Haemodynamic and renal effects of intravenous enalaprilat during coronary artery bypass graft surgery in patients with ischaemic heart dysfunction{dagger}

F. Ryckwaert1, P. Colson1, J. Ribstein2, G. Boccara1 and G. Guillon3

1Department of Anaesthesiology and Intensive Care, Hopital Arnaud de Villeneuve, avenue du Doyen Giraud, F-34295 Montpellier, France. 2Internal Medicine, Hôpital Lapeyronie, F-34295 Montpellier, France. 3INSERM U 469, CCIPE, F-34295 Montpellier, France*Corresponding author

{dagger}This article is accompanied by Editorial II.

Accepted for publication: August 20, 2000


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Renal dysfunction occurring after open heart surgery is multifactorial in origin but activation of the renin–angiotensin system may have a prominent role. Fourteen patients with ischaemic heart dysfunction scheduled for elective coronary artery bypass graft (CABG) surgery were allocated to a treatment group [enalaprilat for 2 days; ACEI (angiotensin-converting enzyme inhibitor) group, n=7] or a control group (n=7). The cardiac index was significantly higher in ACEI-treated patients than in the controls before and after cardiopulmonary bypass (CPB) (P<0.05) and on postoperative day 2 (P<0.05). The systemic vascular resistance was significantly lower in the ACEI-treated patients than in the controls before and after CPB (P<0.05). Renal plasma flow, measured as [131I]orthoiodohippuran clearance (ClH), was higher in the ACEI group than in the control group before CPB, as was endogenous creatinine clearance after CPB (P<0.05). On post-operative day 7, ClH was significantly higher in the ACEI group than in the control group (P<0.05). Plasma renin activity and vasopressin concentration increased in both groups during CPB (P<0.05). The study demonstrates that administration of an i.v. ACEI, enalaprilat, improves cardiac output during CABG surgery in patients with ischaemic heart dysfunction. Moreover, renal perfusion was better maintained during surgery, and this effect was sustained up to post-operative day 7.

Br J Anaesth 2001; 86: 169–75

Keywords: surgery, cardiovascular; hormones, antidiuretic, vasopressin; kidney, function; pharmacology, ACE inhibitors


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Renal dysfunction may occur after open heart surgery. Depending on the definition used for renal dysfunction, 3–30% of patients may develop a transient decline in renal function.1 2 Acute renal failure, as defined by the need for dialysis, is a rare (3%) but severe complication of cardiac surgery.3 Moreover, significant resource use results from renal dysfunction-induced care (mortality, intensive care unit stay, total hospital stay).3

Renal dysfunction associated with cardiac surgery is multifactorial in origin, but cardiopulmonary bypass (CPB) and peri-operative low-output syndrome, both of which decrease renal perfusion, have a prominent role.4 Many studies have reported that CPB in patients who undergo cardiac surgery induces an increase in renal vascular resistance and a decrease in renal blood flow and glomerular filtration rate.5 6 A recent large-scale study demonstrated that congestive heart failure is an independent pre-operative predictor of renal dysfunction.3 Among the hormones that may adversely affect renal function, the renin–angiotensin system (RAS) has been shown to be involved in CPB-induced renal dysfunction6 and heart failure-induced renal impairment.7 Although RAS blockade with an angiotensin-converting enzyme inhibitor (ACEI) may improve renal function during CPB in patients without pre-existing cardiac or renal failure who are undergoing coronary artery bypass graft surgery,6 little is known about the effect of ACEI in patients with pre-operative heart dysfunction. The present study was undertaken to evaluate the hypothesis that acute administration of an i.v. ACEI, enalaprilat, may improve haemodynamic and renal function during coronary artery surgery in patients with pre-operative cardiac dysfunction.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients
After we had obtained institutional ethics committee approval and informed consent, 14 patients (aged 45–76 yr, 13 males) scheduled for elective coronary artery bypass graft surgery (CABG) were included in the study. All had altered global left ventricular function (ejection fraction less than 40%, as estimated by ventriculography) after myocardial infarction (between 1 month and 17 yr previously). Patients with prior renal dysfunction (serum creatinine >160 µmol l–1), with unstable congestive heart failure, with valvular pathology, or chronically treated with ACEI were excluded. Patients were allocated in a randomized double-blind fashion to the treatment group (ACEI group, n=7) or to the control group (n=7). Patients in the ACEI group received i.v. enalaprilat (Merck Sharp and Dohme Chibret Lab., Paris, France) 1 mg at intervals of 6 h for 2 days, starting at the time of surgical incision (a dose expected to provide more than 90% inhibition of converting enzyme even in patients weighing up to 100 kg). Patients in the control group received a placebo.

Patient management
The patients were given the usual cardiac treatment, consisting of nitrates (n=11), ß-adrenergic blocking drugs (n=7), calcium antagonists (n=7), diuretics (n=2) or amiodarone (n=2). This treatment was maintained until the day before surgery, except that the calcium antagonists were given on the day of surgery to prevent coronary vasospam.

After overnight fasting, each patient received midazolam 5–10 mg i.m. 30 min before induction of anaesthesia. General anaesthesia was induced and maintained with titrated midazolam 0.10–0.15 mg kg–1 and fentanyl 3–5 µg kg–1. Pancuronium 0.1 mg kg–1 was used to facilitate endotracheal intubation. After tracheal intubation, ventilation was controlled to ensure normal blood gases, using an inspired oxygen concentration of 50% (oxygen–air mixture) before CPB and 100% after CPB. In all patients, a peripheral vein was cannulated before anaesthesia, then radial artery and pulmonary artery catheters were inserted after induction of anaesthesia for the continuous monitoring of mean arterial pressure (MAP), central venous pressure and for the intermittent determination of cardiac output by the thermodilution technique. Before CPB, hypertension and hypotension were defined as an increase and a decrease in MAP of 20% or more from baseline (preinduction MAP) respectively. Hypertension was treated with additional doses of fentanyl 100–200 µg. Hypotension was treated by rapid i.v. administration of lactated Ringer’s solution. Phenylephrine (bolus of 250 µg) was permitted when the MAP was equal to or less than 60 mm Hg (severe hypotension).

After cannulation of the aorta and right atrium, CPB was instituted with a membrane oxygenator primed with 1.5 litres of crystalloid solution and the body temperature was cooled to 27–29°C. After aortic clamping, a cardioplegic solution (hyperkalaemic crystalloid solution) was infused into the root of the aorta until the myocardial temperature fell to 15°C or less. A non-pulsatile pump flow rate greater than 1.6 litre min–1 m–2 was maintained during hypothermia and increased up to 2.2 litre min–1 m–2 during rewarming. After completion of the surgical procedure and systemic rewarming, patients were weaned from CPB when a rectal temperature of at least 36°C had been reached.

In the intensive care unit, repeated boluses of morphine were used to keep the patient pain-free. Weaning from the ventilator was started during emergence from anaesthesia and when stable haemodynamic variables and normothermia had been maintained for at least 1 h.

Measurements and calculations
Cardiac output was averaged from three consecutive determinations and the cardiac index (CI) was obtained as cardiac output divided by body surface area. The systemic vascular resistance index (SVRi) was calculated by the standard formula (MAP – central venous pressure/CI) (IU m–2). Systemic haemodynamic variables [heart rate, MAP, pulmonary capillary wedge pressure (PCWP), central venous pressure (CVP), CI, SVRi] were recorded at the following times: after induction of anaesthesia and before surgical incision; at least 30 min after injection of the first dose of enalaprilat or placebo (before CPB); during CPB (at this time, CI equals the indexed PFR); 30 min after the end of CPB; 6 h after the end of CPB and complete rewarming (postoperative day 0); on the morning of postoperative day 1; and on the morning of postoperative day 2.

Arterial blood was sampled before anaesthesia and during each haemodynamic measurement period. Blood was collected in 5-ml polypropylene tubes containing ethylenediaminetetraacetic acid, and after cold centrifugation the decanted plasma was stored frozen until analysis. Radioimmunoassay was used to measure plasma renin activity (PRA) (2 SD–range normal value 0.2–2.7 ng ml–1 h–1), arginine vasopressin (AVP) (kit from Bühlmann Laboratories, Allschwil, Switzerland; 2 SD–range normal value 0.8–6.5 pmol l–1) and aldosterone (2 SD–range normal value 6–12 ng 100 ml–1). Hormone concentrations were corrected for the haemodiluting effect of CPB according to the change in haematocrit, i.e. hormone concentration x Hctb/Hctd, where Hctb and Hctd are the haematocrit values prevailing before and during CPB respectively.

Effective renal plasma flow was estimated by clearance of [131I]orthoiodohippuran (ClH). The labelled compound was injected just after induction of anaesthesia as a bolus of 30 µCi [131I]orthoiodohippuran. In addition, a continuous infusion of 40 µCi [131I]orthoiodohippuran in 30 ml sodium chloride at a rate of 5 ml h–1 was administered throughout the peroperative period in order to obtain a stable blood concentration less than 100 µg l–1 for [131I]ortho iodohippuran.6 8 The glomerular filtration rate was estimated as endogenous creatinine clearance (Clc). After an equilibration period of 45 min, Clc and ClH were recorded during surgery and before CPB, and during and after CPB. Urine was collected carefully over at least 30 min and blood was sampled in the middle of each collection period. On the postoperative day 7, the protocol of [131I]orthoiodohippuran administration was used, but fluid volume loading (sodium chloride 500 ml h–1 for 3 h) was used to get substantial urine production and spontaneous micturition, and the measurements were repeated three times before averaging. Clc and ClH were calculated as (urine concentration/plasma concentration) x urine volume in ml min–1; these data were corrected for standard body surface area (1.73 m2).

Data analysis
Data are expressed as mean (SD). We used two-way analysis of variance for between- and within-group comparisons, corrected for repeated measures when appropriate (Bonferroni’s correction). Fisher’s exact test was used to compare percentages of patients in the two groups. A P value of <0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patient characteristics
The two groups of patients were similar with regard to physical characteristics, preoperative left ventricular ejection fraction and preoperative treatment (Table 1). In the ACEI group, the median dose of enalaprilat was 16.7 (2.8) µg kg–1 each 6 h (range 13.2–22.2 µg kg–1).


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Table 1 Preoperative data and treatment. Mean (SD) (range)
 
The total dose of anaesthetic medications, intravascular fluid administration and details of CABG surgical procedures were similar in the two groups (Table 2).


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Table 2 Intraoperative patient characteristics. Mean (SD) or median (range)
 
Haemodynamic effects
MAP and heart rate before induction of anaesthesia were not statistically different between the two groups: for controls and ACEI-treated patients, MAP was 85.9 (15.3) and 92.3 (10.8) mm Hg respectively (P=0.38), and heart rate was 72.1 (17.0) and 70.3 (12.8) beats min–1 (P=0.82). Induction of anaesthesia induced severe hypotension (MAP <60 mm Hg) in three patients (two controls and one ACEI-treated patient), which was treated successfully with phenylephrine (250 µg for each patient). Nine patients (including four controls) received additional lactated Ringer’s solution (250–500 ml) after induction of anaesthesia. Administration of enalaprilat or placebo did not induce severe hypotension in either group.

In the control group, the haemodynamic variables were not significantly altered during the intraoperative period except for the heart rate, which increased after CPB (P<0.05) (Table 3). In the ACEI group, the CI increased significantly before and after CPB compared with baseline values (P<0.05); therefore, the CI was significantly higher in ACEI-treated patients than in control patients before and after CPB (P<0.05). The SVRi was significantly lower in the ACEI-treated patients than in the control patients before and after CPB (P<0.05) (Table 3). One patient in each group received vasopressor during CPB.


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Table 3 Systemic haemodynamic variables after induction of anaesthesia and before surgical incision (Anaesthesia), at least 30 min after injection of the first dose of enalaprilat or placebo (Before CPB), during CPB (CPB) and 30 min after the end of CPB (After CPB). Mean (SD). *P<0.05 vs control group; {dagger}P<0.05 vs anaesthesia period. NA=not applicable; UN=unknown; PCWP=pulmonary capillary wedge pressure; CVP=central venous pressure; CI=cardiac index; SVRi=systemic vascular resistance index; SvO2 = central venous oxygen saturation
 
In the intensive care unit, the CI increased in both groups from postoperative day 0 to postoperative day 2 (P<0.05 and P<0.05 in controls and ACEI-treated patients respectively); CI was higher in the ACEI group than in the control group at postoperative day 2 (P<0.05). The SVRi was lower in ACEI-treated patients than in controls at postoperative day 0 (Table 4).


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Table 4 Haemodynamic variables 6 h after the end of CPB and complete rewarming after surgery (post-operative day 0) and on the mornings of postoperative days 1 and 2. Mean (SD). *P<0.05 vs control group; {dagger}P<0.05 vs postoperative day 0. PCWP=pulmonary capillary wedge pressure; CVP=central venous pressure; CI=cardiac index; SVRi=systemic vascular resistance index
 
Renal effects
During surgery, the ClH was higher in the ACEI group than in the control group before CPB (P<0.05) and on postoperative day 7 (P<0.05). The Clc was significantly higher in the ACEI group than in the control group after CPB (P<0.05) (Table 5).


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Table 5 Urinary output, effective renal plasma flow as estimated by clearance of [131I]orthoiodohippuran (ClH), glomerular filtration rate as estimated by endogenous creatinine clearance (Clc) during surgery and before, during and after CPB and on postoperative day 7. Mean (SD). *P<0.05 vs control group
 
Hormonal changes
In both groups, PRA increased significantly from baseline during CPB (P<0.05 in controls and ACEI-treated patients); at this time PRA was significantly higher in ACEI-treated patients than in controls (P<0.05) (Table 6). AVP concentration increased in both groups during CPB (P<0.05 in controls and ACEI-treated patients); there was no significant difference between groups (Table 6). There was no difference in the plasma concentration of aldosterone between groups, and no significant change was observed within either group (Table 6).


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Table 6 Plasma renin activity (PRA) and plasma concentrations of arginine vasopressin (AVP) and aldosterone before anaesthesia (Baseline), after induction of anaesthesia and before surgical incision (Anaesthesia), at least 30 min after injection of the first dose of enalaprilat or placebo (Before CPB), during CPB (CPB) and 30 min after the end of CPB. Mean (SD). *P<0.05 vs control group, {dagger}P<0.05 vs baseline period
 
Outcome
One patient in the ACEI group died during the first 24 h after operation, from acute cardiac failure. The need for inotropic support was not statistically different between the two groups. No patient complained of intraoperative awareness.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The study demonstrates that i.v. enalaprilat given to patients with altered left ventricular ejection fraction improves cardiac output during surgery. Moreover, i.v. enalaprilat improves renal perfusion during surgery, and this effect is sustained up to the seventh day after surgery.

The doses of enalaprilat used in the present study were expected to suppress circulating levels of angiotensin II: doses of enalaprilat ranging from 10 to 30 µg kg–1 produce marked inhibition (>90%) of plasma angiotensin-converting enzyme activity for 6 h.9 In vitro measurements of angiotensin-converting enzyme inhibition or plasma angiotensin II concentration were not done. However, there was indirect but strong evidence of RAS blockade in the ACEI group in the hormonal profile found in this study. PRA increased at the time of CPB in both groups, which suggests stimulation of the RAS. However, PRA was significantly higher in ACEI-treated patients than in controls, which reflects the lack of negative feedback of angiotensin II on renin release.10

The RAS is involved in the regulation of blood pressure, and conflicting results have been obtained with the use of ACEI during surgery with regard to haemodynamic stability. ACEIs have been reported to facilitate the incidence of severe hypotension, to improve haemodynamic status or to be without any significant effect.11 12 ACEIs given preoperatively in hypertensive patients just before surgery increase the incidence of serious hypotension after the induction of anaesthesia.13 14 By contrast, the induction of anaesthesia in patients with left ventricle dysfunction after myocardial infarction may cause a significant decrease in blood pressure, but the risk of severe hypotension is not increased by the ACEI treatment.15 The underlying cardiac pathology is therefore one of the main factors in the haemodynamic instability of patients with decreased sympathetic tone due to anaesthesia and blocked RAS due to ACEI treatment. In the present study, i.v. enalaprilat was administered to patients with ischaemic left ventricular dysfunction but after the induction of anaesthesia. At the time of the peak effect of enalaprilat,16 there was no significant change in blood pressure; no severe hypotension occurred, so that no vasopressor was required. Similar results were found by Boldt and co-workers when larger doses of enalaprilat (about 40 µg kg–1) were used after induction of anaesthesia in patients with ischaemic heart disease but without left ventricular dysfunction.17 An action of AVP to prevent a fall in blood pressure when both the sympathetic nervous system and the RAS are blocked has been suggested as a possible compensatory mechanism.18 19 Plasma AVP concentration may increase during heart failure, even when sympathetic responsiveness is decreased.20 In our study, plasma AVP concentration did not change significantly in either group before CPB. The contribution of any vasopressor system in supporting blood pressure in ACEI-treated patients may be further questioned because vascular resistance did not increase significantly: after enalaprilat, systemic vascular resistance was decreased by 3.1%. Just before CPB, ACEI-treated patients had a lower systemic vascular resistance than controls (by 32%) and an increased CI (by 26%); these effects were maintained after CPB and during the first 2 days after surgery. Such an improvement in cardiac output after acute ACEI treatment in patients with cardiac failure has been observed at rest21 and during episodes of cardiac failure occurring during22 or after23 cardiac surgery. The haemodynamic effect was sustained for the period of ACEI treatment, a fact established several years ago.7 However, the need for vasoconstrictors and inotropes was not increased in the ACEI group. This contrasts with the observation of an increase in vasoconstrictor requirements after chronic ACEI treatment,24 possibly related to attenuated adrenergic responsiveness,25 but corroborates the results of a more recent study.11 On the basis of these results, it appears that the use of ACEI during CABG surgery reduces the risk of haemodynamic instability in patients with left ventricular ischaemic dysfunction.

The haemodynamic improvement probably played a role in the improved renal perfusion found in the ACEI group. Enalaprilat may also have a direct beneficial effect on renal circulation. The vasodilating effect of enalaprilat may indeed be effective at the level of the renal arteries, so as to reduce renal resistance and to increase renal blood flow in heart failure even when non-hypotensive doses of ACEI are used.26 The lower Clc/ClH ratio in the enalaprilat-treated group than in controls before and after CPB (before CPB, 22.7 vs 27.8%; after CPB, 16.9 vs 21.4%) could reflect the preferential vasodilator effect of ACEI on the postglomerular arteriole. Although no instance of renal failure occurred after operation in either group, the study confirms that RAS may be involved in perioperative renal dysfunction during cardiac surgery.6 However, the beneficial effect of RAS blockade was observed during and after surgery.

Conversely, the role of AVP remains unclear. Plasma AVP concentrations were within normal limits before CPB but increased strikingly in both groups during CPB. Light anaesthesia may have contributed to a marked increase in stress-related hormones during CPB, but fentanyl administration may have attenuated the AVP response.27 Although the mean dose of fentanyl was moderate in our study, plasma AVP concentration did not increase before CPB in either group. The marked increase in plasma AVP concentration could not be related to any changes in haemodynamic variables, though even vasoconstriction should be observed at these plasma concentrations.28 More surprisingly, renal plasma flow (ClH), Clc and urinary output were not adversely affected by such elevated AVP concentrations. Such a paradoxical effect of AVP at plasma concentrations above the physiological range has been observed previously during CPB.28 29

The changes in renal perfusion thus appeared to parallel the improvement in haemodynamic variables in ACEI-treated patients, and this improvement was also observed 5 days after the enalaprilat treatment had been stopped. The ACEI-induced improvement in haemodynamic variables during and for 2 days after surgery may have contributed to the sustained improvement in renal circulation.30 Many mechanisms can account for a prolonged improvement in myocardial function beyond the period of ACEI treatment, such as myocardial protection during cardiac surgery,17 improved coronary circulation31 and better postischaemic contractile function of the heart.32 In addition to its macrohaemodynamic effects secondary to the blockade of systemic angiotensin II formation, enalaprilat may have interfered with other vasoconstrictive substances, such as endothelin, epinephrine and norepinephrine.33 Further investigations are required to assess the exact role of enalaprilat in providing sustained renal preservation after cardiac surgery.

The limitations of the present study include the sample size and the difficulty in assessing renal plasma flow and glomerular filtration rate by means of clearance measurements. The study design allowed patients suffering from ischaemic heart failure but not chronically treated with ACEIs to be included in the study. However, in our university hospital, most patients with ischaemic heart failure scheduled for CABG surgery were already being treated with ACEI because of the proven efficacy of ACEI treatment of heart failure.12 Consequently, only a small number of patients could be included for the period of the study. Though the small sample size of the study may have weakened the power of the statistical analysis, significant results have been found that show the beneficial effect of enalaprilat on haemodynamic variables during the perioperative period and on some aspects of renal function during and after surgery.

Glomerular filtration rate was estimated by endogenous Clc, which has been shown to correlate closely with inulin clearance,34 but the clinical conditions of CABG surgery make the measurements more difficult. The reliability of ClH as an indicator of renal blood flow is even more questionable because of inter-individual fluctuations and the uncertainty of hippuran extraction during hypothermic CPB.35 Accordingly, a large degree of variability was obtained for most Clc and ClH measurements. However the few statistically significant differences observed between the groups are in favour of renal preservation in the ACEI-treated patients.

In conclusion, the study showed that enalaprilat administered during coronary artery bypass surgery may have improved haemodynamic variables and renal perfusion in patients with ischaemic cardiac dysfunction. Nevertheless, the results obtained in the small number of patients taking part in this study require confirmation.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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