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Effects of carprofen on renal function during medetomidine-propofol-isoflurane anesthesia in dogs

Jan H. M. Frendin DVM, PhD1, Ingrid M. Boström DVM, PhD2, Naruepon Kampa DVM, PhD3, Per Eksell DVM, PhD4, Jens U. Häggström DVM, PhD5, and Görel C. Nyman DVM, PhD6
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  • 1 Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, University of Agricultural Sciences, SE-750 07 Uppsala, Sweden.
  • | 2 Östersund Small Animal Hospital, Inspektörsvägen 19, SE-831 48 Östersund, Sweden
  • | 3 Department of Biomedical Sciences and Veterinary Public Health, Faculty of Veterinary Medicine and Animal Science, University of Agricultural Sciences, SE-750 07 Uppsala, Sweden.
  • | 4 Department of Biomedical Sciences and Veterinary Public Health, Faculty of Veterinary Medicine and Animal Science, University of Agricultural Sciences, SE-750 07 Uppsala, Sweden.
  • | 5 Small Animal Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, University of Agricultural Sciences, SE-750 07 Uppsala, Sweden.
  • | 6 Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, University of Agricultural Sciences, SE-750 07 Uppsala, Sweden.

Abstract

Objective—To investigate effects of carprofen on indices of renal function and results of serum bio-chemical analyses and effects on cardiovascular variables during medetomidine-propofol-isoflurane anesthesia in dogs.

Animals—8 healthy male Beagles.

Procedures—A randomized crossover study was conducted with treatments including saline (0.9% NaCl) solution (0.08 mL/kg) and carprofen (4 mg/kg) administered IV. Saline solution or carprofen was administered 30 minutes before induction of anesthesia and immediately before administration of medetomidine (20 μg/kg, IM). Anesthesia was induced with propofol and maintained with inspired isoflurane in oxygen. Blood gas concentrations and ventilation were measured. Cardiovascular variables were continuously monitored via pulse contour cardiac output (CO) measurement. Renal function was assessed via glomerular filtration rate (GFR), renal blood flow (RBF), scintigraphy, serum biochemical analyses, urinalysis, and continuous CO measurements. Hematologic analysis was performed.

Results—Values did not differ significantly between the carprofen and saline solution groups. For both treatments, sedation and anesthesia caused changes in results of serum biochemical and hematologic analyses; a transient, significant increase in urine alkaline phosphatase activity; and blood flow diversion to the kidneys. The GFR increased significantly in both groups despite decreased CO, mean arterial pressure, and absolute RBF variables during anesthesia.

Conclusions and Clinical Relevance—Carprofen administered IV before anesthesia did not cause detectable, significant adverse effects on renal function during medetomidine-propofol-isoflurane anesthesia in healthy Beagles.

Abstract

Objective—To investigate effects of carprofen on indices of renal function and results of serum bio-chemical analyses and effects on cardiovascular variables during medetomidine-propofol-isoflurane anesthesia in dogs.

Animals—8 healthy male Beagles.

Procedures—A randomized crossover study was conducted with treatments including saline (0.9% NaCl) solution (0.08 mL/kg) and carprofen (4 mg/kg) administered IV. Saline solution or carprofen was administered 30 minutes before induction of anesthesia and immediately before administration of medetomidine (20 μg/kg, IM). Anesthesia was induced with propofol and maintained with inspired isoflurane in oxygen. Blood gas concentrations and ventilation were measured. Cardiovascular variables were continuously monitored via pulse contour cardiac output (CO) measurement. Renal function was assessed via glomerular filtration rate (GFR), renal blood flow (RBF), scintigraphy, serum biochemical analyses, urinalysis, and continuous CO measurements. Hematologic analysis was performed.

Results—Values did not differ significantly between the carprofen and saline solution groups. For both treatments, sedation and anesthesia caused changes in results of serum biochemical and hematologic analyses; a transient, significant increase in urine alkaline phosphatase activity; and blood flow diversion to the kidneys. The GFR increased significantly in both groups despite decreased CO, mean arterial pressure, and absolute RBF variables during anesthesia.

Conclusions and Clinical Relevance—Carprofen administered IV before anesthesia did not cause detectable, significant adverse effects on renal function during medetomidine-propofol-isoflurane anesthesia in healthy Beagles.

Carprofen is an NSAID that is extensively used in veterinary medicine, both for long-term relief of arthritic pain and for preemptive analgesia before surgery. Nonsteroidal anti-inflammatory drugs inhibit the COX-1 and COX-2 enzymes in the prostaglandin synthesis cascade. Various canine in vitro and in vivo studies1–5 have revealed that carprofen has greater ability to inhibit COX-2 than COX-1 in several target tissues and in blood. Cyclooxygenase-2 is constitutively expressed in renal tissues of all species.6–9 This isoform may therefore be intimately involved in prostaglandin-dependent renal homeostatic processes.7

Prostaglandin synthesis increases during inflammation, but prostaglandins are also necessary to maintain the gastric mucosa and maintain RBF in situations with hypovolemia and hypotension. Dogs are relatively susceptible to the adverse effects of NSAIDs,10 compared with other species. Gastrointestinal disturbances are common, especially with long-term use,11 and renal adverse effects are a concern with the use of NSAIDs during surgery with general anesthesia when there is a risk for hypovolemia or hypotension.12–14

Renal blood flow is maintained by a complex interaction among several factors, including the sympathetic nervous system, various hormones, and local internal control systems.15 Although changes in arterial pressure have some influence on RBF, GFR and RBF are maintained fairly constantly (MAP ranges from 80 to 170 mm Hg16) through a process termed autoregulation. When blood pressure decreases, angiotensin II maintains GFR by constricting arterioles in the kidneys.17 Its effect is greater on efferent arterioles than afferent arterioles.18 The systemic blood pressure is also affected because angiotensin II acts on all arterioles in the body. Other hormones that have a role in maintaining systemic blood pressure are vasopressin and aldosterone.19,20 Prostaglandins that have vasodilatory effects may dampen the vasoconstrictor effects of angiotensin II, especially effects on the afferent arterioles, helping to maintain the perfusion pressure in the glomeruli.7,21,22

Methods that have been used to evaluate kidney function in veterinary medicine include determination of serum creatinine and BUN concentrations because of ease of measurement and, more recently, determination of different urinary enzyme concentrations. The urine γ-glutamyltransferase–to–creatinine ratio has been used as indicator of acute nephrotoxicosis in experimental models.23 However, in a clinical study,24 the urine AP:creatinine was found to be more useful as an indicator of acute renal damage in dogs. In addition, measurement of GFR provides accurate assessment of renal function regarding the severity of disease.25 The use of nuclear scintigraphy after administration of technetium Tc 99m pentetate is a rapid method for determining renal function without the need for indwelling catheters or prolonged urine collection.25 This method was used in studies26–29 concerning the effects of carprofen on renal function in healthy, anesthetized dogs with different anesthetic protocols. The dogs were either sedated before anesthesia (eg, with acepromazine) or not sedated. Renal function was determined by measurement of GFR via scintigraphy and analyses of blood and urine samples. In those studies, no negative effects caused by carprofen on renal function were observed. However, the effects of pre-anesthetic medication with carprofen in combination with α2-adrenoceptor agonists have not yet been studied, to our knowledge.

α2-Adrenoceptor agonists (eg, medetomidine) are frequently used for sedation of dogs and other animals in clinical practice, both alone for examinations and simpler procedures and before surgery with general anesthesia. These substances affect circulation and respiration and initially decrease peripheral circulation.30–32 α2-Adrenoceptors are constitutively expressed in the renal cortex of dogs and potentially can influence the regulation of renal function.33–35 If the peripheral circulation decreases through the effects of α2-adrenoceptor agonists, renal function may be affected.

The purpose of the study reported here was to examine the effects of carprofen during short-term anesthesia, at a dose recommended for preemptive analgesia, on GFR and other indices of renal function in dogs by use of medetomidine-propofol-isoflurane as an anesthetic protocol. Serum hormone concentrations were measured to help evaluate the effects of anesthesia on blood pressure.

Materials and Methods

Dogs—Eight healthy male Beagles were included in the study; mean age was 63 months (range, 41 to 89 months), and mean body weight was 18.2 kg (range, 15.2 to 21.0 kg). The dogs were kept and cared for by the Department of Small Animal Clinical Sciences at the Swedish University of Agricultural Sciences and remained there after completion of the study. They were fed a standard diet, and water was accessible ad libitum. Approval of the study was obtained from the local ethical Committee on Animal Experiments.

Study design and drugs—A crossover study was conducted with treatments allocated randomly. The study medication was carprofen (50 mg/mL), with physiologic saline (0.9% NaCl) solution as control; both were administered IV 30 minutes before anesthesia. Carprofen was administered at 0.08 mL/kg of body weight, corresponding to 4 mg of carprofen/kg, and an equivalent volume of saline solution was administered. Medetomidine was injected IM simultaneously with both treatments at a dose of 20 μg/kg. There was a 4-week washout period between subsequent treatments.

Blood samples were collected via venipuncture the day before and 24 hours and 7 days after the end of the anesthetic period, whereas all other samples were collected via an indwelling arterial catheter. Urine samples obtained the day before the experiment, before anesthesia, and 24 hours and 7 days after the end of the period of anesthesia were collected during natural voiding to avoid the need for additional catheterizations and an increased risk of urinary tract infection. During sedation and anesthesia, urine was collected via a urinary catheter that was allowed to remain in place until the final sample was collected on that day.

On the day of the anesthetic procedure, the dogs were not fed and water was withheld for 2 hours prior to induction of anesthesia. Baseline values for heart and respiratory rates and rectal temperature were obtained. A baseline ECG also was obtained. An IV catheter was placed in a cephalic vein. The catheter was used for IV administration of carprofen and for injection of technetium Tc 99m pentetate. Following the administration of local analgesia, a 20-gauge cathetera was inserted into the femoral artery by use of the Seldinger technique.36 The catheter was used for invasive measurement of cardiovascular variables and collection of blood samples for serum biochemical analyses, blood gas determinations, and assessment of acid-base balance during the anesthetic procedure. A central venous catheterb was also placed in the right jugular vein for injection of ice-cold saline solution for thermodilution calibration.

Samples were obtained for serum biochemical analysis, urinalysis, and determination of hormone concentrations before and 30 minutes after sedation and 30 and 60 minutes after induction of anesthesia. The GFR, hemodynamic variables, RBF, and rectal temperature were also measured at these time points.

Sedation, anesthesia, and monitoring—Medetomidine (20 μg/kg) was administered in the right triceps brachii muscle to induce sedation. Thirty minutes after injection of medetomidine, anesthesia was induced with propofol (10 mg/mL) administered slowly IV to effect to enable endotracheal intubation (mean ± SD dosage, 1.6 ± 0.5 mg of propofol/kg). Anesthesia was maintained with isoflurane (mean ± SD end-tidal isoflurane concentration, 0.48 ± 0.22%) in oxygen in a rebreathing circle system. Each dog was anesthetized for 60 minutes. Dogs were positioned in left lateral recumbency and were covered with a blanket during anesthesia, except during scintigraphy and insertion of a urinary catheter.

Cardiovascular variables, ECG, and respiratory rate were monitored continuously throughout anesthesia. Fraction of inspired oxygen, end-tidal CO2, end-tidal and inhaled isoflurane concentration, arterial oxygen saturation of hemoglobin, and tidal and minute volume were measured by use of a gas monitor.c Respiratory rate was measured from end-tidal CO2 measurements. Cardiovascular variables including heart rate, arterial pressure, and pulse contour CO index were recorded.d Values were recorded as a mean of 10 measurements (1 registration/min) centered around the time points; before and at 30 minutes after sedation; and at 30 and 60 minutes after induction of anesthesia. A lead II ECG was monitored and recorded by use of an ink-jet recorder.e Arterial blood samples for blood gas analysis and assessment of acid-base balance, including arterial pH, PaCO2, and PaO2, were obtained anaerobically from the femoral artery and stored in airtight syringes on ice until assayed by use of a standard electrode technique with an electrode temperature of 37°C.f Rectal temperature was measured with a battery-powered thermometer.g

During recovery from anesthesia, the jugular and femoral catheters were removed and pressure was manually applied to the femoral artery for approximately 20 minutes to prevent hemorrhage attributable to removal of the catheter.

Twenty-four hours after induction of anesthesia, blood and urine samples were collected and used to determine the status of the dogs after complete recovery from the anesthetic period. Serum biochemical analyses and urinalysis were conducted. In the event of a substantial decrease in GFR during the anesthetic period, follow-up measurements were performed 24 hours after anesthesia. On day 7 after the anesthetic period, blood and urine samples were collected from each dog and used for comparison with baseline values (ie, the first values obtained before each anesthetic period and administration of any drug) and to determine suitability for crossover studies.

Renal scintigraphy, GFR, and RBF measurements—Renal function was determined via GFR and scintigraphic measurements by use of the method of Krawiec et al,25 with slight modifications to make the measurements more reproducible.37 An aliquot (70 mBq) of technetium Tc 99m pentetate was injected in a cephalic vein. A dynamic acquisition was performed with each dog positioned in left lateral recumbency, and the gamma camera was positioned against the dorsum of the dog to obtain a dorsal view. A 64 × 64 matrix was used and corrected when needed by use of a special motion-correction program.h Each kidney's activity was corrected for absorption attributable to depth. The net activity in counts accumulated in each kidney from 30 to 120 seconds after injection was adjusted on the basis of the injected dose, and the total GFR was the sum of the GFR for each kidney. The relative blood flow to each kidney was measured by use of a computer program with a method based on calculating the fraction of CO that flows to each kidney.38 The absolute blood flow to the kidneys was then calculated from the CO measurements.

Hematologic examinations, serum biochemical analyses, and urinalysis—A CBC was performed by use of an automated hematology analyzer.i Serum activity of alanine aminotransferase, serum and urinary concentrations of creatinine, and activities of AP and the AP:creatinine were determined by use of an autoanalyzer.j Commercial reagents were used for all analyses. Glucose and hemoglobin concentrations in urine were determined with urine dipsticks.k

Hormone analysis—Immunoreactive angiotension II, arginine-vasopressin, and aldosterone concentrations were determined in plasma by use of modified human radioimmunoassays for angiotensin II and arginine-vasopressin28 and an aldosteronel radioimmunoassay.

Statistical analysis—Data were analyzed by use of a repeated-measures ANOVA, with treatment and time as within-dog factors. Equal variances between groups were tested via the F test (variance ratio test). Variance between paired differences was tested by use of the Mauchley sphericity test. When the test resulted in a value of P < 0.05, the Greenhouse-Geisser correction was used and adjusted P values were reported. When the overall F test of the ANOVA was significant, the Tukey honest post hoc analysis was performed, unless the Mauchley sphericity test indicated significance or an interaction was observed. In those instances, a planned comparison test was performed. Comparisons were made for blood and serum variables at the time of entry into the study and after the final washout period by use of a t test for paired samples. Statistical analysis was performed by use of a commercial software program.m Results were reported as mean ± SD. Significance was defined as values of P < 0.05 for all statistical analyses.

Results

Anesthesia, cardiovascular measurements, and hormone concentrations—There were no differences in cardiovascular, hormone, or anesthetic variables between treatments (Tables 1 and 2). Values for MAP were significantly lower in dogs during anesthesia, compared with values obtained when the dogs were conscious, but there was no difference between treatments. Concurrently, there was a significant decrease in heart rate in both groups over time. There was a significant decrease in pulse contour CO index over time but no difference between treatments. The mean decrease in CO for the 2 groups was 20% 30 minutes after medetomidine administration, after which there was a decrease by a mean of 60% during anesthesia, compared with baseline values.

Table 1—

Mean ± SD values for cardiovascular and hormonal variables measured in 8 dogs in a randomized crossover study of the effects of administration of carprofen and saline (0.9% NaCl) solution during medetomidine-propofol-isoflurane anesthesia.

TreatmentPeriodHeart rate (bpm)MAP(mm Hg)PCCI (L/min/m2)Angiotensin (pmol/L)Vasopressin (pmol/L)Aldosterone (pmol/L)
SalinePresed104 ± 20119 ± 244.6 ± 2.113.6 ± 4.20.5 ± 0.9296 ± 267
CarprofenPresed122 ± 16124 ± 225.3 ± 1.212.7 ± 6.41.2 ± 1.4214 ± 55
SalinePostsed92 ± 67121 ± 214.0 ± 3.9*17.4 ± 4.01.4 ± 2.0176 ± 200*
CarprofenPostsed80 ± 67125 ± 194.0 ± 3.915.1 ± 7.60.3 ± 0.399 ± 77*
SalineAnest 3055 ± 12102 ± 16*1.6 ± 0.614.9 ± 7.30.5 ± 0.9114 ± 92*
CarprofenAnest 3061 ± 53107 ± 22*2.4 ± 3.214.2 ± 5.70.4 ± 0.697 ± 77*
SalineAnest 6054 ± 1997 ± 141.9 ± 0.913.4 ± 6.41.4 ± 1.8105 ± 112*
CarprofenAnest 6056 ± 10104 ± 211.8 ± 0.713.0 ± 4.20.7 ± 0.886 ± 88*

Significant (P < 0.05) difference, compared with baseline value.

Significant (P = 0.005) difference, compared with baseline value.

Significant (P < 0.001) difference, compared with baseline value.

PCCI = Pulse contour CO index. Bpm = Beats per minute. Presed = Presedation. Postsed = Postsedation. Anest 30 = At 30 minutes of anesthesia. Anest 60 = At 60 minutes of anesthesia.

Table 2—

Mean ±SD values for respiratory variables and rectal temperature in 8 dogs used in a randomized crossover study of the effects of administration of carprofen and saline solution during medetomidine-propofol-isoflurane anesthesia.

TreatmentPeriodPaCO2 (mmHg)Respiratory rate (breaths/min)Arterial pHRectal temperature (C°)
SalinePresed4.9 ± 0.414 ± 57.38 ± 0.0138.5 ± 0.6
CarprofenPresed4.9 ± 0.414 ± 37.38 ± 0.0338.6 ± 0.6
SalinePostsed4.8 ± 0.312 ± 47.36 ± 0.0238.0 ± 0.36
CarprofenPostsed4.9 ± 0.312 ± 77.37 ± 0.0138.3 ± 0.6
SalineAnest 307.0 ± 0.7‡7 ± 3*7.25 ± 0.02‡37.5 ± 0.4*
CarprofenAnest 307.0 ± 0.6‡6 ± 2‡7.26 ± 0.03‡38.0 ± 0.4*
SalineAnest 606.4 ± 0.9‡8 ± 2*7.27 ± 0.03‡37.0 ± 0.5†
CarprofenAnest 606.9 ± 0.6‡7 ± 2†7.27 ± 0.01‡37.3 ± 0.3‡

See Table 1 for key.

No significant differences from baseline values between the treatments or over time in angiotensin II and vasopressin serum concentrations were detected. Aldosterone decreased significantly over time, but there was no difference between treatments (Table 3).

Table 3—

Mean ±SD values for renal variables in 8 dogs used in a randomized crossover study of the effects of administration of carprofen and saline solution during medetomidine-propofol-isoflurane anesthesia.

TreatmentPeriodGFR (mL/min/kg)Time to peak (s)Renal blood flow (%)RBF (L/min/m2)
SalinePresed4.7 ± 1.2195 ± 3019.2 ± 5.50.65 ± 0.19
CarprofenPresed4.6 ± 0.5156 ± 2617.5 ± 3.90.62 ± 0.18
SalinePostsed5.8 ± 0.9*234 ± 6220.2 ± 2.90.46 ± 0.39
CarprofenPostsed5.5 ± 0.5†232 ± 67†21.5 ± 3.1†0.47 ± 0.38
SalineAnest 305.8 ± 0.9*215 ± 3723.3 ± 4.60.3 ± 0.12‡
CarprofenAnest 305.8 ± 0.9†221 ± 70*21.8 ± 2.4†0.28 ± 0.11‡
SalineAnest 606.1 ± 0.9*194 ± 3723.3 ± 3.90.3 ± 0.11‡
CarprofenAnest 605.9 ± 0.8†206 ± 6723.8 ± 2.2†0.3 ± 0.11‡

See Table 1 for key.

Renal scintigraphy, GFR, and RBF measurements—No difference in renal variables was detected between treatments. There was a significant increase in RBFr over time in the carprofen group but not in the control group because of large individual variation (Table 3). Simultaneously, there was a significant decrease in RBFa in both groups during anesthesia.

There was a significant increase in GFR over time but no difference between treatments (Table 3). None of the dogs had a GFR before or during the anesthetic procedures that was less than the reference range of 3.50 to 7.53 mL/min/kg established by our laboratory group. Time to reach maximum activity counts in the kidney (time to peak, mean value of both kidneys) increased significantly in the carprofen group during sedation and anesthesia at 30 minutes, but there was no difference between treatments.

Serum biochemical values and urinalysis— Serum creatinine concentrations were within reference range (40 to 130 μmol/L) throughout anesthesia in both groups (Table 4). There were no significant changes in serum AP activities from baseline values throughout anesthesia, whereas values were significantly (P < 0.001) increased 24 hours after anesthesia in both groups. Creatinine concentration in urine decreased significantly (P < 0.001) in both groups during anesthesia. There was a significant (P < 0.05) increase in urine AP without a difference between groups after sedation, with a maximum concentration at 30 minutes of anesthesia, after which values were decreased (Table 4). Twenty-four hours after anesthesia, urine AP activity had returned to baseline values in both groups. The AP:creatinine in urine was significantly increased over time in both groups, with no difference between groups. Serum activity of alanine aminotransferase did not differ during anesthesia or among treatments.

Table 4—

Mean ± SD values for serum and urine biochemical analyses measured in 8 dogs in a randomized crossover study of the effects of administration of carprofen and saline solution during medetomidine-propofol-isoflurane anesthesia.

TreatmentPeriodSerum AP (μmol/L)Serum creatinine (μmol/L)Urine AP (μmol/L)Urine creatinineUrine AP:creatinine
SalineDay –12.0 ± 0.868 ± 131.0 ± 1.315,893 ± 5,2220.09 ± 0.13
CarprofenDay –11.8 ± 3.169 ± 91.8 ± 3.114,668 ± 6,7710.16 ± 0.31
SalinePresed1.8 ± 0.778 ± 250.4 ± 0.2a14,862 ± 5,901a0.03 ± 0.03
CarprofenPresed1.7 ± 0.972 ± 89.3 ± 24a14,118 ± 7,118a1.17 ± 3.13
SalinePostsed1.7 ± 0.768 ± 940.0 ± 65.118,725 ± 8,5142.63 ± 4.73
CarprofenPostsed1.7 ± 0.867 ± 827.3 ± 49.815,850 ± 10,8706.23 ± 14.3
SalineAnest 301.7 ± 0.666 ± 788.7 ± 106.57,743 ± 5,017*10.6 ± 8.7‡
CarprofenAnest 301.7 ± 0.764 ± 479.2 ± 946,337 ± 5,723*9.69 ± 5.75‡
SalineAnest 602.4 ± 1.365 ± 855.4 ± 80.24,556 ± 5,160*18.5 ± 36‡
CarprofenAnest 602.1 ± 1.164 ± 420.1 ± 18.23,931 ± 3,178*4.97 ± 3.05‡
SalineDay 12.9 ± 2.063 ± 111.9 ± 3.116,618 ± 9,2460.11 ± 0.15
CarprofenDay 12.2 ± 0.965 ± 150.9 ± 0.715,661 ± 11,9330.40 ± 1.0
SalineDay 72.4 ± 1.365 ± 12NANANA
CarprofenDay 72.1 ± 1.162 ± 9NANANA

Day –1 = Day before anesthetic period. NA = Not analyzed.

Baseline value for statistical analysis.

See Table 1 for remainder of key.

Hematologic values—Hemoglobin concentration and Hct decreased significantly (P < 0.001) in both groups during anesthesia, but there was no difference between groups. Values were within reference range 7 days after anesthesia. Mean corposcular volume did not change during the study. White blood cell count did not change during anesthesia, but there was a significant (P < 0.001) increase in both groups 7 days after anesthesia, compared with values before anesthesia.

Discussion

Results of the present study suggest that neither GFR nor other indices of renal function were impaired by carprofen in dogs anesthetized with medetomidinepropofol-isoflurane. There was no difference between the carprofen and control groups, indicating that the sedative and anesthetic drugs were sole causes of the cardiovascular and serum and urine biochemical changes that were measured. A significant finding was the increase in urinary AP activity in both groups, measured 30 minutes after medetomidine administration with a maximum concentration at 30 minutes of anesthesia. However, the urine AP values were within reference range 24 hours after the anesthetic period, and no dogs had clinical signs of renal dysfunction.

In the present study, it was possible to continuously measure MAP, heart rate, and CO through pulse contour CO measurement. From CO and RBFr measurements, it was also possible to calculate the RBFa. After induction of anesthesia, there was a 50% decrease in heart rate, 60% decrease in CO, and 50% decrease in RBFa.

Concurrently, as indicated by results of calculations of the RBFr, there was a diversion of CO to the kidneys. Further, MAP remained greater than the minimum pressure reported for RBF (mean, 65 mm Hg; range, 61 to 71 mm Hg) and glomerular filtration (mean, 81 mm Hg; range, 72 to 88 mm Hg) autoregulation in concious dogs,39 and angiotensin II and vasopressin remained at baseline concentrations. This was in contrast to previous carprofen studies,28,40 in which acepromazine-induced low blood pressures during anesthesia resulted in systemic pressures less than the pressure limits for GFR and RBF autoregulation in 16 of 18 dogs with ensuing triggering of compensatory hormone mechanisms. In the present study, aldosterone concentration decreased significantly in both groups over time after sedation and throughout anesthesia, suggesting an effect from medetomidine administration. This was similar to results of a previous in vitro study41 indicating that the imidazole type α2-adrenoceptor ligands atipamezole, detomidine, and medetomidine are potent inhibitors of aldosterone release from porcine adrenocortical cells.

Moreover, a significant increase in GFR was detected in the carprofen and saline solution groups, presumably as an effect of medetomidine administration. These results were consistent with those of other studies42,43 on GFR in dogs anesthetized with medetomidine-propofol-isoflurane, without concurrent administration of carprofen and with medetomidine doses up to 40 μg/kg IV or IM.

Studies33–35 of the role of α2-adrenoceptors in regulation of renal function indicate that IV infusion of guanabenz, another α2-adrenoceptor agonist, induces dose-related renal vasoconstriction and increased GFR. Inhibition of prostaglandin synthesis with the NSAID indomethacin does not affect the increase in GFR caused by guanabenz.33 The mechanisms by which α2-adrenoceptor agonists increase GFR are not clear and may involve secondary release of hormones affecting glomerular dynamics and permeability.35 In a study42 on the effects of medetomidine and butorphanol administered IM as sedative protocol for GFR measurement by use of nuclear scintigraphy in dogs, a significant increase in GFR was detected, compared with the saline solution control group. It was theorized that the increase in GFR may be attributable to preferential constriction of the efferent arterioles of the kidney.

In the present study, effects of sedation and anesthesia on serum creatinine were evident; creatinine concentration decreased continuously after sedation and during the ensuing anesthesia. The decrease in serum and urine creatinine concentrations may have been an effect of decreased rate of metabolism during anesthesia-induced hypothermia, as suggested by others.28 Serum AP activity remained at a nearly constant value during anesthesia, whereas AP activity in urine increased significantly without difference between treatments after medetomidine sedation with a maximum concentration measured at 30 minutes of anesthesia. Twenty-four hours after the anesthetic period, urine AP had returned to baseline activity.

Alkaline phosphatase in urine is derived mainly from the renal proximal tubular epithelium. Normally, very small amounts of this enzyme are released into the urine. High AP activity in urine is considered to be an early indication of renal damage.24 In the study by Heiene et al,24 dogs with acute renal failure had a mean urine AP:creatinine of 0.8 (range, 0.07 to 6.4). In healthy, awake dogs, the ratio did not exceed 0.1. In the present study of healthy but sedated and anesthetized dogs, the high urine AP and low urine creatinine values were reflected in extreme urine AP:creatinine, which increased after medetomidine sedation and resulted in mean ratios of 10.6 ± 8.7 and 9.7 ± 5.8 in the saline solution and carprofen groups, respectively, at 30 minutes of anesthesia. These results were in sharp contrast to the slightly increased ratios (≤ 0.3) detected in 2 dogs in a previous carprofen study28 that used acepromazine as the sedative. The transient increase in urine AP after medetomidine administration in our study seemed to reflect a transient stress on the proximal renal tubular epithelium, which may have an α2-adrenoceptor agonist mechanism of action. Results of our study suggested that the AP:creatinine in urine may be an unreliable indicator of kidney function in dogs sedated with medetomidine.

Results of the present study indicated that IV administration of carprofen at doses recommended for preemptive analgesia before surgery did not affect renal function in healthy dogs anesthetized with medetomidine-propofol-isoflurane. On the contrary, GFR increased, possibly because of the α2-adrenoreceptor agonistic actions of medetomidine in the kidneys despite its systemic effects of causing a decrease in CO and RBFa. Concurrently, however, diversion of the CO to the kidneys was evident. Mean arterial pressure did not decrease to less than threshold limits for RBF and glomerular filtration autoregulation after medetomidine was administered IM, which suggests that carprofen can be used in dogs at recommended doses during short-term anesthesia in combination with medetomidine at a dose of 20 μg/kg before anesthesia. However, it should be emphasized that these studies were carried out in normovolemic dogs without painful stimulation. Further studies on the effects of carprofen during medetomidine-propofol-isoflurane anesthesia are warranted in clinical situations during activation of vasoconstrictor systems in the presence of volume contraction and painful stimulation, such as hemorrhage and major surgery, or disease states associated with high concentrations of vasoconstrictor hormones.

ABBREVIATIONS

NSAID

Nonsteroidal anti-inflammatory drug

COX

Cyclooxygenase

RBF

Renal blood flow

GFR

Glomerular filtration rate

MAP

Mean arterial pressure

AP

Alkaline phosphatase

AP:creatinine

AP-to-creatinine ratio

CO

Cardiac output

RBFr

Relative RBF

RBFa

Absolute RBF

a.

4-F thermodilution catheter, 16 cm, Pulsion Medical Systems AG, Germany.

b.

1.75 × 150 mm, BD Careflow, Becton-Dickinson Critical Care Systems, Franklin Lakes, NJ.

c.

Capnomac-Ultima, Datex-Ohmeda, Helsinki, Finland.

d.

PiCCO, Pulsion Medical Systems AG, Germany.

e.

Siredoc 220, Siemens-Elema, Solna, Sweden.

f.

ABL 5 radiometer, Copenhagen, Denmark.

g.

Therumo digital clinical thermometer, Therumo Corp, Tokyo, Japan.

h.

Hermes nuclear medicine programs, Nuclear Diagnostics, Stockholm, Sweden.

i.

Cell-Dyn 3500, Abbott Laboratories, North Chicago, Ill.

j.

Konelab 30, Thermo Clinical Labsystems Oy, Vantaa, Finland.

k.

Combur-test D, Rocke Diagnostics Ltd, Bromma, Sweden.

l.

Coat-a-Count aldosterone RIA, Diagnostic Products Corp, Los Angeles, Calif.

m.

Statistica, Statsoft, StatSoft Inc, Tulsa, Okla.

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Contributor Notes

Supported by the Animal Health Group, Pfizer Incorporated.

Presented in part at the Association of Veterinary Anesthetists Autumn Meeting, Vienna, September 2004.

The authors thank Anna Edner, Pia Funkquist, Lais de Matos Malavasi, and Anneli Rydén for technical assistance.

Address correspondence to Dr. Frendin.