Three types of colored urine-green [1,2], white [3], and cloudy pink [4]-have been observed during propofol anesthesia or sedation. The cloudy urine is also described in the prescribing information of propofol as having a causally related incidence of less than 1%. Recently, we examined the sediment of the cloudy pink urine by light microscopy and observed large quantities of crystals, which are compatible with those of uric acid (UA). Further qualitative analysis of the sediment confirmed the presence of UA. Since approximately 73% of propofol metabolites were eliminated into the urine in one day [5], there is a possibility that propofol and its metabolites may directly increase urine UA concentration and that the UA may crystallize in the urine under conditions of low urinary pH and temperature. Although the cloudy urine may not be detrimental to patients receiving propofol anesthesia, this phenomenon is interesting for the renal effects of propofol and its metabolites. However, there are no earlier reports concerning the uricosuric effect under propofol anesthesia. In contrast, the renal effects of inhaled anesthetics are well studied because the increased concentration of plasma inorganic fluoride under inhaled anesthesia may induce nephrotoxicity, such as renal tubular damage [6].
In this study, we compared the effect of propofol anesthesia with that of sevoflurane anesthesia on renal function, focusing particularly on UA excretion in patients with normal renal function.
Methods
This study was approved by the hospital ethics committee, and written, informed consent was obtained from all patients. The patients were all ASA physical status I or II, scheduled for elective otorhinolaryngologic, orthopedic, or gynecologic surgery. Excluded from the study were patients with hyperuricemia (>7.9 mg/dL for male and >6.0 mg/dL for female patients) or hypouricemia (<3.5 mg/dL for male and <2.6 mg/dL for female patients) and renal compromise (i.e., preoperative serum urea nitrogen >20 mg/dL or creatinine >2.0 mg/dL). Patients were randomly assigned to two groups: a propofol group (n = 18, male/female 8/10) and a sevoflurane group (n = 18, male/female 8/10). Patients with hourly urine volume of 200 mL or more were also excluded from the study for two reasons: a) we wanted to assess the hourly UA concentrations based on a similar urine volume in the two groups and b) the urine UA concentrations were actually low in the excluded patients. We finally evaluated 11 patients receiving propofol anesthesia and 12 patients receiving sevoflurane anesthesia.
Patients received atropine 0.5 mg and midazolam 2-5 mg or hydroxyzine 25-50 mg intramuscularly 45 min before induction of anesthesia. Anesthesia was induced with propofol 2-2.5 mg/kg and fentanyl 50-100 micro g intravenously in the propofol group. The trachea was intubated after vecuronium 0.1 mg/kg was administered. Anesthesia was maintained with an infusion of propofol 3-10 mg [centered dot] kg-1 [centered dot] h-1 and nitrous oxide 60% and with supplementary administration of fentanyl 25-50 micro g. In the sevoflurane group, anesthesia was induced with thiamylal 3-4 mg/kg and fentanyl 50-100 micro g. The trachea was intubated after vecuronium administration, and anesthesia was maintained with sevoflurane 0.5%-2%, nitrous oxide 60%, and fentanyl. Anesthetic management for patients was identical in both groups except for the anesthetic administered.
Blood samples and urine specimens were obtained before induction of anesthesia, 1, 2, and 3 h after induction, and on Postoperative Day 1 (POD 1). UA concentrations were analyzed by enzymatic assay using a uricase reaction (HITACHI 7450 automatic analyzer; Hitachi Co., Tokyo, Japan). Creatinine (Cr) and urea nitrogen (UN) concentrations were analyzed by spectrophotometric assay using Jaffe reaction and urease reaction, respectively (HITACHI 7450 automatic analyzer). N-acetyl-beta-D-glucosaminidase (NAG) concentrations were analyzed by spectrophotometric assay using sodium cresolsulfonphthaleinyl NAG (AU800 automatic analyzer; Olympus Co., Tokyo, Japan). beta2-microglobulin (beta2-MG) concentrations were determined by immunochemical method (automated immunochemistry analyzer LX-3000; Eiken Chemical, Tokyo, Japan). Urine pH values were determined by a blood gas analyzer (ABL-520; Acid Base Laboratory, Copenhagen, Denmark). Plasma clearance of UA (CUA) and Cr (CCr) were calculated by the following formula: Equation 1
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All data are expressed as mean +/- SD. The unpaired Student's t-test was used to compare the demographic and anesthetic data, CUA and CCr, between the propofol and sevoflurane groups. Repeated-measures analysis of variance was used to detect intergroup difference and intragroup changes over time in renal function. Significance was defined as P < 0.05.
Results
There was no difference in age, body weight, duration of surgery and anesthesia, total fentanyl dose, intraoperative fluid administration, urine volume, or blood losses between the propofol and sevoflurane groups (Table 1). The preoperative serum UA level was also similar in both groups. No patient required blood transfusion during or after surgery.
Table 1: Demographic and Anesthesia Data in Patients with Propofol and Sevoflurane Anesthesia
Urine and serum UA were measured every 1-4 h to POD 1 in one patient with the propofol anesthesia. The hourly UA excretion (UA concentration x hourly urine volume) increased abruptly at 2 h after the induction of anesthesia and returned decrementally to the preinduction level 4 h after the end of anesthesia (Figure 1). The serum UA concentrations decreased gradually during propofol anesthesia and were stable thereafter.
Figure 1: Time course of uric acid (UA) excretions and serum UA concentrations in one patient during and after propofol anesthesia. Pre = before induction of anesthesia.
There were no differences between the groups with regard to serum UA, Cr, or UN concentrations (Table 2). The serum UA concentration decreased significantly at POD 1 in both groups.
Table 2: Effect of Anesthesia on Renal Function
The concentration of urine UA increased significantly at 3 h in the propofol group, while it remained unchanged in the sevoflurane group. Statistically, both the hourly UA concentration and excretion in the former were higher than those in the latter. The urine UN concentration decreased significantly during propofol and sevoflurane anesthesia. However, other variables in urine were similar in the two groups. One patient showed abnormal NAG (12.8, normal range 0-10 U/L) concentration in the sevoflurane group, and two patients in each group showed abnormal beta2-MG (730, 1005 and 407, 940 in the propofol and sevoflurane groups, respectively; normal range 5-253 mg/dL) on POD 1.
Hourly urine volumes correlated significantly with their urine UA concentrations in the propofol (r = 0.58, P < 0.01) and sevoflurane (r = 0.51, P < 0.01) groups (Figure 2). The mean CUA of 1-3 h was significantly higher in the propofol group than in the sevoflurane group (22.9 +/- 10.6 vs 5.9 +/- 3.4 mL/min, P < 0.05). In contrast, the mean CCr was similar in both groups (96 +/- 28 vs 93 +/- 31 mL/min, Figure 3).
Figure 2: Urine uric acid (UA) concentration against the hourly urine volume was plotted for each patient in the propofol group (n = 33) and the sevoflurane group (n = 36). Cloudy urine was observed in two patients 3 h after induction of propofol anesthesia ([arrow left]). Logarithmic curves of best fit are shown. The correlations were r = 0.58, P < 0.01 in the propofol group and r = 0.51, P < 0.01 in the sevoflurane group.
Figure 3: Uric acid clearance (CUA) and creatinine clearance (CCr) during propofol and sevoflurane anesthesia. Mean values of the hourly clearance are shown for the propofol group (n = 11) and the sevoflurane group (n = 12). Statistical difference was observed in CUA: *P < 0.01.
In this study, cloudy urine was observed 3 h after the induction of propofol anesthesia in two patients. Their hourly urine volume, UA concentration, and pH values were 20 mL, 249 mg/dL, 7.23 and 20 mL, 171 mg/dL, 5.58, respectively. When the urine specimens containing sediment were heated to 37 degrees C, they became clear. The urine became cloudy again when the specimens were cooled to 24 degrees C.
Discussion
This investigation was a prospective comparison of renal responses to propofol and sevoflurane anesthesia in patients with normal renal function. The urine UA concentration increased in the propofol group, whereas that of the sevoflurane group showed no detectable change, which indicates that propofol anesthesia increases UA excretion.
Gale et al. [7] compared propofol with thiopental for short anesthetics in gynecologic outpatients. The median anesthesia duration and total administration of propofol and thiopental were 10.0 minutes, 249.3 mg and 10.4 minutes, 446.2 mg, respectively. They found that propofol patients showed greater decreases in serum UA concentration one hour after treatment than did thiopental patients, although they did not examine the urine UA concentration. In our study, the serum UA concentration also decreased gradually during propofol anesthesia and was stable thereafter. In contrast, Higgins et al. [8] used propofol for sedation in the intensive care unit. The mean duration of administration and total propofol dose were 9.2 hours and 583.2 mg. The serum UA concentration showed no remarkable change after propofol sedation.
In the present study, the CUA of the propofol group was significantly higher than that of the sevoflurane group. The CCr was similar in both groups. There are no earlier reports concerning the uricosuric effect of Intralipid[TM] (Kabi Pharmacia, Stockholm, Sweden), although we initially questioned whether the solvent of propofol was a causal drug. In the preliminary study, one of us received 150 mL of 10% Intralipid[TM] for two hours and showed normal CUA and CCr levels. Cr is not reabsorbed in the renal tubulus, which is nearly compatible with the glomerular filtration rate. Consequently, renal blood flows in both groups were similar and well preserved in this study [9]. In contrast, UA is filtrated through glomeruli, and approximately 90% of the filtrated UA is reabsorbed by anion transport exchanger. The normal CUA of nonanesthetized humans is 6-12 mL/min. The CUA of the propofol group was 3.8 times higher than that of the sevoflurane group. This indicates that propofol anesthesia inhibited the UA reabsorption and sevoflurane did not. Probenecid is well known as a uricosuric drug. The drug competes with UA at anion transport exchanger in the renal tubulus, thereby inhibiting UA reabsorption [10]. Therefore, we speculate that propofol and its metabolites have an effect similar to probenecid, because the main structure of propofol and probenecid consists of a benzene ring. Propofol is biotransformed to four propofol metabolites [6]: propofol glucuronide, 1-quinol glucuronide, 4-quinol glucuronide, and 4-quinol sulfate. Further investigation is needed to clarify whether one or all four of these metabolites exhibit a uricosuric effect.
Propofol nephrotoxicity has not been reported. The serum Cr and UN concentrations showed no effects attributable to propofol in normal patients [11] and those with renal failure [12]. It has been reported that the serum Cr level was unchanged from preoperative values in propofol and sevoflurane anesthesia [13]. However, there are no earlier reports concerning the concentrations of beta2-MG and NAG during propofol anesthesia. These substances are used as sensitive indicators of proximal or distal tubular damage. Tsukamoto et al. [14] showed significant increases in urine beta2-MG levels after surgery in sevoflurane and isoflurane anesthesia in patients with moderately impaired renal function. In this study, it tended to increase the NAG and beta2-MG concentrations, but these were not significant changes. Therefore, in this study, the renal tubular function was well preserved during and after both propofol and sevoflurane anesthesia.
In the present study, cloudy urine was observed in two patients under propofol anesthesia. The crystal formation is closely related to urine UA concentration, pH value, and temperature. UA is the end product of purine metabolism in humans, and normal excretion of UA is 500-1000 mg/day. In urine, UA exists in two forms: free UA and urate salt. UA is relatively insoluble in water but is 20 times more soluble in the form of sodium urate. The pKa of UA is near 5.75. At that point, half of the uric ions exist as free UA and the other half are associated with other ions as urate salts [15]. Low urine pH contributes to the concentration of the relatively insoluble UA. Moreover, urate in plasma at 37 degrees C is twice as soluble as that at 25 degrees C. We have already experienced 18 cases of cloudy urine in our operating department, where the room temperature is kept constant at 24 degrees C. However, cloudy urine has never been observed in one of our affiliated hospitals, where the room temperature is kept at 27 degrees C. Consequently, we speculate that the UA crystals are formed in the connecting tube between the vesical catheter and urinary bag, not in the kidney, ureter, or bladder. In clinical practice, therefore, cloudy pink urine is not detrimental to patients under propofol anesthesia.
In conclusion, this is the first report describing the uricosuric effect of propofol anesthesia. The present study demonstrated that hourly urine UA concentration and excretion and CUA were significantly increased under propofol anesthesia, while they remained stable under sevoflurane anesthesia. These findings explain the cloudy urine that occurs during propofol anesthesia. Our data suggest that propofol may be a beneficial anesthetic for patients with hyperuricemia.
We thank A. Haji, Associate Professor of Pharmacology at our university, for his constructive criticism.
REFERENCES
1. Bodenhan A, Culank LS, Park GR. Propofol infusion and green urine [letter]. Lancet 1987;2:740.
2. Ananthanarayan C, Fisher JA. Why was the urine green? [correspondence]. Can J Anaesth 1995;42:87-9.
3. Nates J, Avidan A, Gozal Y, Gertel M. Appearance of white urine during propofol anesthesia [letter]. Anesth Analg 1995;81:210.
4. Masuda A, Hirota K, Satone T, Ito Y. Pink urine during propofol anesthesia. Anesth Analg 1996;83:666-7.
5. Simons PJ, Cockshott ID, Douglas EJ, et al. Disposition in male volunteers of a subanaesthetic intravenous dose of an oil in water emulsion of 14C-propofol. Xenobiotica 1988;18:429-40.
6. Cousins MJ, Mazze RI. Methoxyflurane nephrotoxicity: a study of dose-response in man. JAMA 1973;225:1611-6.
7. Gale DJ, Thain LMF, Stefaniu R. A comparison of propofol with thiopental for short anesthetics in gynecological outpatients. Sem Anesth 1988;7(Suppl):29-43.
8. Higgins TL, Yared J-P, Estafanous FG, et al. Propofol versus midazolam for intensive care unit sedation after coronary artery bypass grafting. Crit Care Med 1994;22:1415-23.
9. Guyton AC. Formation of urine by the kidney. II. Processing of the filtrate in the tubules. Textbook of medical physiology. Philadelphia: WB Saunders, 1991;229-307.
10. Weiner IM. Inhibitors of tubular transport of organic compounds. In: Goodman Gilman A, Rall TW, Nies AS, Taylor P, eds. The pharmacological basis of therapeutics. New York: Pergamon, 1990:743-63.
11. Stark RD, Binks SM, Dutka VN, et al. A review of the safety and tolerance of propofol (Diprivan). Postgrad Med J 1985;61:152-6.
12. Morcos WE, Payne JP. The induction of anaesthesia with propofol (Diprivan) compared in normal and renal failure patients. Postgrad Med J 1985;61:62-3.
13. Jellish WS, Lien CA, Fontenot HJ, Hall R. The comparative effects of sevoflurane versus propofol in the induction and maintenance of anesthesia in adult patients. Anesth Analg 1996;82:479-85.
14. Tsukamoto N, Hirabayashi Y, Shimizu R, Mitsuhata H. The effects of sevoflurane and isoflurane anesthesia on renal tubular function in patients with moderately impaired renal function. Anesth Analg 1996;82:909-13.
15. Drach GW. Urinary lithiasis: etiology, diagnosis, and medical management. In: Walsh PC, Retik AB, Stamey TA, Vaughan ED, eds. Campbell's urology. Philadelphia: WB Saunders, 1992:2085-156.
