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From the *Department of Anesthesiology; Department of Surgery, Emeritus Staff; Division of Biostatistics; and Department of Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota.
Address correspondence and reprint requests to William C. Oliver, Jr., MD, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905. Address E-mail to oliver.william{at}mayo.edu.
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Abstract |
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Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Arterial hypertension consistently occurs with aortic cross-clamping and may be severe. Various measures may be used to treat it, but arterial vasodilators are frequently chosen (1). Sodium nitroprusside (SNP) has been administered for severe perioperative hypertension in conjunction with abdominal aortic surgery, but it is linked with coronary steal and reduced renal blood flow and function (2).
Renal failure may occur in up to 13.9% of cases involving infrarenal aortic cross-clamping, with a corresponding mortality rate of 58%–86% (3). Moreover, renal impairment and subclinical renal damage occur in 28% of such cases (4), impacting clinical care more than previously believed (5). To prevent or lessen renal ischemic injury accompanying cross-clamping of the aorta, it has long been thought that renal blood flow must be augmented (6). However, most vasodilators necessary to treat hypertension associated with aortic cross-clamping do not preserve renal blood flow.
Fenoldopam mesylate (Abbott Laboratories, Abbott Park, IL), a systemic vasodilator (7), with selective activity at the dopamine 1 (DA1) receptor, has been shown to be associated with greater renal blood flow in healthy males (8), animals (9), and individuals undergoing elective aortic surgery (10). Fenoldopam was selected for the current investigation as a pharmacological strategy to manage hypertension in this patient population because of its potential to influence renal dysfunction or failure due to activity at the DA1 receptor (2,8). SNP was chosen as an alternative conventional therapy to manage hypertension, but it tends to reduce renal perfusion (11) and function (12). Therefore, low-dose DA was added as a renal-sparing drug because it continues to be administered in situations where renal blood flow may be adversely affected (3).
We hypothesized that alternate pharmacological strategies to manage hypertension and provide renal protection in patients undergoing abdominal aorta vascular surgery requiring cross-clamping of the aorta are equivalent to the systemic vasodilation and increased renal blood flow of fenoldopam administration. Therefore, we planned to compare the combination of SNP and low-dose DA with fenoldopam in terms of the occurrence of hypertension and renal dysfunction.
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METHODS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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All patients received their routine medications the morning of surgery. Upon arrival in the operating room, standard ASA monitoring was placed. A 20-g catheter was inserted in the radial artery followed by introduction of a lumbar epidural catheter. The epidural catheter was checked for proper placement with a test dose of 2% lidocaine with 1:200,000 epinephrine, but no infusion was begun before patients reached the intensive care unit (ICU), whereupon a narcotic infusion was initiated for analgesia.
Anesthesia consisted of 15–25 mcg/kg of fentanyl, 0.05–0.10 mg/kg of midazolam, isoflurane in oxygen and nitrous oxide and vecuronium, 0.10–0.25 mg/kg, for muscle relaxation. A pulmonary artery catheter was placed for monitoring pulmonary artery pressures and cardiac index (CI). Additional monitoring included nasopharyngeal temperature and end tidal CO2. A Bair Hugger (Arizant Health Care, Minnetonka, MN) was placed above the diaphragm. All patients were tracheally intubated and ventilated with a Siemens D ventilator (Siemens, Solna, Sweden) beginning with a 10 cc/kg tidal volume. Subsequent changes in ventilator settings were made to maintain an arterial carbon dioxide tension (Paco2) of 35–45 mm Hg and an arterial oxygen tension (Pao2) more than 80 mm Hg. A urinary catheter was placed and urine output (UOP) was measured.
Lactated Ringer’s solution and colloid (albumin 5% or hetastarch) were administered in accordance with the instructions of the physician caring for the patient to maintain a minimal UOP of 0.5 mL · kg–1 · hr–1 or a pulmonary capillary wedge pressure (PCWP) of 20 mm Hg. Allogeneic packed red blood cells were administered for a hemoglobin 
7.0 g/dL in patients 70 yr of age and 8.0 g/dL in patients 70 yr of age or older. Transfusion of platelets or fresh frozen plasma (FFP) was in response to clinical evidence of microvascular bleeding and the following supporting laboratory studies for platelets: Evidence of platelet dysfunction (e.g., thromboelastogram) or platelet count < 50 x 109 · L–1; and for FFP-an activated partial thromboplastin time or prothrombin time 
1.5 times the upper limit of normal. Cryoprecipitate was generally given if transfusion of FFP and platelets failed to resolve the bleeding or a fibrinogen level below 100 mg/dL was identified. Blood was collected from the surgical field and converted to intraoperative autologous transfusion with a Medtronic AT-1000 (Medtronic, Parker, CO).
Patients were randomized by a computer-generated randomization table. Each subject received two infusions labeled "antihypertensive" and "urine maintenance" from the pharmacy before induction of anesthesia. The two infusions received by the SNP/DA group included SNP and DA at 2 mcg · kg–1 · min–1 for control of arterial blood pressure and maintenance of UOP, respectively. The two infusions received by the treatment group included fenoldopam to maintain UOP and manage hypertension and a sham DA infusion administered at a rate to mimic the volume delivery of a DA infusion of 2 mcg · kg–1 · min–1. The concentrations of SNP or fenoldopam were prepared by the pharmacy to achieve identical volumes for corresponding maximum rates of 5 and 1.5 mcg · kg–1 · min–1, respectively to insure complete blinding. The SNP/DA and fenoldopam infusions were begun after induction of anesthesia and placement of the pulmonary artery catheter before incision. The infusions of fenoldopam and SNP were initiated through a central venous catheter at 0.05 and 0.16 mcg · kg–1 · min–1, respectively. The starting dose of fenoldopam was chosen based on a previous investigation in which a fenoldopam infusion was started at 0.05 mcg · kg–1 · min–1 in a trial using fenoldopam for prevention of contrast-induced nephropathy (13). Additionally, Garwood and Hines (14) also reported that 0.03 mcg · kg–1 · min–1 of fenoldopam was associated with significant increases in renal blood flow and UOP without alterations in arterial blood pressure. Initiating low-dose fenoldopam at the beginning of the case would likely provide renal effects to the fenoldopam subjects similar to the SNP/DA subjects who received DA to begin the study. The infusions of fenoldopam or SNP were subsequently increased incrementally to maintain mean arterial blood pressure (MAP) within 20% of the baseline value.
All operating room personnel were blinded to the identity of the study infusions. The blinding was discontinued upon transfer to the ICU. The fenoldopam infusion was replaced with SNP and a DA infusion of 2 mcg · kg–1 · min–1 before entering the ICU. Both groups continued to receive SNP and DA postoperatively as indicated.
Patients received 0.5 g/kg of mannitol 12.5% (15) approximately 30 min before the cross-clamp was applied to the aorta. If the UOP fell below 0.5 mL · kg–1 · hr–1, fluid was administered to achieve a PCWP of 20 mm Hg. If UOP remained below 0.5 mL · kg–1 · hr–1 for a second consecutive hour, 20 mg of furosemide was given.
Heart rate (HR), systolic blood pressure, diastolic blood pressure, MAP, PCWP, and CI were recorded at these intervals: immediately before skin incision, immediately before placement of cross-clamp on the aorta, 5 min after release of cross-clamp, and at completion of surgery.
Assessment of renal function included measurements of serum creatinine at these intervals: preoperatively, 1 hr postoperatively, 24 hr postoperatively, and 5 days postoperatively. Creatinine clearance was measured at 1, 24, and 72 hr postoperatively. The UOP was measured intraoperatively at 30-min intervals. The collective UOP was recorded before placement of the aortic cross-clamp, during the period when the aorta was cross-clamped, and after release of the aortic cross-clamp. Intravascular fluid balance was calculated according to the volume of colloid and crystalloid administered intraoperatively and during the initial 24 hr in the ICU. Moderate renal insufficiency was defined previously as an increase in the serum creatinine of 0.5 mg/dL (16).
The following variables and complications were recorded: demographics, duration of aortic cross-clamp, associated medical conditions, current medications, ICU and hospital duration, reintubation within 72 hr, renal failure, dialysis without renal failure, clinically evident myocardial infarction, cerebral vascular accident (defined clinically and imaged), reexploration of the abdomen, reoperation for revascularization within 24 hr, and death.
Based on data from Knos et al. (17), regarding change in serum creatinine for patients undergoing aortic reconstructive surgery (which had a standard deviation of 0.38 mg/dL), a total sample size of 60 patients (30 in each group) provides statistical power of 85% to detect a difference in serum creatinine of 0.3 mg/dL (two-sided, 
= 0.05 level test) between the two groups. Characteristics were compared between the groups using a two-sample rank sum test for continuous variables and Fisher’s exact test for discrete variables with P values < 0.05 used to denote statistical significance.
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RESULTS |
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The amount of fentanyl, thiopental, vecuronium, midazolam, and volatile anesthetic administered was similar between the two groups. Surgical characteristics are displayed in Table 2. Aortic cross-clamp duration was similar for both the fenoldopam and SNP/DA (72.8 ± 25.4 vs 63.9 ± 28.7 min, respectively) groups. The volume of albumin 5% and crystalloid fluid administered intraoperatively and the percentage of patients in each group exposed to albumin 5% were similar between groups. Although significantly more intraoperative autologous transfusion (810 ± 493 vs 559 ± 281 mL, respectively, P = 0.017) was administered to fenoldopam patients than to SNP/DA patients, there was no difference between the two groups in allogeneic blood transfusion requirements intraoperatively (Table 2) or in the first 24 hr in the ICU. Only 24.1% and 20% of patients in the fenoldopam and SNP/DA groups respectively were exposed to allogeneic blood products that were the same between the groups. There was no difference between the groups in the amount of albumin 5% or crystalloid given in the first 24 hr or percentage exposed to albumin 5% during the first 24 hr in the ICU.
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The HR and MAP measurements are displayed in Figure 1. HR was significantly slower before placement of the aortic cross-clamp in the fenoldopam group compared with that in the SNP/DA group (P = 0.03). HR exceeded 110/min in 38.0% and 50.0% of fenoldopam and SNP/DA patients, respectively. Peak systolic blood pressure was not different between patients in the fenoldopam and SNP/DA group (170 ± 19 vs 169 ± 20 mm Hg, respectively). The frequency of hypertension requiring additional drugs to decrease arterial blood pressure was similar between the fenoldopam (13.8%) and SNP/DA (23.3%) groups (P = 0.50). Systolic blood pressure decreased to <80 mm Hg in 69% and 70% of patients in the fenoldopam and SNP/DA groups, respectively. There were no differences between the two groups regarding pulmonary artery systolic, diastolic, and capillary wedge pressure (Fig. 2) or CI (Fig. 3) measurements.
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Table 3 summarizes the effects of the two treatment modalities on renal function. Preoperative serum creatinine was similar in fenoldopam and SNP/DA subjects (1.2 ± 0.3 vs 1.3 ± 0.2 mg/dL, respectively). The number of patients who experienced an increase in their serum creatinine of 0.5 mg/dL at 1 hr, 24 hr, and 4–8 days after arrival in the ICU did not differ between fenoldopam (0/28, 0/28, 0/24) and SNP/DA groups (0/27,1/28, 1/20) (17,18). The creatinine clearance did not differ between groups at 3, 24, and >72 hr after arrival in the ICU. Intraoperative UOP was similar for fenoldopam and SNP/DA groups before cross-clamping of the aorta, after release of the aortic cross-clamp, and during the initial 24 hr in the ICU. The percentage of patients in each group who received mannitol 12.5% and furosemide intraoperatively was not different. One patient in the fenoldopam (3.5%) and one in the SNP/DA (3.3%) group developed renal failure postoperatively; however, dialysis was not required in either subject. A patient in the SNP/DA group who developed renal failure 7 days postoperatively died subsequently from massive thrombosis of unknown etiology, accounting for the only death.
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The duration of tracheal intubation for the fenoldopam and SNP/DA groups was not different (581 ± 596 vs 767 ± 1734 min, respectively, P = 0.88). Three patients in the fenoldopam group were reintubated after 72 hr (10.3%) compared with none in the SNP/DA group. Duration of stay in the ICU for fenoldopam and SNP/DA groups was not different (56.3 ± 37.0 vs 94.2 ± 181.7 hr, respectively, P = 0.44). Duration of stay in the hospital for fenoldopam and SNP/DA groups was not different (10.1 ± 5.4 vs 12.5 ± 13.5 days, respectively, P = 0.94).
Fenoldopam and SNP/DA groups were not different concerning the incidence of adverse events. One patient in the fenoldopam group (3.5%) developed a myocardial infarction postoperatively while there were no adverse events in the SNP/DA group. A patient in the SNP/DA group also had a transient ischemic attack while none occurred in the fenoldopam group. A patient in the SNP/DA group required reexploration of the abdominal cavity for small bowel obstruction approximately one month after the AAA repair.
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Infrarenal clamping of the aorta increases renal vascular resistance by 75%, with a corresponding 30%–40% reduction in mainly cortical renal blood flow, although the mechanism of renal injury is not entirely understood. Two studies (10,19) concluded that fenoldopam provided a measure of renal protection during aortic abdominal surgery requiring infrarenal aortic cross-clamping. Gilbert et al. (19) demonstrated, in an open label investigation without controls, that fenoldopam hastened the return of renal function according to creatinine clearance in 22 patients who underwent infrarenal cross-clamping. The patients’ baseline creatinine clearance (104.6 ± 27.1 mL/min) was initially reduced by 40% with application of the aortic cross-clamp and continued to decrease by 70% at the time of clamp removal. However, within 2 hr of the aortic cross-clamp removal, creatinine clearance had returned to 60% of baseline (58.7 ± 24.9 mL/min), which is uncharacteristic for these cases. Halpenny et al. (10) reported that fenoldopam had renal-protective ability compared with control in 28 patients undergoing infrarenal aortic cross-clamping evidenced by maintenance of creatinine clearance immediately after removal of the cross-clamp and 24 hr postoperatively.
The goal of this investigation was to compare the renal protective ability of the systemic vasodilator, fenoldopam, with another therapeutic regimen, SNP and DA, in patients similar to those investigated by Halpenny et al. (10). The present study, which involved more patients (totalling 60) than that in Ref. 10, demonstrated no difference in creatinine clearance at 3, 24, and >72 hr after arrival in the ICU between the two therapies. Serial serum creatinine measurements were also no different in the fenoldopam group compared with the SNP and DA regimen, although creatinine clearance is a more accurate assessment of early renal dysfunction than serum creatinine levels (17). Similarly, intraoperative UOP was not different between the groups before aortic cross-clamping, after release of the aortic cross-clamp, and during the initial 24 hr in the ICU. None of the measures of renal protection used pointed towards the superiority of one therapy over another.
The pharmacological alternative to fenoldopam was chosen for the ability to control hypertension and maintain renal function. Since the 1960s, DA has been used to prevent or treat renal impairment (20,21), based on reports of increased renal blood flow (22), glomerular filtration rate (21), and UOP (23). These effects occurred within the dose range of 0.5–3 mcg · kg–1 · min–1. Renal blood flow is augmented largely by stimulation of the DA1 receptors of the kidney (24). DA1 receptors are located postsynaptically on renal tubular cells and vascular smooth muscle, resulting in direct vasodilation of the vascular beds with stimulation. Additional stimulation of the DA1 and DA2 receptors in the proximal tubule leads to natriuresis and diuresis. The effects of DA reach a maximum in the healthy individual but diminish as renal function progressively worsens. Increased UOP may falsely suggest a renal protective effect with DA. Stimulation of ß and receptors and DA2 receptors with DA may instead limit renal blood flow, glomerular filtration rate, and sodium excretion. DA2 receptors are located presynaptically on sites in the sympathetic nervous system and inhibit sympathetic activity with stimulation (25). Moreover, it is becoming more apparent that increased UOP associated with low-dose DA may be attributed to improved CI, rather than a direct renal effect.
Conclusive evidence for renal protection in surgical patients with perioperative oliguria is lacking, as some studies are flawed (20,21). Furthermore, a large study by the Australian and New Zealand Intensive Care Society group (26) has demonstrated an inability of low-dose DA to prevent or reverse acute renal failure or alter outcome. Consequently, some have concluded that low-dose DA is ineffective (24).
Hypertension and elevated systemic vascular resistance often develop proximal to the infrarenal aortic cross-clamp and may be severe (1). This hypertension is generally managed with a direct vasodilator (1). SNP is a direct vasodilator (27) that has been used not only as treatment for hypertension, but also for afterload reduction in patients with poor ventricular function and in situations where pulmonary vasodilation is needed (28). Its popularity is primarily attributed to its effectiveness, low price, and brief duration of action. However, toxic levels have been associated with reduced renal perfusion and function (12) as well as other adverse reactions involving pronounced base deficits, lactic acidosis, and even death (28,29). Cyanide may accumulate in the blood to toxic levels even with brief exposure to SNP. One concern about administering SNP to patients with reduced renal function is that it is metabolized to intermediate cyanide, and then converted to thiocyanate, which is excreted by the kidneys.
Because renal blood flow is reduced by approximately 40% (30), even with infrarenal cross-clamping of the aorta, further reduction from administration of SNP to this patient population is disconcerting. In contrast, fenoldopam, also a vasodilator with rapid onset and short duration of action (31) maintains renal blood flow and UOP according to studies in volunteers (8). In the current study, hemodynamics were well maintained and arterial blood pressure was reduced as effectively with SNP and DA compared with fenoldopam without evidence of adverse renal function.
Another concern with the treatment of hypertension in these patients with a direct vasodilator is HR. Patients with AAA and aorto-occlussive disease have an increased incidence of coronary artery disease that may contribute to the higher incidence of perioperative myocardial infarction and cardiac death in patients undergoing major vascular operations (32). Both pharmacological strategies in this study may pose a risk for patients with coronary artery disease. In this study, HR was similar between the fenoldopam and SNP/DA groups, except at the preclamp period when the fenoldopam group had a significantly slower HR than the SNP and DA combination group. In an evaluation of fenoldopam for management of hypertensive patients, fenoldopam infusions caused a mild sympathetic response and increased HR in conjunction with increased plasma norepinephrine levels (7). However, the combination of SNP and DA may also promote tachycardia. de Lasson et al. (23) found HRs well above 80 bpm in patients receiving DA during infrarenal aortic cross-clamping when compared with those not receiving it. Our results suggest marginally better HR control with fenoldopam than with SNP and DA, but no apparent clinical benefit.
There are several limitations to this investigation. The administration of fenoldopam was restricted to the intraoperative period, in part because of financial considerations and long-standing treatment preferences. Renal vasoconstriction associated with infrarenal aortic cross-clamping does not completely resolve even with release of the clamp, so that continuation of fenoldopam in the postoperative period may have increased the likelihood of identifying a renal protective effect (30). Second, assessment of renal function in this study was limited to UOP, serum creatinine, and creatinine clearance. More specific biochemical end-points of renal dysfunction may have more effectively identified evidence of renal protection. Determination of renal blood flow would also have strengthened the findings of the study. Third, the number of patients did not allow any determination of changes in outcome associated with the use of fenoldopam compared with the combination of SNP and DA. Finally, there was no strict algorithm to guide fluid administration, so it is possible that larger amounts of chloride-containing solutions may have resulted in hyperchloremic acidosis and subsequent renal dysfunction (33). However, there was no difference in the amount of crystalloids administered to the groups and the association of hyperchloremic acidosis and subsequent renal dysfunction have not been firmly established (34).
In conclusion, fenoldopam was found to have no greater renal protection in patients undergoing infrarenal aortic cross-clamping for abdominal aortic reconstruction than the combination of SNP and DA. The significantly slower HR of patients receiving fenoldopam only, evident before application of aortic cross-clamp, conferred no evident clinical advantage. With the current economic pressures confronting health care, selection of equivalent therapies may allow for future savings. Future studies should focus on larger trials to identify any difference in outcome with fenoldopam if the risk of renal injury is increased.
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Footnotes |
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Presented at the American Society of Anesthesiologists, October 15, 2001.
Supported by the Mayo Clinic College of Medicine for Medical Education and Research.
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