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CARDIOVASCULAR ANESTHESIA

The Chronic Inhibition of Angiotensin-Converting Enzyme Impairs Postoperative Renal Function

Département d’Anesthésie-Réanimation, Groupe Hospitalier Pitié-Salpêtrière, Université Paris VI, Paris, France

Address correspondence and reprint requests to Dr. M. L. Cittanova, Département d’Anesthésie-Réanimation, Groupe Hospitalier Pitié-Salpêtrière, 47 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. Address e-mail to marie-laure.cittanova{at}psl.ap-hop-paris.fr

	Abstract

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Postoperative renal impairment can increase postoperative mortality and morbidity. We sought to identify preoperative risk factors responsible for postoperative renal impairment in patients undergoing aortic surgery. This prospective study included 249 patients admitted for aortic surgery. Preoperative and postoperative glomerular filtration rates (GFRs) were assessed with pre- and postoperative creatinine clearance measurements. Postoperative renal impairment was defined as a 20% decrease in GFR between Day 0 (before surgery) and Day 7 ±1 day (after surgery). Preoperative and intraoperative variables considered as potentially responsible for postoperative renal impairment were tested. Chronic treatment with angiotensin-converting enzyme inhibitors (ACEIs) was the only factor significantly associated with postoperative renal impairment (odds ratio [95% confidence interval] = 2.01 [1.05–3.83]). Chronic preoperative ACEI treatment is significantly associated with postoperative renal impairment. Inhibition of renal compensatory mechanisms caused by renin angiotensin system blockade might be responsible for the observed decrease in renal function in patients chronically treated with ACEIs undergoing aortic surgery. However, age and preoperative renal dysfunction were not associated with a postoperative decrease in GFR, but they were associated with a postoperative creatinine clearance <60 mL/min.

IMPLICATIONS: The aim of this study was to identify preoperative risk factors responsible for postoperative renal impairment in vascular surgery. Chronic angiotensin-converting enzyme inhibitor treatment was the only factor significantly associated with postoperative renal impairment. Inhibition of renal compensatory mechanisms caused by renin angiotensin system blockade might be responsible for the observed decreased renal function.

	Introduction

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Postoperative renal impairment is responsible for increased postoperative mortality and morbidity, especially in renal high-risk procedures such as aortic surgery (1,2). Identifying predictive factors for postoperative renal impairment will help identify intra- and postoperative strategies to limit this complication.

When considering predictors for postoperative renal dysfunction, the difference between pre- and postoperative renal function must be compared. Two preoperative criteria have often been associated with postoperative renal insufficiency: advanced age and preoperative renal dysfunction (3,4). In these studies, postoperative renal dysfunction was defined as increased serum creatinine (3,4), a late sign of renal dysfunction that increases only when the glomerular filtration rate (GFR) is reduced by 75% (5,6). Apparent full recovery of renal function, assessed with creatinine serum level, especially in the postoperative period, does not mean complete recovery of renal lesions (7,8). Therefore, the aim of this prospective study was to determine the actual incidence of renal dysfunction after aortic surgery and to identify preoperative risk factors for postoperative renal impairment, evaluated with pre- and postoperative creatinine clearance measurements to assess GFR.

	Methods

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After Institutional Board approval, patients admitted to the Pitié-Salpêtrière hospital for abdominal or thoraco-abdominal aortic surgery were enrolled in this prospective study. Two-hundred-forty-nine consecutive patients were included over a 2-yr period. Patients with planned extracorporeal circulation, those with chronic extrarenal dialysis, nonscheduled patients, and patients in whom difficulties in determining creatinine clearance were anticipated (psychiatric illnesses, prostatic problems) were excluded. A standardized procedure was followed for patients undergoing long-term therapy. Angiotensin-converting enzyme inhibitors (ACEIs) and diuretics were withdrawn the day before surgery, according to the results of a study performed in our department (9), whereas ß-adrenergic blockers and calcium channel blockers were continued. ACEIs were restarted the day after surgery, usually at a half dose for 1 day and then at the preoperative dose.

We measured creatinine clearance before surgery (Day 0) and at the seventh day (Day 7) ±1 day after surgery. The measurements were performed between 12:00 am and 5:00 PM to minimize diurnal variations (10). Four hours before the study, patients were asked to drink a glass of water every hour to obtain a regular urine output (11). At the beginning of the study, the patients had to empty their bladders completely. Therefore, the patients were in the standing position, alone in their room, and not stressed, to avoid the presence of any residue. For the next 2 hr, the patients had to urinate only into a urinal. Two hours later, they had to empty their bladders in the urinal in the same conditions, and the urine volume was then measured. During the 2 hr, a serum creatinine concentration measurement was performed to obtain a reference value and to allow creatinine clearance calculation. Creatinine concentration was measured in the urine sample. The entire procedure was checked by a physician. For patients who had received urethral catheterization for other reasons, urine collection was performed by catheter. The following preoperative variables were considered: sex, age, coronary disease (defined as an history of angina, myocardial infarction, or both), hypertension, left ventricular ejection fraction <30% (assessed with echocardiography or ventriculography), the administration of radiocontrast agents, use of ACEIs, use of diuretics, respiratory insufficiency, renal disease, diabetes mellitus, hyperuricemia, stroke, cancer, preoperative serum albumin, hemoglobin, and calcium concentrations. The following intraoperative variables were considered: surgery duration, sepsis, perioperative hypotension, aprotinin administration, transfusion, colloid and crystalloid administration, and suprarenal clamping. All these variables had been previously defined in other studies (4). To ensure that differences in creatinine clearances on postoperative Day 7 were not related to postoperative events between Day 2 and Day 7, postoperative events were recorded: nephrotoxic drugs, i.e., antibiotics with renal toxicity (aminosides and vancomycin) and contrast agents, hydroxyethylstarch administration, and catecholamine requirement. To ensure that differences in creatinine clearances on postoperative Day 7 were not related to postoperative events between Day 2 and Day 7, postoperative events were recorded: nephrotoxic drugs, i.e., antibiotics with renal toxicity (aminosides and vancomycin) and contrast agents, hydroxyethylstarch administration, catecholamine requirement, transfusion requirement, and surgical complications.

We defined postoperative renal impairment as a 20% decrease in GFR between the pre- and postoperative period, to assess the pre- and postoperative nephron population.

In addition, to compare our results with those of other previously published studies, we analyzed our results with another paradigm, defined as a postoperative GFR <60 mL/min.

Data are shown as mean ± SD or numbers and percentages. Comparison of two means was performed with Student’s t-tests, and comparison of two percentages was performed with Fisher’s exact test.

A forward stepwise logistic regression (criteria for entry, P < 0.05) was used to determine the predictive factors of either postoperative decrease in renal function (defined as a decrease of >20% in creatinine clearance) or of a low postoperative renal function (defined as a creatinine clearance of <60 mL/min). All variables with a P value of at least 0.20 in the univariate analysis were included in the logistic regression. Odds ratios and their 95% confidence intervals were calculated. Comparisons were two tailed, and a P value of <0.05 was required to reject the null hypothesis. Statistical analysis was performed on a computer by using NCSS 6.0 software (Statistical Solutions Ltd, Cork, Ireland).

	Results

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We studied 249 consecutive patients (67 ± 10 yr; 224 men and 25 women) prospectively. Serum creatinine was 99 ± 29 µmol/L before surgery and 100 ± 60 µmol/L 7 days after surgery. Extrarenal hemodialysis or hemodiafiltration was required in three patients. Thirty-three (13%) patients had preoperative serum creatinine >120 µmol/L. Creatinine clearance was 88 ± 34 mL/min before and 100 ± 60 mL/min 7 days after surgery. Fifty-one (20%) patients had a preoperative creatinine clearance <60 mL/min. A postoperative decrease in creatinine clearance >20% was observed in 61 (24%) patients. Table 1 summarizes the results of the univariate analysis between patients with and those without a postoperative decrease in renal function. In the multivariate analysis, only the preoperative treatment with ACEIs was significantly associated with a postoperative decrease in renal function (Table 2).

Second, to compare our results with those of other studies, we analyzed them with another paradigm. We defined a renal impairment as going below a preestablished renal limit, defined here as a postoperative creatinine clearance <60 mL/min. Two factors were significantly associated with decreased postoperative renal function: a preoperative serum creatinine >120 µmol/L and age >60 yr (Table 3).

	Discussion

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Pre- and postoperative measurement of creatinine clearance was used to assess GFR, and a postoperative renal impairment was defined as a 20% decrease in GFR. Indeed, it is critical to assess the pre- and postoperative nephron population. Numerous end-stage renal diseases are of unknown origin. From this standpoint, all events that induce moderate renal insults may ultimately participate in the development of irreversible renal failure (7). In particular, the perioperative period, because of hemodynamic variations, drug administration, and blood loss, is highly sensitive. As a result, it is a challenge for anesthesiologists to detect and prevent all moderate renal insults in the perioperative period. By using creatinine clearance to evaluate GFR, we have demonstrated that postoperative renal dysfunction occurred in 61 (24%) patients.

Chronic preoperative ACEI use was identified as the only risk factor for postoperative nephron loss. In our study, as part of a clinical procedure established after a study from our group (9), ACEIs were withdrawn the day before surgery. Although this strategy limits the risk for hypotension after induction, it does not lead to a complete recovery of renin angiotensin system function. Without ACEI treatment, in response to a reduction in perfusion pressure, angiotensin II preserves GFR by increasing systemic arterial pressure and by triggering selective constriction of efferent arterioles (6). The renin angiotensin system is one of the main compensatory systems that responds to a decrease in systemic arterial blood pressure (6). Other mechanisms participate in GFR maintenance, such as sympathetic nervous system activation and antidiuretic hormone release (6). All these compensatory renal responses are maximal at a mean systemic arterial blood pressure of approximately 80 mm Hg; hypotension less than this level is associated with a precipitous decline in GFR (6,13). In such conditions, it is not surprising to observe particular sensitivity to ACEI in the perioperative period, because ACEIs blunt these compensatory responses.

Former studies investigated the potential beneficial role of ACEIs given prophylactically in normotensive patients (14–16). Colson et al. (16), after a two-day ACEI administration before cardiac surgery, showed a maintained GFR during cardiopulmonary bypass, whereas GFR was decreased in the placebo group. However, in this study, GFR improvement was not maintained 30–60 min after cardiopulmonary bypass in the ACEI group (16). Licker et al. (15) studied 22 patients undergoing aortic surgery who received a single IV dose of ACEI or placebo. Creatinine clearance on the first day after surgery was significantly more rapid in the ACEI group (15). The beneficial role of ACEIs observed in these studies is explained by the very different situations from those of our study. In these studies, ACEIs were given prophylactically the day of surgery or the day before in normotensive patients. Besides, short-term improvements in renal function in small groups of patients might not be definitely considered as clinically relevant. In contrast with patients who received prophylactic preoperative administration of ACEIs, patients chronically treated with ACEIs show a heightened hypotensive effect of anesthesia. As a result, several studies have emphasized the increased incidence of intraoperative hypotension in such patients. In patients undergoing cardiac surgery, ACEI-treated patients received a lesser amount of anesthetic to maintain a stable arterial blood pressure, and the pressor effects of norepinephrine were markedly attenuated in the ACEI group (14). Other studies, conducted in chronically treated ACEI patients, indicated a larger vasoconstrictor dose requirement during anesthesia (9,17,18). Ryckwaert et al. (19) demonstrated that mean arterial blood pressure after the induction of anesthesia was further decreased in chronically ACEI-treated patients. Such results strongly suggest a potential deleterious effect of ACEI use on blood pressure, and randomized studies are needed to compare early versus late ACEI interruption in the preoperative period on postoperative renal function.

To compare our study with previously published ones, we analyzed our results with another paradigm. We defined postoperative renal dysfunction as a GFR <60 mL/min, which is equivalent as a predetermined serum creatinine value, that is to say, a preestablished renal status. From this point of view, there were two predictive factors for postoperative renal dysfunction: age >60 years and preoperative renal dysfunction defined as serum creatinine >120 µmol/L. These two factors have been reported in 16 of 20 articles in a recent review analyzing preoperative risk factors (4). This result is not surprising because the chance of going below a preestablished value could be anticipated to be higher if the preoperative value is low for whatever reason, such as advanced age or preoperative renal impairment. The poorer the preoperative renal status, the greater the postoperative renal risk, and from this point of view, our results are consistent with the literature. The different results obtained with the two paradigms clearly emphasize that they are two aspects of the same phenomenon and strongly suggest that studies assessing the renal function in the perioperative period should consider the postoperative changes by using an accurate GFR measure and that prospective studies should be planned to assess long-term consequences of moderate perioperative renal insults. Indeed, because the cause of end-stage renal disease remains unknown in many cases, nephrologists have suggested that many events potentially responsible for repeated renal insults may contribute to end-stage renal failure (7). Such events may include toxic drugs and perioperative renal impairment.

In conclusion, our results reveal an increased risk of postoperative renal dysfunction in patients chronically treated with ACEIs, although this treatment was withdrawn the day before surgery. This reinforces the importance of providing these patients with a stable arterial blood pressure throughout the perioperative period to counterbalance the deleterious effect of ACEI use on arterial blood pressure.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999