Effect of high-dose fentanyl on renal function in dogs

Our objective was to determine the effects of high-dose fentanyl on canine renal function (RF). We anesthetized with sodium pentobarbital (SP) 16 dogs, randomly divided into 2 groups: in G1, SP was given alone, and in G2, combined with 0.05 mg.kg-1 fentanyl. Ali animais were ventilated artificially and had catheterized left and right femoral veins and left femoral artery for fluid infusion, drug administration, blood collection, and hemodynamic measurement. Urine was collected throughout the experiment. Attributes of RF were studied. SP did not alter RF, which was significantly altered by fentanyl. In G2, slower heart rates, mean arterial pressure, creatinine clearance, urinary output, osmolar c1earance and fractional excretion of sodium and potassium were observed. G1 had a behavior attributed to extracellular volume expansion and no RF alterations. In G2, we observed significant decreases in RF due to opioid-induced hemodynamic changes, not discarding the possible action of aldosterone. .


INTROOUCTION H
igh-dOSe fentanyl anesthesia is often used because this technique is usually associated with a stable cardiovascular hemodynamic course.However, there are few reports on the effects of high-dose fentanyl on renal function (RF) and authors have not obtained similar results, performing their studies on man as well as on dogs.t - 4 Fentanyl has also been used in combination with other drugs known to alter RF.
The primary aim of this study is to report the renal response of dogs to a high dose of fentanyl.These dogs were compared to a reference group receiving sodium pentobarbital (SP), a drug which does not alter RF. 5 ,6   Anddress for correspondence: Profa.Ora.Yara Marcondes Machado Castiglia Deptº de Anestesiologia da FMB -UNESP Distrito de Rubião Junior -Caixa Postal 530 Botucatu/SP -Brasil-CEP 18618-970

MATERIAL ANO METHOOS
Anesthesia was induced in 16 healthy male mongrel dogs (8 to 20 kg) with 30 mg.kg-t of SP.In the first experimental phase, anesthesia was maintained with SP (5 mg.kg-t ).In the second phase, animaIs were randomly divided into 2 groups of 8 dogs and were differentiated as follows: Group 1 (Gl) -control group, maintenance with SP only, and; Group 2 (G2)maintenance with SP and 0.05 mg.kgt fentanyl.A cuffed endotracheal tube was inserted, and the animaIs received pancuronium bromide (0.08 mg.kg-t in the first dose and 0.03 mg.kg-t for maintenance).Ventilation was controlled by a K. Takaoka model 660 apparatus with room air and adjusted to maintain n.ormal blood-gas pressures.Left.and right femoral veins were catheterized for fluid infusion, drugs administration, blood collection and measurement of inferior vena cava pressure (ICP).Channelization of the left femoral artery was carried out for measurements of mean arterial pressure (MAP) (Hg manometer).Urethral catheterization was performed.

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• 1434 During the first phase, the animaIs received Ringer's solution ( 0.4 ml.kg-l.min-l-extracellular volúme expansion) for 30 min, followed by a prime dose of 30 mg.kg-l creatinine and 4 mg.kg-lpara-aminohipuric acid (PAH).Immediately afterwards, a solution ofO.15 percent creatinine and 0.06 percent PAH in Ringer ( 0.6 mg.kgl.min-Icreatinine and 0.24 mg.kg-I.min-lPAH) was administered by continuous drip infusion with a Gilson pump model Hpl, until the end of the experimento There were 4 clearance periods, each lasting 15 mino Forty-five min after prime, the first clearance period began with V measurement (always after emptying the bladder), venous blood cOllection and determinations of MAP, ICP, and heart rate (HR).After the first clearance period end, the second phase of the experiment started with the second clearance period immediately after fentanyl administration.The third clearance period began immediately after the end of the second, and the fourth started 30 min after the end of the third.
The bladder was emptied and urine always collected at the end of each period.Blood samples were collected in the middle of each period.The mean values of the readings were calculated from those obtained at the beginning and end of each clearance period.The following attributes were recorded: PS and pancuronium maintenance dose was carried out 30 min before Ml and M4.
All serum and urine samples were later assayed for creatinine and PAH concentrations using colorimetric techniques. 7,8 Osmolarity was obtained through cryoscopic lowering.Na and K leveIs were determined using a flame photometer with oxyacetylene.Statistical analysis was carried out using the pro 1 e analysis. 9,lO For attributes presenting a high coefficient of variation (greater than 40 percent), the transformations were studied according Kempthorne.ll A value of p < 0.05 was considered statistically significant.
The a prefixed was 0.05.

RESULTS
Among the hemodynamics attributes of Gl, MAP (Fig. 2) was higher at M4 and C pAH was lower at M4.With respect to RF, V (Fig. 4) increased from M2 to M3 and M4.Uos m (Fig. 5) decreased from Ml on, C H20 (Fig. 7) increased from Ml on, and FE Na and FE K (Figs. 8, 9) increased from M2 to M4 (Table 1).
In comparison with the baseline valuss, HR (Fig. 1) and MAP (Fig. 2) decreased immediately after 0.05 mg.kg-I of fentanyl (G2).All values of C cr ' V, Cos m ' FE Na and FE K (Figs. 3,4,6,8,9) decreased after fentanyl.On the other hand, all values of C H20 increased from M2 onwards (Table 1).There were no consistent changes in any of the remaining attributes over the experimental period.

DISCUSSION
SP is a useful agent to induce and maintain anesthesia for experimental research and does not produce significant RF changes. 5,6 In small-to medium-sized dogs, such as the ones we used, HR is between 60-120 beats per minute. 12 In our study, the early observed increase in HR was attributed to a sympathetic l3 or vagolytic 14 origin or reflex through the arterial baroreceptor. 15 The increase in MAP only at M4 was probably due to a superficial anesthesia leveI.Greater sympathetic activity as well as an increase in RVR (not significant) and a decrease in C pAH (is actually indexed to renal plasma flow) may have occurred from M3 to M4.The large extracellular volume expansion performed in order to obtain high urinary output and more reliable results of C

G1 G2
FE Na (%) C H20 (ml.min-There is inpibition of vasopressin release by arterial distention and also of renin release by extracellular volume expansion.Thus, with the increase in extracellular volume, as expected there was greater elimination of water, and also of solutes.
The administration of fentanyl to the well-anesthetized .dogs of G2 resulted in rapid decreases in HR and MAP.Because fentanyl has no significant direct peripheral cardiovascular effects, the HR decrease must have been due to a central effect -a reduction of efferent neurogenic and humoral sympathetic tone.It follows that the higher the preexisting sympathetic activity, the greater the possibility for cardiovascular depression from fentanyl.l7However, the mechanism involved may be bradycardia caused by fentanyl mediated by vago.1S -20 Hypertension seems to be dependent on action on sympathetic ,nerv terminals,21 or fentanyl may even lower the plasma leveIs of techolamines 17,22 through a central effect -a reduction in efferent neurogenic tone and humoral sympathetic tone.However, Priano 4 believes fentanylliberates catecholamines from the adrenal medulla and peripheral nerves by central mediation, which may explain the increase he observed in the RVR of dogs to which only fentanyl (25 and 50 flg.kg-I ) had been administered.Results differing from these may be due to the previous administration of other drugs such as barbiturates, which cause central depression and sympathetic inhibition.Cos m (ml.min-1 ) 6 .There are two main mechanisms responsible for the preservation of renal perfusion in the presence of a decreased blood pressure.First, the normal kidney autoregulates its blood flow, keeping an almost constant RBF within a MAP range of 80 -180 mmHg.The second possible mechanism is the intrarenal secretion of prostaglandins PGE 2 and PGI 2 .Both are potent vasodilators.24 Our data suggest that these two responses may be preserved during high-dose fentanyl-induced hypotension.C pAH and RBF did not change and RVR was only slightly (and not significantly) reduced, despite a marked decrease in perfusion pressure.Thus, the significant decrease of GFR (Cc) possibly was minimized.
Fentanyl, a Jl opiate receptor agonist, diminishes V in the dog.,,2This effect, common to most opiates, has been attributed to the stimulation of vasopressin (an antidiuretic hormone) release.25 More recent evidence suggests that this is not the decisive factor, although in this study mediated, may be a reduction in GFR.26,27 In our study, MAP and C cr decreased in G2, while C pAH and RBF did not.However, GRF begins to decrease at higher renal perfusion pressure than RBF.As diuresis is governed mainly by two physiological mechanisms -by 60 .

CONCLUSIONS
ACKNOWLEDGEMENT: We thank Prof. Dr. Paulo Roberto Curi for statisticaI advice and analysis.
In the population of dogs which received only SP, the observed behavior can be attributed to extracellular volume expansion.These animaIs were compared to others received high-dose fentanyl.There were significant decreases in RF, probably due to significant opioid-induced hemodynamic changes.However, we cannot eliminate the possibility of main action due to aldosterone.
Another factor affecting renin-angiotensin activity is the prostaglandin system.These materiaIs are synthesized from fatty acids and are secreted by the ren'al medulla.Apart from being dilators of the renal vasculature, they produce renin release but enhance sodium excretion by the tubules.On the contrary, our data demonstrate that FE diminished after fentanyl administration.

Na
Prostaglandins can also be released from the kidney by angiotensin and norepinephrine and under a vasoconstrictive state (hypotensive).24 In contrast to what happened in G 1, Na and K output decreased.
Aldosterone normally enhances Na reabsorption and K secretion by the distaI tubule.However, there is no mandatory coupling between these cellular mechanisms.In other words, the Na amount in the distaI lumen tubule is not a limiting fact~r to K secretion, and there is no observed one-to-one exchange between Na and K at this nephron leveI.For this reason, our results are consistent with aldosterone having an important effect on Group 2.