessap A, Houël R, Soustelle C, Kirsch M, Thébert D, Loisance DY. Risk factors for post-cardiopulmonary bypass vasoplegia in patients with preserved left ventricular function. Ann Thorac Surg 2001;71:1428–1432.
5. Carrel T, Englberger L, Mohacsi P, Neidhart P, Schmidli J. Low systemic vascular resistance after cardiopulmonary bypass: incidence, etiology, and clinical importance. J Card Surg 2000;15:347–353.
6. Pigott DW, Nagle C, Allman K, Westaby S, Evans RD. Effect of omitting regular ACE inhibitor medication before cardiac surgery on haemodynamic variables and vasoactive drug requirements. Br J Anaesth 1999;83:715–720.
7. Boeken U, Feindt P, Mohan E, Zimmermann N, Micek M, Kalweit G, Gams E. Post-perfusion syndrome and disturbed microcirculation after cardiac surgery: the role of angiotensin-converting-enzyme inhibitors. Thorac Cardiovasc Surg 1999;47:347–351.
8. Webb CM, Underwood R, Anagnostopoulos C, Bennett JG, Pepper J, Lincoln C, Collins P. The effect of angiotensin converting enzyme inhibition on myocardial function and blood pressure after coronary artery bypass surgery – a randomised study. Eur J Cardiothorac Surg 1998;13:42–48.
9. Deakin CD, Dalrymple-Hay MJ, Jones P, Monro JL. Effects of angiotensin converting enzyme inhibition on systemic vascular resistance and vasoconstrictor requirements during hypothermic cardiopulmonary bypass. Eur J Cardiothorac Surg . 1998;13:546–550.
10. Licker M, Neidhart P, Lustenberger S, Valloton MB, Kalonji T, Fathi M, Morel DR. Long-term angiotensin-converting enzyme inhibitor treatment attenuates adrenergic responsiveness without altering hemodynamic control in patients undergoing cardiac surgery. Anesthesiology 1996;84:789–800.
11. Tuman KJ, McCarthy RJ, O'Connor CJ, Holm WE, Ivankovich AD. Angiotensin-converting enzyme inhibitors increase vasoconstrictor requirements after cardiopulmonary bypass. Anesth Analg 1995;80:473–479.