Acute renal failure is an important complication of cross-clamping the abdominal aorta [1-3]. Surgery of the infrarenal aorta may be associated with 3-5% incidence of renal failure requiring haemodialysis . Acute tubular necrosis accounts for 80-90% of perioperative acute renal failure, the underlying mechanism being renal ischaemia [3,5].
Although no pharmacological agent has been shown to be consistently effective in preventing postoperative acute renal failure following surgery which requires aortic cross-clamping, evidence exists of a protective effect mediated by dopamine receptor agonists [6,7]. During elective surgical reconstruction of the aorta, dopamine administration has been shown to increase creatinine clearance, urine output and sodium excretion . However there is no experimental or clinical evidence to support the use of dopamine either to prevent or treat acute renal failure [8-10]. Dopamine's lack of consistent effect may be attributable in part to its dose-dependent effect on renal DA2 and α1 adrenergic receptors [12,13].
Fenoldopam mesylate, a highly selective DA1 agonist, causes selective renal vasodilation and inhibition of tubular sodium reabsorption [14-16]. In healthy volunteers, and in hypertensive patients, intravenous (i.v.) infusion of fenoldopam increased renal blood flow and decreased renal vascular resistance [17-19]. In dogs, low doses of fenoldopam (0.125 μg kg−1 min−1) produced diuresis and natriuresis . In dogs with spontaneous renal failure, as well as those with normal renal function, renal plasma flow increased by 100% after i.v. administration of fenoldopam (0.5 μg kg−1 min−1) or oral administration of fenoldopam 10 mg kg−1.
Our hypothesis was that fenoldopam (0.1 μg kg−1 min−1) would have a renoprotective effect in patients undergoing elective aortic surgery which required infrarenal aortic cross-clamping. In order to test this hypothesis, we compared the effects of fenoldopam (0.1 μg kg−1 min−1) with placebo on renal tubular function in this setting.
With institutional ethical approval and having obtained written informed consent, 28 ASA II-III patients undergoing elective aortic surgery requiring infra-renal aortic cross-clamping were studied. None of the patients had a history of renal disease or evidence of renal artery stenosis on preoperative angiogram. Patients with preoperative serum creatinine > 120 μmol L−1 were excluded. Other exclusion criteria were: concurrent administration of nephrotoxic drugs or diuretics, unstable angina, myocardial infarction within the previous 6 months and diabetes mellitus.
The patients received diazepam 10 mg orally as a premedicant 1 h preoperatively. Anaesthesia was standardized in all participating patients. General anaesthesia was induced with sodium thiopental 2-5 mg kg−1 and fentanyl 10 μg kg−1 and maintained with isoflurane 0.5-1.5% end-tidal concentration. Muscle relaxation was achieved using vecuronium 0.1 mg kg−1 initially and subsequent increments as required. Patients received a lumbar (L3-4) epidural block prior to induction of general anaesthesia: a catheter was passed 3 cm into the epidural space and a test dose of 0.5% bupivacaine (3 mL) was administered followed by 0.25% bupivacaine (10 mL). A standard epidural infusion (0.1% bupivacaine, 2 μg fentanyl mL−1) was commenced and continued for 36 h. Monitors included comprised electrocardiography (leads II and V5 with automated ST analysis, Datex AS/3®; Datex-Ohmeda, Madison, Finland), mean arterial (MAP) and central venous pressures (CVP). Positive pressure ventilation (FiO2 = 0.40-0.50) was adjusted to maintain end-tidal CO2 in the normal range (35-40 mmHg). The bladder was catheterized with a silicone catheter of adequate size (Foley catheter®; Bard Ltd, West Sussex, UK) and residual urine drained and discarded.
By random allocation an infusion of either fenoldopam (Corlopam®; Neurex Corporation, CA, USA) (0.1 μg kg−1 min−1) or placebo (0.9% NaCl) was administered via a central infusion port by a blinded investigator immediately prior to surgical skin incision, and was discontinued immediately after release of the aortic cross-clamp. Syringes containing either fenoldopam (0.1 μg kg−1 min−1) or 0.9% saline were prepared and coded by the hospital pharmacy. Following exposure of the aorta and iliac vessels and i.v. administration of heparin (5000 IU), the aortic cross-clamp was applied below the renal arteries. A straight or bifurcated Haemashield graft® (B. Braun, Melsungen, Germany) was used. Duration of aortic cross-clamping, and volumes of i.v. fluid and blood administered were recorded. Patients returned to the intensive care unit (ICU) at the end of the operation and weaning was started with intermittent mandatory ventilation of the lungs followed by continuous positive airway pressure breathing. The endotracheal tube was removed when the patients were awake and if their blood gas analyses were comparable to those prior to surgery.
Urine collection was performed at the following times for the purpose of measuring creatinine (Jaffe method), sodium (indirect ion specific electrode analysis), osmolality (depression of freezing point) and microalbumin (spectrophotometric immunoturbidimetric assay) concentrations: (a) during a 24-h period prior to admission to hospital; (b) during the period from insertion of the urinary catheter until application of the aortic cross-clamp; (c) during the period of aortic cross-clamping; (d) from 0-4 h, and (e) 4-8 h after release of the cross-clamp. Twenty-four hour urine collections were also performed on days 1, 2, 3, and 5 postoperatively.
Creatinine clearance (CrCl) was calculated using the formula: CrCl = (UC × UV × 1.73)/SC × BSA, where UC is creatinine concentration in urine (mg mL−1), UV is urine volume (mL min−1), SC is creatinine concentration in serum (mg mL−1), and BSA is estimated body surface area. Serum creatinine was determined from a blood sample taken at approximately the mid-point of these periods. Fractional excretion of sodium (FENa), urinary microalbumin, and free water clearance (FWC) were also measured at each of these times. Blood loss was estimated both intraoperatively and during the following 18 h based on suction volumes, swab weights and from drainage.
Demographic data, haemodynamic data, fluid and blood administration were analyzed using unpaired t-tests. Renal data were compared at baseline using unpaired t-tests. Fisher exact tests were used to compare medications between groups and epidural placement.
Renal data were analyzed by repeated measures ANOVA using group as the between subjects factor and time as the within subject factor, and Dunnett's test where appropriate. P < 0.05 was taken to indicate statistical significance.
Based on: α = 0.05; β = 0.2; and using an unpaired, one tail, t-test; (a) Effect size (ES): (increase in plasma creatinine concentration at 24 h after elective infrarenal aortic surgery) = (136* − 93*). 50% = 21 μmol L−1 (b) Standardized ES: 21/20* = 1.05. Minimum sample size = 12/group.
Of 28 patients recruited, one (in the placebo group) required inotropic support upon release of aortic cross-clamp and thus was excluded from the study. The two groups were similar in terms of age, BSA, gender, aneurysm size, aortic cross-clamp time, and surgical time (Table 1). Epidural catheters were placed in 10 (of 13) and 11 (of 14) patients in the placebo and fenoldopam groups respectively (Table 1). Fluid and blood administration both intraoperatively and during the subsequent 5 days was similar in the two groups (Table 2). Blood loss was similar in the two groups (Table 2). Concurrent medications were similar in the two groups (Table 3).
Prior to commencing the infusion of fenoldopam or 0.9% saline, heart rate (HR), MAP and CVP were similar in the two groups (Table 4). Administration of fenoldopam (0.1 μg kg−1 min−1) did not alter HR, MAP or CVP (Table 4). Application of the aortic cross-clamp induced a significant increase in HR and CVP in both groups. The increase in HR persisted until 6 h after release of clamp (Table 4).
Preoperative plasma creatinine concentrations were similar in the two groups. There was a significant increase in plasma creatinine concentration in the placebo group but not in the fenoldopam group on the first postoperative day (87 ± 12 to 103 ± 28 μmol L−1 (mean ± SD)) (P < 0.01) (Fig. 1). This returned to normal by the second postoperative day (Fig. 1).
Creatinine clearance was similar in both groups prior to surgery (Fig. 2). Creatinine clearance decreased significantly in the placebo group but not the fenoldopam group following application of the aortic cross-clamp (83 ± 20 to 42 ± 29 mL min−1 (mean ± SD)) (P < 0.01). This decrease in creatinine clearance persisted into the period from 4-8 h after release of the clamp (83 ± 20 to 54 ± 33 mL min−1 (mean ± SD)) (P < 0.05).
There was a significant increase in urine output and FENa in both groups during the period from release of the aortic cross-clamp until 4 h after its release (P < 0.01) (Table 5). Before operation, free water clearance was similar in both groups. No significant changes occurred in either group until the second postoperative day. At this stage there was a similar significant decrease in FWC in both groups that persisted for a further 24 h in the placebo group but not the fenoldopam group (Table 5).
Urinary microalbumin concentrations increased significantly in both the fenoldopam and placebo groups during the period of aortic cross-clamping (P < 0.01). This increase persisted over the following 4 h in the placebo group (15 ± 19 to 89 ± 76 mg L−1 (mean ± SD)) (P < 0.01) but not in the fenoldopam group (Fig. 3).
The most important findings of this study were that (a) fenoldopam (0.1 μg kg−1 min−1) preserved creatinine clearance during the period of aortic cross-clamping and the subsequent 8 h after its release, and (b) plasma creatinine concentration increased significantly from baseline on the first postoperative day in the placebo group (87 ± 12 to 103 ± 28 μmol L−1 (mean ± SD)) (P < 0.01) but not in the fenoldopam group.
The most common cause of perioperative acute renal failure is acute tubular necrosis secondary to ischaemia [3-5]. It appears that damaged tubular cells slough and obstruct the narrow portion of the descending part of the loop of Henle, causing the filtrate to leak back into the renal interstitium (backleak) . Tubuloglomerular feedback may secondarily contribute to the injury by activating the renin angiotensin system, thus causing glomerular mesangial constriction and decreased glomerular filtration rate . The luminal cells of the proximal convoluted tubule and medullary thick ascending limb of Henle are highly metabolically active and thus susceptible to ischaemic injury . Reasonable strategies to prevent ischaemia-mediated acute tubular necrosis include increasing tubular oxygen delivery and decreasing tubular oxygen consumption . In the setting of elective aortic surgery in which infrarenal aortic cross-clamping is routinely employed, a state of renal hypoperfusion is induced . Infratenal aortic cross-clamping produces profound alteration in renal haemodynamics, characterized by a 75% increase in renal vascular resistance and a 38% decrease in renal blood flow . A maldistribution of blood flow within the kidney occurs with decrease in renal cortical blood flow, which persists for at least 60 min after unclamping the aorta . Such a decrease in tenal blood flow and redistribution of flow within the kidney are associated with a temporary decrease in glomerular filtration [23,25].
Goldberg and colleagues classified the peripheral dopamine receptors into two groups, the DA1 and DA2 subtypes, on the basis of synaptic localization . DA1 receptors are located postsynaptically on smooth muscle cells in the peripheral vasculature as well as in the renal, mesenteric, and coronary vasculature, in the proximal tubule and in the cortical collecting ducts of nephrons [26,27]. Selective DA1 agonists such as fenoldopam activate adenylate cyclase, causing renal artery vasodilatation (and increased total renal blood flow) and natriuresis by inhibiting active Na+K+ ATPase dependent processes at the proximal collecting tubule and in the thick part of the ascending loop of Henle [15,16]. The presumptive effect is an increase in renal oxygen delivery and decrease in renal oxygen consumption. These effects may decrease the likelihood of ischaemia-related injury occurring during conditions of renal hypoperfusion. Fenoldopam has no DA2, α-adrenergic, or β-adrenergic agonist activity and has been found to be 3.5 times as potent as dopamine in dilating the renal vasculature .
In our study, we chose the greatest dose of fenoldopam (0.1 μg kg−1 min−1), that in previous studies had been shown not to induce significant hypotension [17,28]. No significant changes in HR and blood pressure (BP) resulted from administration of fenoldopam (0.1 μg kg−1 min−1) in our study. This is consistent with the findings of Murphy and colleagues who examined the effects of i.v. infusion of fenoldopam (using an increasing dose regimen) to patients with uncomplicated essential hypertension . In only one of the 17 patients studied did fenoldopam (0.1 μg kg−1 min−1) decrease diastolic BP by more than 10 mmHg . In that study, HR increased in proportion to the decrease in systemic BP. During infusion of fenoldopam (0.1 μg kg−1 min−1) to healthy volunteers, no change in diastolic arterial pressure was observed .
Infrarenal aortic cross-clamping is associated with a large increase in renal vascular resistance and as much as a 30% decrease in renal blood flow . Although restoration of renal blood flow with i.v. volume resuscitation is ineffective in restoring renal function once tubular necrosis is established, adequate fluid replacement substantially decreases the incidence of renal complications after surgery involving aortic cross-clamping [22,25,29]. This effect may result from volume loading-induced inhibition of the production of certain vasoconstrictive compounds such as endothelin-1 , and preventing the stimulation of the renin-angiotension system . The urine output and fractional excretion of sodium significantly increased in both the fenoldopam and placebo groups during the subsequent 4 h after release of the aortic cross-clamp. During aortic cross-clamping, using CVP and mean arterial BP as a guide, intravascular volume was maintained by the judicious administration of i.v. fluids. This administration of fluids may account for the increase in urine output and FENa after the unclamping of the aorta. Optimization of systemic haemodynamics, including circulating blood volume has so far been shown to be the most effective measure to protect the kidneys from ischaemic insults induced by aortic cross-clamping [25,32]. Cross-clamping the abdominal aorta is associated with an increase in circulating catecholamines . However, renal sympathetic blockade induced by epidural anaesthesia at T6 does not prevent the renal vasoconstriction or the impaired renal haemodynamics and function following infrarenal aortic cross-clamping . Epidural anaesthesia does not prevent or modify the decrease in glomerular filtration rate associated with aortic cross-clamping . In our study, whenever clinically possible and with the patients consent, a lumbar epidural was performed for the purpose of postoperative pain relief. Epidural catheters were placed in 10 (of 13) and 11 (of 14) patients in the placebo and fenoldopam groups respectively.
All patients undergoing aortic surgery suffer some degree of organ dysfunction as a result of reperfusion of the relatively ischaemic lower body . The underlying cause of this phenomenon appears to be a systemic increase in vascular endothelial permeability . Reperfusion of ischaemic tissue with oxygenated blood produces an inflammatory response with inflammatory mediators and neutrophil activation resulting in endothelial damage and increased vascular permeability [36-38]. In the kidney the increase in vascular permeability can be detected by an increase in urinary protein excretion. Smith and colleagues showed that aortic clamping and reperfusion initiated an increase in urinary protein excretion . The rise in urinary microalbumin concentration was proportional to the severity of the injurious stimulus . Because of its large filtration area and high blood flow, the kidney is ideally placed to detect small changes in endothelial permeability [40,41]. In our study there was a significant increase in urinary microalbumin in both the fenoldopam and placebo group during the period of ACC that persisted significantly high in the placebo group for the following 4 h (Fig. 3). This may imply that the severity of the injury was greater in the placebo group.
It must be noted that there was no difference in clinical outcome between the two groups. No patient developed acute renal failure in either group. By studying patients with normal preoperative renal function and excluding those with intraoperative haemodynamic instability, the likelihood of identifying an effect on the incidence of acute renal failure was decreased. However, Mangano and colleagues recently showed that reductions of creatinine clearance of 10% were significantly and independently associated with increased hospitalization and ICU stay in patients undergoing coronary revascularization . The patients that were recruited into our study were low risk for developing acute renal failure. However, if a beneficial effect is demonstrable in a group of patients with normal preoperative renal function, the benefit is likely to be even greater in those that are at greater risk including those with pre-existing renal impairment. Further work needs to be done to assess the effects of fenoldopam in patients at greater risk of developing acute renal failure or even in patients with established renal failure.
In summary, we have demonstrated that in the setting of infrarenal aortic cross-clamping in ASA II-III patients without renal failure or diabetes mellitus, fenoldopam preserved creatinine clearance during the period of aortic cross-clamping and the subsequent 8 h and prevented an increase in plasma creatinine concentration on the first postoperative day.
We thank Ms K. O'Sullivan (Statistician, Department of Statistics, University College Cork) and the Biochemistry Departments (Cork University Hospital and Beaumont Hospital) for assistance during the study. We would also like to thank Neurex/Elan Pharmaceutical, San Franciso, CA, USA for supplying the drug.
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