Skip Navigation

European Journal of Heart Failure 2001 3(5):587-592; doi:10.1016/S1388-9842(01)00155-6
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Bennett, S. R.
Right arrow Articles by Griffin, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bennett, S. R.
Right arrow Articles by Griffin, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2001 European Society of Cardiology

Angiotensin in cardiac surgery: efficacy in patients on angiotensin converting enzyme inhibitors

Sean R. Bennetta,*, June McKeownb, Phil Drewc and Steve Griffind

a Department of Anaesthesia, Castle Hill Hospital Cottingham, East Yorkshire HU16 5JQ, UK
b Cardiothoracic Surgical Unit Aberdeen Royal Infirmary, Foresterhill, Aberdeen, UK
c Department of Surgery, Castle Hill Hospital Cottingham, East Yorkshire, UK
d Department of Cardiothoracic Surgery, Castle Hill Hospital Cottingham, East Yorkshire, UK

* Corresponding author. Tel.: +44-1482-624096. E-mail address: sean{at}kemproad.freeserve.co.uk (S.R. Bennett)


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Patients presenting for cardiac surgery are often treated with angiotensin converting enzyme inhibitors (ACEIs), either for heart failure or hypertension. Control of systemic vascular resistance (SVR) during surgery can be difficult in such patients. Angiotensin II has been available as an unlicensed vasoconstrictor, but there is concern about renal damage and its use.

Aim: This study compared a standard vasoconstrictor with angiotensin II and examined the effect on renal function after cardiac surgery.

Method: Twenty consecutive, consenting patients scheduled for cardiac surgery that had been taking ACEIs for at least 6 months, were randomly assigned to receive either phenylephrine or angiotensin II for the control of SVR during and for 24 h after cardiac surgery. A pulmonary artery catheter was used to guide therapy. Creatinine clearance was measured before, 24 and 48 h after surgery.

Results: Low SVR and blood pressure requiring intervention was seen in all patients, particularly during cardiopulmonary bypass. One patient in the control group failed to respond to P, but responded normally to angiotensin II. Neither drug caused renal impairment.

Conclusion: Angiotensin II is a safe alternative to phenylephrine in patients on ACEIs and should be considered in patients who fail to respond to conventional vasoconstrictors.

Key Words: Heart failure • Angiotensin • Renal function

Received March 27, 2001; Accepted April 10, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Angiotensin II (AII) is an octapeptide formed by the cleavage of angiotensin I by angiotensin converting enzyme, a process first carried out in 1957. Since then, it has been available as an unlicensed product in Europe for almost 30 years. AII is the most active of the angiotensins and has three physiologically effects: (1) on vascular tone; (2) on renal function; and (3) on the cardiovascular system [1].

Several drugs are available for the control of systemic vascular resistance (SVR), e.g. Phenylephrine, metaraminol, and noradrenaline. Early research showed that ATII reduced glomerular filtration rate, hence, AII never became a first line drug.

However, in the late 1970s, the first angiotensin converting enzyme inhibitors (ACEIs) were produced and by the late 1980s, were being widely used not only in patients with renin-induced hypertension, but also in patients with essential hypertension [2], congestive heart failure [3], myocardial infarction [4] and diabetic nephropathy [5]. Nowadays, it is common for patients to present for cardiac surgery whilst on long-term ACEI therapy. Experience suggests that control of blood pressure can be difficult in these patients and there have been reports of low vascular resistance on cardiopulmonary bypass (CPB) [6] in addition to case reports using angiotensin for patients in whom phenylephrine had failed [7]; however, this has been refuted by others [8]. Furthermore, it has been demonstrated that renal function may be preserved in abdominal aortic surgery using ACEIs [9].

This study examines the efficacy of AII in the control SVR during cardiac surgery with CPB and studies the effect of this treatment on renal function in patients on ACEIs.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
Ethics approval was obtained and all patients consented to receive either AII or phenylephrine, should they require intervention for the control of SVR.

Twenty consecutive patients presenting for elective cardiac surgery with CPB who had been on ACEIs for at least 6 months prior to surgery, were randomly allocated to group AII (n=10) or group P (n=10). Patients would receive AII or P for control of arterial blood pressure with measured low SVR. Both coronary artery disease and valvular disease were included. Hence, there was a mix of patients on ACEIs for hypertension and for heart failure. No specific ACEI drug was used, though all were taking medium- to long-acting preparations.

ACEIs were continued to the night before surgery; calcium channel and beta blockers to the morning of surgery. Patients received standard premedication before establishing haemodynamic monitoring with 5 lead electrocardiogram, pulse oximeter, venous cannula, arterial line and pulmonary artery catheter, 8F, 5 lumen (Abbott Lab, Chicago, IL, USA).

Haemodynamic measurements included: heart rate (HR); mean arterial pressure (MAP); central venous pressure (CVP); pulmonary artery wedge pressure (PAWP); cardiac output (CO); systemic vascular resistance (SVR); and pulmonary vascular resistance (PVR). Measurements were carried out using an Abbott 3300 cardiac output computer (Abbott Lab, Chicago, IL, USA); the average of three measurements excluding the first and last of five readings were used.

The same anaesthetic with midazolam, fentanyl, pancuronium and propofol as required plus Ringer's lactate (200 ml/h) was used on all patients.

Measurements were made awake, post-induction, post-incision, pressures and flows on CPB, 10 min after protamine, and at 1, 6 and 24 h after arrival into the intensive care unit (ICU). Measurements were made at other times if indicated clinically. All values were indexed for body surface area.

Anaesthesia was maintained with propofol and patients ventilated with air and oxygen.

2.1. Haemodynamic interventions
Patients whose MAP was less than 50 mmHg with an SVRI below 1500 dynes cm–5 m2 (normal range=1900–2400) were initially given 200 ml of colloid bolus if the PAWP was below 16 mmHg. If PAWP was >16 mmHg, treatment was determined by the patient's cardiac index. A cardiac index less than 2.2 l min–1 m–2 was treated with inotropes; values above that were treated with AII or P. Also, persistently low PAWP (despite colloid treatment) would be treated with AII or P. This strategy was used throughout the study. During CPB the target MAP at full flow (2.1l min–1 m–2) was 50–70 mmHg. Below this range, the trial drug was infused. Body temperature was reduced to 32°C during CPB. Apart from the trial drugs, all other anaesthetic and cardiac drugs were administered according to the clinical needs of the patient. Haematocrit was maintained at greater than 18 and 26% in CPB and post-operative cases, respectively. A maximum of 500 ml of colloid was used at any one intervention. Crystalloid prime with mannitol (25 g) was used for CPB and the aim for overall fluid balance for crystalloid at 24 h was plus 2 l. Frusemide (10 mg) was given for diuresis of <0.5 ml kg–1 h–1; dopamine was not used.

Patients requiring inotropes to come off bypass were treated with a low dose of adrenaline (up to 0.1 µg kg–1 min–1) and/or milrinone (50 µg kg–1 for loading and 0.375 µg kg–1 min–1 for maintenance) in patients with pulmonary hypertension.

2.2. Trial drug preparation
Angiotensin (Ciba–Geigy) 2.5 mg and phenylephrine 10 mg, both in 50 ml of normal saline were infused via the central catheter.

If the patient was not responding adequately to the trial drug, i.e. continuing low pressures, then the other trial drug was used instead.

2.3. Post operative management
ICU sedation involved propofol and analgesia with 1 mg of morphine iv as required. Sedation was terminated at the onset of haemostasis, if temperature >36.0°C and PO2>10 kPa (FiO2 of 0.4). Patients were extubated when awake. Haemodynamic measurements were ceased 24 h post-operatively.

2.4. Renal function monitoring
Creatinine clearance (Ccl) was chosen as a measure of the rate of glomerular filtration. Patients began urine collection preoperatively and continued for 2 days postoperatively for Ccl before, and 24 and 48 h post operatively.

The outcomes for the study were: response to AII or P as measured by SVRI; and the effect of each drug on Ccl.

Statistical analysis was performed using SPSS version 7.0 (SPSS Ltd, Surrey, UK). A repeated measures ANOVA was used to assess between-group differences with a post hoc Mann–Whitney test where appropriate. Data on the graphs are expressed as means with the S.E. bars shown.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Twenty patients were recruited; one patient from group AII suffered an intraoperative myocardial infarction and died on the second post-op day.

The patients’ demographics are shown in Table 1.


View this table:
[in this window]
[in a new window]

  		Table 1 Patient demographicsa

 
Seven patients were on ACEIs because of heart failure (3 in group AII, 4 in group P). Five of the six patients requiring inotropes were those with preoperative heart failure. Only one hypertensive patient in group P required adrenaline. All patients required intervention with AII or P during surgery, initiated during CPB, except one in each group that started after induction of anaesthesia. Requirements for vasoconstrictors were greater in the patients with preoperative heart failure Table 2.


View this table:
[in this window]
[in a new window]

  		Table 2 Vasoconstrictor requirementsa

 
The general trend in SVR and MAP was the same in the two groups. Stable pre-bypass, decrease going onto CPB, return to pre-op values post bypass then rising in the early post-op period, with a fall below pre-op values at 24 h (Figs. 1 and 2).


Figure 1
View larger version (18K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Systematic vascular resistance index.

 


Figure 2
View larger version (19K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Mean arterial blood pressure.

 
Cardiac index followed a similar trend, but taking slightly longer to recover postoperatively, returning to preoperative values at 6 h postoperatively (Fig. 3).


Figure 3
View larger version (18K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Cardiac index.

 
Pulmonary vascular pressure tended to increase with anaesthesia recovering to preoperative levels later on in the postoperative period (Fig. 4).


Figure 4
View larger version (20K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Pulmonary vascular resistance index.

 
One patient failed to respond to 20 mg of phenylephrine and switched to AII group. The patient showed a normal response to AII and made a full recovery.

Renal function showed no statistical change throughout the study period (Fig. 5).


Figure 5
View larger version (32K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 5 Creatinine clearance.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Patients on ACEIs represent a perioperative challenge, especially those treated for heart failure. By inhibiting the production of angiotension II they deprive themselves of their most potent endogenous vasoconstrictor (on a molar basis it is 40 times more potent than noradrenaline) and potentiate a potent vasodilator, bradykinin [10]. Indeed, early research into ACEIs describes them as bradykinin-potentiating factors. The upset caused by less AII and more bradykinin is likely to be pronounced at the start of CBP as these play a major role in the maintenance of perfusion pressure at this time [11].

AII acts on pre-capillary arterioles, but at normal doses has little effect on the brain, lung and skeletal muscle. It increases release and inhibits re-uptake of noradrenaline at the sympathetic nerve terminals. It can cause splanchnic and renal vasoconstriction [12]. However, during renal artery hypotension the predominant effect on renal vasculature is efferent arteriole constriction [13].

Little has been published on the effects of AII in patients taking ACEIs. Eyraud published haemodynamic data including transoesophageal echocardiography data to support the efficacy of AII in restoring arterial blood pressure preoperatively [14]. They used the same AII preparation and preoperative regime as in our study with similar effect, but showed deterioration in left ventricular performance with bolus AII, which we did not use. Our study looked at the efficacy of AII in the treatment of hypotension in patients on ACEIs during cardiac surgery with phenylephrine as the vasoconstrictor in the control group.

All patients required treatment for low SVR with either AII or P during CPB and two in each group required continued treatment. These were all patients with heart failure preoperatively, which as a group, required notably more vasoconstrictor therapy than the hypertensive patients. The one patient who was switched from P to AII, represented the type of patient that clinically responds well to AII when other vasoconstrictors have failed [7]. A comparative study of these ‘non-responders’ would be interesting, but it would take several years to achieve a large enough group. Furthermore, in view of the concern regarding renal function, we felt that this must be addressed before a larger study could be undertaken.

It has been shown that patients with normal pre-operative renal function do not show a fall in glomerular filtration rate postoperatively [15,16]. We have confirmed this in patients on ACEIs. Our results show no significant change in Ccl during the first 48-h postoperative period. This suggests that AII is safe in this regard.

Several patients were treated with milrinone, known to cause a vasodilatation, but this did not interfere with the control of SVR.

Recent developments have led Ciba–Giegy to cease production of AII in the formulation used in this study. Angiotensin I, II and III are now available individually under a new formulation prepared by Calbiochem Novabiochem (UK) Ltd.

In summary, patients on ACEIs require vasoconstrictor support during cardiac surgery. AII has proved to be a safe and simple drug to administer. It is safe and reliable and should be considered early in the management of patients with a persistent low SVR, rather than risking under perfusion of vital organs.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Jackson E.K., Garrison J.C. Renin and angiotensin: the pharmacological basis of therapeutics, 9th ed. chapter 31 (1996) Goodman and Gillman. 733–758.
  2. Oren S., Grossman E., Frohlich E.D. Reduction in left ventricular mass in patients with systemic hypertension treated with ACEIs. Am J Card (1996) 77:93–95.[CrossRef][Medline]
  3. The SOLVD Investigators. Effects of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med (1991) 325:293–302.[Abstract]
  4. The Consensus II Study Group. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. N Engl J Med (1992) 327:678–684.[Abstract]
  5. Lewis E.J., Hunsicker L.G., Bain R.P., Rohde R.D. The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med (1993) 329:1456–1462.[Abstract/Free Full Text]
  6. Carle J. ACE inhibitors and low systemic vascular resistance during cardiopulmonary bypass. The Perfusionist (1994) 1 (Sept.):18–20.
  7. Thaker U., Geary V., Chalmers P., Sheikh F. Low systemic vascular resistance during cardiac surgery: case reports, brief review and management with angiotensin. J Cardiothorac Vasc Anesth (1990) 4:360–363.[CrossRef]
  8. Myles P.S., Olenikov I., Bujor M.A., Davis B.B. ACE-inhibitors, calcium antagonists and low systemic vascular resistance following CPB. Med J Australia (1993) 158:675–677.[Medline]
  9. Licker M., Bednarkiewicz P., Neidhart R., et al. Preoperative inhibition of angiotensin-converting enzyme improves systemic and renal haemodynamic changes during aortic abdominal surgery. Brit J Anaesth (1996) 76(5):632–639.[Abstract/Free Full Text]
  10. Luscher T.F. Angiotensin, ACE-inhibitors and endothelial control of vasomotor tone. Basic Res Cardiol (1993) 88:15–24.
  11. Bailey D.R., Miler E.D., Kaplan J.A., Rogers P.W. The renin–angiotensin–aldosterone system during cardiac surgery with morphine nitrous oxide anesthesia. Anesthesiology (1977) 42:538–544.
  12. Motwani J.G., Struthers A.D. Interactive effects of indomethacin, angiotensin II and frusemide on renal haemodynamics and naturesis in man. Brit J Clin Pharm (1994) 37(4):355–361.[Web of Science][Medline]
  13. Hall J.E., Coleman T.G., Guyton A.C., Kastner P.R., Granger J.P. Control of glomerular filtration rate by circulating angiotensin II. Am J Physiol (1981) 241:R190–R197.[Web of Science][Medline]
  14. Eyruad D., Mouren S., Teugels K., Betrand M., Coriat P. Treating anesthesia-induced hypotension by angiotensin II in patients chronically treated with angiotensin converting enzyme inhibitors. Anesth Analg (1998) 86:259–263.[Abstract]
  15. Zanardo G., Michielon P., Paccagnella A., et al. Acute renal failure in the patient undergoing cardiac operation. J Thorac Cardiovasc Surg (1994) 107(6):1489–1495.[Abstract/Free Full Text]
  16. Dehne M.G., Boldt J., Heise D. Tamm–Horsfall protein, alpha-1 and beta-2 microglobulin as renal function markers in heart surgery. Anaesthesist (1995) 44(8):545–551.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Ann. Thorac. Surg.Home page
M. Egi, R. Bellomo, C. Langenberg, M. Haase, A. Haase, L. Doolan, G. Matalanis, S. Seevenayagam, and B. Buxton
Selecting a Vasopressor Drug for Vasoplegic Shock After Adult Cardiac Surgery: A Systematic Literature Review
Ann. Thorac. Surg., February 1, 2007; 83(2): 715 - 723.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Bennett, S. R.
Right arrow Articles by Griffin, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bennett, S. R.
Right arrow Articles by Griffin, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?