Glucocorticoids are used to treat a wide variety of diseases in human and veterinary medicine including inflammatory, neoplastic, and immune-mediated disorders.1 Glucocorticoids act on multiple organ systems and can cause adverse effects. Although cats are believed to be more resistant than dogs to the adverse effects of glucocorticoids, clinical consequences of glucocorticoid treatment in cats can include marked cutaneous atrophy, skin fragility, increased susceptibility to diabetes mellitus, and precipitation of CHF.2,3
Concern regarding the role of glucocorticoids in the induction of CHF in cats arose from anecdotal reports and a case series3 of 12 cats that developed CHF < 1 week after injection of long-acting methylprednisolone acetate. A follow-up study by Ployngam et al4 into the hemodynamic effects of methylprednisolone acetate (5 mg/kg, IM) in healthy cats investigated 4 potential mechanisms by which glucocorticoids might induce CHF: sodium and water retention secondary to mineralocorticoid effects leading to intravascular volume overload; glucocorticoid-induced hyperglycemia and subsequent plasma volume expansion by the shift of fluid from the extravascular to intravascular space; glucocorticoid-induced structural remodeling of the heart, specifically left ventricular concentric hypertrophy and diastolic dysfunction; and corticosteroid-induced vasoconstriction leading to an increase in left ventricular afterload. On the basis of the moderate to severe hyperglycemia and increase in plasma volume following injection of methylprednisolone acetate to the cats of that study,4 the investigators concluded that an extravascular-to-intravascular fluid shift owing to glucocorticoid-induced hyperglycemia was the most likely mechanism for steroid-induced CHF.
In a canine study5 with a design similar to that of the Ployngam et al4 study, the blood glucose concentration and echocardiographic variables did not differ significantly between healthy dogs that were and were not administered prednisolone (1 mg/kg, PO) once daily for 14 days. Interestingly, the prednisolone-treated dogs of that study5 developed a significant and clinically relevant increase in SAP after 7 days of treatment. Those results suggest that vasoconstriction and an increase in left ventricular afterload rather than changes in glucose homeostasis may be clinically relevant effects of anti-inflammatory glucocorticoid administration in dogs.
It remains unknown whether oral administration of anti-inflammatory doses of intermediate-acting glucocorticoids to cats results in any of the previously proposed mechanistic changes, such as diabetogenesis or an increase in SAP. The purpose of the study reported here was to investigate whether oral administration of anti-inflammatory doses of an intermediate-acting glucocorticoid alters clinicopathologic, hemodynamic, or echocardiographic variables enough to precipitate CHF in systemically normal cats. In cats, the oral formulation of prednisolone is the most biologically active among intermediate-acting glucocorticoids.6,7 Therefore, prednisolone was used for the study reported here, and a short (14-day) course of treatment was chosen to mimic common clinical use of glucocorticoids in cats. We hypothesized that oral administration of prednisolone to systemically normal cats with allergic dermatitis at the low (1 mg/kg/d) and high (2 mg/kg/d) ends of the recommended anti-inflammatory dosage range1,2 for 14 days would not significantly alter clinicopathologic, hemodynamic, or echocardiographic variables, compared with those in untreated (control) healthy cats.
Materials and Methods
Animals
Results of an a priori sample size calculation indicated that 10 prednisolone-treated cats and 10 control cats would be required to detect a mean difference of 20 mg/dL in the blood glucose concentration between the 2 groups with 80% power and an α of 0.05. A mean difference in blood glucose concentration of 20 mg/dL was chosen on the basis of the mean increase in blood glucose concentration observed in cats following methylprednisolone acetate administration in the Ployngam et al study.4 The study protocol was approved by the ISU Institutional Animal Care and Use Committee (IACUC No. 1-17-8425-F).
All cats were owned by students or employees of the ISU College of Veterinary Medicine, and owner consent was obtained for each cat prior to study enrollment. The prednisolone-treated group consisted of 10 cats with clinical signs consistent with allergic dermatitis that were evaluated by a board-certified veterinary dermatologist (DJB) for short-term anti-inflammatory treatment. Each prednisolone-treated cat was matched to a healthy control cat on the basis of sex, neuter status, age (± 1 year), and body weight (± 10%). Cats were excluded from study enrollment if they had received steroids within 3 months prior to study initiation; had evidence of systemic disease as determined by results of a physical examination, CBC, and serum biochemical analysis; had echocardiographic evidence of structural cardiac disease; or were receiving hemodynamically active drugs (eg, vasodilators). Cats that were too fractious for performance of a routine physical examination, venipuncture, and echocardiographic evaluation without sedation were also excluded from the study.
Study design
The study was a prospective clinical trial with a 35-day observation period. Baseline measurements (physical examination, CBC, and serum biochemical analysis) were obtained for all cats on the morning of day 0. The 10 prednisolone-treated cats were randomly assigned by means of a random number generator to either group A (n = 5) or group B (5). Cats assigned to group A received prednisolone at a dosage of 1 mg/kg, PO, once daily (dosage 1), on days 0 through 6 then at a dosage of 2 mg/kg, PO, once daily (dosage 2), on days 7 through 13. Cats assigned to group B received prednisolone at dosage 2 on days 0 through 6 and at dosage 1 on days 7 through 13 (Supplementary Figure S1, available at avmajournals.avma.org/doi/suppl/10.2460/ajvr.80.8.743). After day 13, the prednisolone dosage was gradually tapered for both groups. Cats in group A received prednisolone at a dosage of 1 mg/kg, PO, once daily for 3 days (ie, days 14, 15, and 16) then every 48 hours for 3 doses (ie, days 18, 20, and 22). Cats in group B received prednisolone at a dosage of 0.5 mg/kg, PO, once daily for 3 days, then every 48 hours for 3 doses. When indicated, prednisolone-treated cats also received systemically or topically administered antimicrobials for adjunctive treatment of secondary infections associated with allergic dermatitis. Prednisolone was administered in the morning by study personnel on the days that the cats were in the hospital for the acquisition of study data (days 0, 7, and 14) and by owners on all other days. Control cats did not receive any medications throughout the 35-day observation period. For both prednisolone-treated and control cats, owners were instructed to withhold food in the morning on days when cats were brought to the hospital for the acquisition of study data (days 0, 7, 14, and 35).
Data collection
Data were collected at 6 times (T1 through T6). Baseline (T1) data were obtained on the morning of day 0 prior to administration of prednisolone to the treated cats. Data for T2 were collected 1 hour after administration of the first prednisolone dose for treated cats and 1 hour after collection of baseline data for control cats. Data for T3 were collected prior to treatment on the morning of day 7 (ie, the day that the alternate dosage of prednisolone was initiated for groups A and B), and T4 data were collected 1 hour later. Data for T5 were collected prior to treatment on the morning of day 14, and T6 data were collected on the morning of day 35.
Results of PK studies1,6 in cats indicate that the tmax of prednisolone is approximately 1 hour and the half-life is approximately 3.3 hours after oral administration. The data acquisition times for the study were purposely selected to capture the prednisolone tmax (1 hour after dose administration) and PK steady state (> 5 half-lives; ie, > 7 days after dose administration) for the 2 dosages (1 and 2 mg/kg) of the drug administered. For example, for the prednisolone-treated cats, T2 represented data at the tmax for the first prednisolone dosage (1.0 mg/kg for cats in group A and 2.0 mg/kg for cats in group B), T3 represented data at the PK steady state for the first prednisolone dosage, T4 represented data at the tmax for the second prednisolone dosage (2.0 mg/kg for cats in group A and 1.0 mg/kg for cats in group B), T5 represented data at the PK steady state for the second prednisolone dosage, and T6 represented data 7 days after prednisolone administration was discontinued.
The following examinations were performed and data were collected at T1, T3, T5, and T6: physical examination, body weight, SAP, echocardiographic evaluation, CBC, serum biochemical analysis, urine specific gravity, FENa, serum insulin-to-glucose concentration ratio, serum fructosamine concentration, cTnI concentration, quantitative feline NTproBNP concentration, plasma volume, plasma prednisolone concentration, plasma AngI concentration, and plasma total and free cortisol concentrations. The following examinations were performed and data were collected at T2 and T4: SAP, echocardiographic evaluation, CBC, limited serum biochemistry panel (blood glucose, creatinine, BUN, and electrolyte concentrations), quantitative feline NTproBNP concentration, plasma volume, plasma prednisolone concentration, plasma AngI concentration, and plasma free and total cortisol concentrations. All diagnostic tests were performed in all cats, with the following exceptions: plasma prednisolone concentrations were determined for the prednisolone-treated cats only, and plasma AngI and free and total cortisol concentrations were measured in all prednisolone-treated cats and 3 randomly selected control cats.
A subset of owners volunteered to measure their cats’ blood glucose concentration with a point-of-care glucometera at home to detect short-term alterations in that variable. Owners were instructed to measure the blood glucose concentration daily in the morning before feeding and prednisolone administration on days 1 through 3 and 8 through 10. Blood samples were obtained by pricking the marginal ear pinna with a needle, and the blood glucose concentration was determined by use of the glucometer in accordance with the manufacturer's instructions. At-home blood glucose concentrations were determined for 8 prednisolone-treated and 6 control cats on days 1 through 3 and for 5 prednisolone-treated and 4 control cats on days 8 through 10.
The same digital scale was used to weigh each cat at T1, T3, T5, and T6. All SAP measurements were obtained by means of a standard noninvasive Doppler ultrasonographic method, which was performed by the same trained examiner (IAK) in accordance with standard methods8 with the patient positioned in the same position and use of a consistently sized cuff at all data acquisition times. Cats were allowed to acclimate to the hospital environment for at least 15 minutes prior to SAP measurements. At each data acquisition time, at least 3 consistent SAP measurements were obtained, and the mean SAP was calculated and used for subsequent analyses.
All peripheral venous blood samples were obtained from an external jugular or medial saphenous vein by use of a 1-inch, 22-gauge needle attached to a 3- to 12-mL chilled syringe. From each cat, 8 mL of blood was collected at T1, T3, T5, and T6 and 6 mL of blood was collected at T2 and T4. Also, at T1, T3, T5, and T6, a urine sample (maximum volume, 3 mL) was collected from each cat by means of ultrasound-guided cystocentesis and use of a 1- to 1.5-inch, 22-gauge needle attached to a 3-mL syringe. All CBCs, serum biochemical analyses, and urine tests were performed at the ISU Clinical Pathology Laboratory, Ames, Iowa. Serum insulin and glucose measurements were performed by the Michigan State University Diagnostic Center for Population and Animal Health, Lansing, Mich. Serum fructosamine and feline NTproBNP concentrations were determined by Idexx Laboratories, Westbrook, Me. Serum cTnI concentrations were determined by the Mary Greeley Medical Center Laboratory, Ames, Iowa.
For data acquisition times T2 through T6, the %ΔPV was calculated as follows: (HgbT1/HgbTX) × ([1 - HctTX]/[1 - HctT1]) - 1 × 100, where Hgb is the hemoglobin concentration at the given sample acquisition time and TX is the sample acquisition time in question (ie, T2, T3, T4, T5, or T6). The FENa was calculated as follows: 100 × ([Sodiumurine × Creatinineplasma]/[Sodiumplasma × Creatinineurine]).
At each sample acquisition time, plasma was harvested, prepared, and stored for later determination of AngI, free and total cortisol, and prednisolone concentrations at the ISU Veterinary Diagnostic Laboratory, Ames, Iowa. Briefly, 0.1 mL of bovine lung-derived aprotinin solutionb (concentration, 5 mg/mL) was added to a 3-mL blood collection tube containing EDTA as an anticoagulant (EDTA tube), which was then chilled. Immediately after a blood sample was collected into a chilled syringe, 2 mL of the sample was placed in the prepared aprotinin-EDTA tube and the remainder of the sample was divided between an EDTA tube and an additive-free blood collection tube for the previously described diagnostic tests. The blood samples in the chilled aprotinin-EDTA tubes were centrifuged at 1,500 × g and 4°C for 30 minutes. The plasma was harvested from each sample, placed in a chilled cryovial, and stored at −80°C until analysis. The plasma prednisolone concentration in samples was determined by liquid chromatographymass spectrometry in batch analysis. Plasma free and bound cortisol concentrations were determined by equilibrium dialysis followed by liquid chromatography-tandem mass spectrometry with cortisol-d4 used as a surrogate analyte for calibration. Equilibrium dialysis was performed with 150 μL of each plasma sample dialyzed against 350 μL of PBS solution. Free and bound cortisol were separated by protein precipitation prior to liquid chromatography-tandem mass spectrometry. The total plasma cortisol concentration was calculated as the sum of free and bound cortisol concentrations. Plasma AngI concentration was determined by the use of a commercially available competitive-binding peptide enzyme immunoassay.c
Transthoracic echocardiographic examinations were performed by a board-certified veterinary cardiologist (JLW or WAW) and use of an ultrasound systemd coupled with 8- to 12-MHz phased-array sector transducers.e Cats were positioned in right and left lateral recumbency to obtain transthoracic 2-D, M-mode, spectral Doppler, color flow Doppler, and tissue Doppler echocardiographic measurements by means of standard methods.9–12 A simultaneous lead II ECG tracing was recorded during each echocardiographic examination. Echocardiographic images were stored digitally and analyzed with an integrated image analysis system.f All measurements were obtained by use of digital calipers. For each echocardiographic evaluation, all measurements were repeated 5 times on images of sufficient technical quality, and the mean was calculated and used for all subsequent analyses.
Left ventricular size, wall thickness, and systolic function assessments were obtained from standard right parasternal short-axis and left apical long-axis images. The IVSd, LVIDd, LVPWd, and left ventricular internal dimension in systole were measured on M-mode images. Left ventricular fractional shortening was calculated as follows: ([LVIDd - left ventricular internal dimension in systole]/ LVIDd) × 100. Left ventricular end-diastolic and end-systolic volume indices and LVEF were determined by use of the modified single-plane Simpson method of disks13 with images acquired from the left apical 4-chamber view that were optimized for the left ventricle. Left atrial size was assessed by measurement of the left atrial and aortic root diameters in 2-D images obtained from the right parasternal short-axis view as described14,15 and calculation of the LA:Ao.
Transmitral flow was recorded by use of pulsed-wave Doppler echocardiography as described.16,17 Left apical 4- and 3-chamber views were used to measure peak velocity of early (E) and late (A) diastolic transmitral flows and IVRT, respectively. The E:A and E:IVRT were calculated. The left apical 4-chamber view was also used for tissue Doppler echocardiography to record the peak early (Ea) and late (Aa) velocities of mitral annulus motion and calculate the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular motion.16,17 Transmitral and tissue Doppler measurements were included in statistical analyses only if distinct E versus A waves could be visualized; summated (EA) measurements were not analyzed. The LVMI was calculated as follows: ([1.04 × {LVIDd + LVPWd + IVSd}3 - LVIDd3] × 0.8 + 0.6)/body surface area.18
Myocardial speckle-tracking echocardiography was used to assess left ventricular strain as described.19,20 High-quality 2-D images of the left ventricle were obtained from left apical 2-, 3-, and 4-chamber views. Images were stored digitally in raw data format. Strain measurements were made with an on-cart strain software package.g For a single cardiac cycle in each view, user-defined reference points guided the software algorithm to define the region of interest that incorporated the entire left ventricular myocardial thickness. The software's speckle-tracking algorithm then calculated the strain and strain rate for each myocardial segment, and the global longitudinal strain was calculated for the entire region of interest.
Statistical analysis
A commercially available software programh was used to perform all analyses. The data distribution for each continuous variable was assessed for normality by means of a Shapiro-Wilk test. All variables were found to be normally distributed; therefore, results were reported as the mean ± SD. Data were analyzed with linear mixed-effects models for each response, and F tests were used to test the significance of main effects and interactions. The treatment group (A, B, or control), period (1 [days 0 through 6] or 2 [days 7 through 13]), sample acquisition time (T1 through T6; time), interaction between treatment group and time, and interaction between period and time on each variable were considered as the fixed effects. Each model included a random effect for cat to account for repeated measures on individual cats. Residual-based diagnostics were conducted to assess the validity of model assumptions. For each variable and cat, the percentage change from baseline was calculated for each time. Then for each variable at each time, linear regression was used to compare the percentage change from baseline between prednisolone-treated and control cats.
Paired t tests were used to compare the baseline blood glucose concentration, which was determined by an automated biochemical analyzer, with the blood glucose concentration determined by a point-of-care glucometer on days 1, 2, 3, 8, 9, and 10.
For each variable and prednisolone dosage (1 and 2 mg/kg), t tests were used to compare the percentage change from baseline between prednisolone-treated and control cats when the drug was at its expected tmax and PK steady state. Thus, to assess the effect of the 1-mg/kg dosage of prednisolone at its expected tmax, the percentage change from baseline data for group-A prednisolone-treated cats at T2 was combined with the same data for group-B prednisolone-treated cats at T4 and compared with the percentage change from baseline data at T2 and T4 for the control cats. Similarly, to assess the effect of the 2-mg/kg dosage of prednisolone at its expected tmax, the percentage change from baseline data for group-A prednisolone-treated cats at T4 was combined with the same data for group-B prednisolone-treated cats at T2 and compared with the percentage change from baseline data at T2 and T4 for the control cats. To assess the effect of the 1-mg/kg dosage of prednisolone at its PK steady state, the percentage change from baseline data for group-A prednisolone-treated cats at T3 was combined with the same data for group-B prednisolone-treated cats at T5 and compared with the percentage change from baseline data at T3 and T5 for the control cats. To assess the effect of the 2-mg/kg dosage of prednisolone at its PK steady state, the percentage change from baseline data for group-A prednisolone-treated cats at T5 was combined with the same data for group-B prednisolone-treated cats at T3 and compared with the percentage change from baseline data at T3 and T5 for the control cats. For all analyses, values of P < 0.05 were considered significant.
Results
Cats
Each treatment group included 5 neutered males and 5 spayed females. The mean ± SD age (5.6 ± 2.8 years) and body weight (5.25 ± 1.48 kg) for the prednisolone-treated cats did not differ significantly from the mean age (5.2 ± 2.8 years; P = 0.80) and body weight (5.24 ± 1.56 kg; P = 0.87) for the control cats. Those findings indicated that the matching protocol was successful. None of the study cats had clinically relevant structural heart disease identified during baseline echocardiographic examinations. The only echocardiographic abnormalities recorded were trace mitral valve regurgitation (n = 2 prednisolone-treated cats) and trace aortic valve regurgitation (1 prednisolone-treated cat).
Effect of prednisolone administration on outcome variables
For the prednisolone-treated cats, the order in which the 2 doses (1 and 2 mg/kg) of the drug were administered was not significantly associated with any outcome of interest; therefore, data for groups A and B were combined for all subsequent analyses involving sample acquisition time (time). Descriptive statistics for measures of glucose metabolism (Table 1); select cardiac biomarkers and echocardiographic variables (Table 2); select hematologic, biochemical, and urinalysis variables (Table 3); and plasma AngI, total and free cortisol, and prednisolone concentrations (Table 4) were summarized.
Mean ± SD values for measures of glucose metabolism in 10 cats with allergic dermatitis that were treated with prednisolone and 10 healthy control cats.
| Sample acquisition time | ||||||||
|---|---|---|---|---|---|---|---|---|
| Variable | Treatment group | Reference range | T1 | T2 | T3 | T4 | T5 | T6 |
| Blood glucose | Prednisolone | 70–120 | 111 ± 36 | 111 ± 16 | 127 ± 47 | 113 ± 18 | 109 ± 12 | 108 ± 24* |
| (mg/dL) | Control | 116 ± 28 | 126 ± 43 | 104 ± 21 | 107 ± 21 | 102 ± 19 | 104 ± 22* | |
| Serum fructosamine | Prednisolone | 191–349 | 228 ± 27 | — | 257 ± 32*† | — | 251 ± 36*† | 218 ± 25 |
| (μmol/L) | Control | 223 ± 28 | — | 213 ± 15 | — | 218 ± 24 | 221 ± 21 | |
| Serum insulin-to-glucose | Prednisolone | 0.07–0.27 | 0.10 ± 0.04 | — | 0.18 ± 0.10 | — | 0.15 ± 0.09 | 0.10 ± 0.04 |
| concentration ratio | Control | 0.10 ± 0.04 | — | 0.12 ± 0.07 | — | 0.12 ± 0.05 | 0.08 ± 0.03 | |
| %ΔPV | Prednisolone | Not established | — | 1.16 ± 2.3 | −0.19 ± 2.0 | 0.34 ± 1.8 | 1.25 ± 2.0 | −5.30 ± 10.8 |
| Control | — | −0.66 ± 3.0 | −1.42 ± 2.3 | 0.11 ± 1.4 | −0.22 ± 2.3 | 13.55 ± 13.3 | ||
Each prednisolone-treated cat was matched to a healthy control cat on the basis of sex, neuter status, age (± 1 year), and body weight (± 10%). Cats in the prednisolone-treated group were randomly allocated to 2 groups (A and B; 5 cats/group) and received prednisolone at 2 dosages (1 and 2 mg/kg, PO, once daily for 7 days) in a crossover study design. The order in which the 2 dosages were administered was not significantly associated with any outcome; therefore, the data for both groups were combined for outcome analyses. T1 (baseline) samples were obtained the morning of day 0 before administration of the first dose of prednisolone to the prednisolone-treated cats. T2 samples were obtained 1 hour after administration of the first dose of prednisolone to prednisolone-treated cats and 1 hour after collection of baseline data for control cats. T3 samples were collected prior to treatment on the morning of day 7, and T4 samples were collected 1 hour later. T5 samples were collected prior to treatment on the morning of day 14, and T6 samples were collected on the morning of day 35. The %ΔPV was calculated as follows: (HgbT1/HgbTX) × ([1 - HctTX]/[1 - HctT1]) - 1 × 100, where Hgb is the hemoglobin concentration at the given sample acquisition time and TX is the sample acquisition time in question (ie, T2, T3, T4, T5, or T6).
Within a treatment group, value differs significantly (P < 0.05) from the corresponding value at baseline (T1).
Within a variable, value differs significantly (P < 0.05) from the corresponding value for the control group.
— = Not evaluated.
Mean ± SD values for select cardiac biomarker concentrations and echocardiographic variables for the cats of Table 1.
| Sample acquisition time | ||||||||
|---|---|---|---|---|---|---|---|---|
| Variable | Treatment group | Reference range | T1 | T2 | T3 | T4 | T5 | T6 |
| cTnI (ng/mL) | Prednisolone | < 0.09 | 0.07 ± 0.07 | — | 0.02 ± 0.01 | — | 0.02 ± 0.04 | 0.03 ± 0.02 |
| Control | 0.30 ± 0.50 | — | 0.08 ± 0.14 | — | 0.08 ± 0.06 | 0.12 ± 0.22 | ||
| NTproBNP | Prednisolone | < 100 | 101 ± 184 | 122 ± 223 | 87.5 ± 90 | 85 ± 98 | 93 ± 107 | 145 ± 394 |
| (pmol/L) | Control | 39 ± 24 | 40 ± 26 | 46 ± 28 | 45 ± 29 | 38 ± 25 | 33 ± 13 | |
| LVPWd (cm) | Prednisolone | 0.43 ± 0.07 | 0.45 ± 0.03 | 0.46 ± 0.05 | 0.44 ± 0.03 | 0.45 ± 0.04 | 0.43 ± 0.05 | 0.45 ± 0.06 |
| Control | 0.45 ± 0.06 | 0.47 ± 0.06 | 0.44 ± 0.05 | 0.45 ± 0.07 | 0.45 ± 0.07 | 0.49 ± 0.05 | ||
| IVSd (cm) | Prednisolone | 0.46 ± 0.06 | 0.47 ± 0.06 | 0.45 ± 0.05 | 0.44 ± 0.04 | 0.45 ± 0.05 | 0.43 ± 0.06 | 0.46 ± 0.06 |
| Control | 0.46 ± 0.05 | 0.47 ± 0.07 | 0.46 ± 0.05 | 0.46 ± 0.05 | 0.45 ± 0.05 | 0.47 ± 0.05 | ||
| LVMI (g/m2) | Prednisolone | Not established | 30.7 ± 4.2 | 31.5 ± 7.0 | 30.5 ± 4.4 | 33.2 ± 5.9 | 32.8 ± 6.3 | 31.5 ± 5.9 |
| Control | 28.9 ± 4.4 | 29.6 ± 5.0 | 29.7 ± 5.2 | 29.0 ± 5.8 | 28.4 ± 4.0 | 30.5 ± 3.2 | ||
| LA:Ao | Prednisolone | 0.97–1.39 | 1.17 ± 0.10 | 1.14 ± 0.11 | 1.11 ± 0.05*† | 1.17 ± 0.07 | 1.17 ± 0.10 | 1.14 ± 0.15 |
| Control | 1.14 ± 0.10 | 1.19 ± 0.12 | 1.20 ± 0.13 | 1.21 ± 0.12 | 1.18 ± 0.08 | 1.19 ± 0.08 | ||
| E:A | Prednisolone | 1.12 ± 0.22 | 1.19 ± 0.30 (9) | 1.20 ± 0.30 (8) | 1.24 ± 0.27 (10) | 1.40 ± 0.61 (8) | 1.10 ± 0.20 (8) | 1.18 ± 0.31 (8) |
| Control | 1.32 ± 0.25 (4) | 1.44 ± 0.42 (7) | 1.24 ± 0.35 (5) | 1.35 ± 0.51 (6) | 1.16 ± 0.30 (8) | 1.13 ± 0.19 (4) | ||
| E:IVRT | Prednisolone | < 2.5 | 1.18 ± 0.14 (9) | 1.19 ± 0.39 (8) | 1.38 ± 0.33 (10) | 1.50 ± 0.56 (8) | 1.26 ± 0.19 (8) | 1.15 ± 0.52 (8) |
| Control | 1.16 ± 0.22 (4) | 1.25 ± 0.34 (7) | 1.11 ± 0.28 (5) | 1.28 ± 0.32 (6) | 1.13 ± 0.21 (8) | 1.11 ± 0.13 (4) | ||
When present, numbers in parentheses represent the number of cats in the given group for which measurements were possible on the basis of separation of diastolic early (E) and late (A) waves during transmitral inflow.
See Table 1 for key.
Mean ± SD values for select hematologic, serum biochemical, and urinalysis variables for the cats of Table 1.
| Sample acquisition time | ||||||||
|---|---|---|---|---|---|---|---|---|
| Variable | Treatment group | Reference range | T1 | T2 | T3 | T4 | T5 | T6 |
| Hct (%) | Prednisolone | 30.0–45.0 | 36.6 ± 3.7 | 35.9 ± 4.8 | 32.7 ± 3.1* | 33.0 ± 3.2* | 31.1 ± 3.0* | 34.9 ± 4.2 |
| Control | 39.6 ± 4.0 | 38.0 ± 3.6 | 34.9 ± 2.8* | 35.2 ± 3.4* | 34.5 ± 3.0* | 37.7 ± 3.8 | ||
| Neutrophil count (× 103 cells/μL) | Prednisolone | 2.5–12.5 | 5.43 ± 2.74 | 5.30 ± 1.87 | 5.88 ± 2.59 | 6.63 ± 2.93* | 6.64 ± 3.72 | 5.10 ± 2.71 |
| Control | 4.15 ± 1.49 | 5.54 ± 1.94 | 3.81 ± 1.51 | 4.67 ± 2.27* | 4.12 ± 2.10 | 4.52 ± 1.55 | ||
| Monocyte count (× 103 cells/μL) | Prednisolone | 0.0–0.85 | 0.21 ± 0.22 | 0.24 ± 0.15 | 0.42 ± 0.47*† | 0.53 ± 0.42 | 0.32 ± 0.18*† | 0.20 ± 0.14 |
| Control | 0.18 ± 0.17 | 0.22 ± 0.14 | 0.11 ± 0.11 | 0.20 ± 0.21 | 0.14 ± 0.10 | 0.19 ± 0.11 | ||
| Sodium (mEq/L) | Prednisolone | 152–159 | 156 ± 2 | 156 ± 2 | 155 ± 2 | 156 ± 2 | 158 ± 3*† | 156 ± 2 |
| Control | 155 ± 2 | 155 ± 2 | 156 ± 1 | 155 ± 1 | 155 ± 2 | 155 ± 1 | ||
| Potassium (mEq/L) | Prednisolone | 3.8–5.4 | 4.3 ± 0.4 | 4.3 ± 0.5 | 4.3 ± 0.4 | 4.4 ± 0.4 | 4.6 ± 0.6* | 4.3 ± 0.4 |
| Control | 4.5 ± 0.4 | 4.6 ± 0.4 | 4.5 ± 0.4 | 4.7 ± 0.4 | 4.8 ± 0.3* | 4.4 ± 0.6 | ||
| Chloride (mEq/L) | Prednisolone | 118–126 | 123 ± 3 | 123 ± 2 | 120 ± 2*† | 121 ± 2*† | 121 ± 1 | 122 ± 1 |
| Control | 123 ± 1 | 123 ± 2 | 123 ± 2 | 123 ± 2 | 123 ± 2 | 122 ± 2 | ||
| BUN (mg/dL) | Prednisolone | 15–29 | 21 ± 5 | 20 ± 5*† | 18 ± 3*† | 18 ± 4*† | 19 ± 5 | 20 ± 7 |
| Control | 21 ± 2 | 21 ± 3 | 21 ± 3 | 22 ± 4 | 20 ± 3 | 20 ± 3 | ||
| Creatinine (mg/dL) | Prednisolone | 0.8–2.1 | 1.3 ± 0.3 | 1.2 ± 0.3 | 1.2 ± 0.3 | 1.2 ± 0.3 | 1.2 ± 0.4 | 1.2 ± 0.3 |
| Control | 1.4 ± 0.4 | 1.4 ± 0.4 | 1.5 ± 0.3 | 1.4 ± 0.3 | 1.5 ± 0.3 | 1.3 ± 0.3 | ||
| Albumin (g/dL) | Prednisolone | 2.8–4.0 | 3.5 ± 0.3 | — | 3.7 ± 0.3*† | — | 3.7 ± 0.3*† | 3.5 ± 0.4 |
| Control | 3.5 ± 0.3 | — | 3.6 ± 0.2 | — | 3.4 ± 0.3 | 3.4 ± 0.3 | ||
| Alkaline phosphatase (U/L) | Prednisolone | 25–70 | 31 ± 5 | — | 35 ± 7 | — | 34 ± 8 | 34 ± 4 |
| Control | 39 ± 12 | — | 39 ± 9 | — | 39 ± 10 | 39 ± 10 | ||
| Alanine aminotransferase (U/L) | Prednisolone | 20–120 | 58 ± 18 | — | 224 ± 529 | — | 78 ± 81 | 52 ± 20 |
| Control | 68 ± 34 | — | 68 ± 30 | — | 63 ± 29 | 74 ± 47 | ||
| Cholesterol (mg/dL) | Prednisolone | 75–260 | 159 ± 30 | — | 188 ± 29*† | — | 178 ± 37 | 138 ± 34*† |
| Control | 198 ± 51 | — | 194 ± 43 | — | 191 ± 49 | 200 ± 52 | ||
| Triglycerides | Prednisolone | 45 ± 12 | — | 396 ±331*† | — | 282 ± 224*† | 46 ± 20 | |
| (mg/dL) | Control | 74 ± 23 | — | 102 ± 122 | — | 74 ± 28 | 69 ± 64 | |
| Urine specific gravity | Prednisolone | 1.050 ± 0 | — | 1.050 ± 0 | — | 1.050 ± 0.01 | 1.050 ± 0 | |
| Control | 1.050 ± 0 | — | 1.050 ± 0 | — | 1.040 ± 0.01 | 1.040 ± 0.01 | ||
| FENa (%) | Prednisolone | 0.37 ± 0.2 | — | 0.45 ± 0.6 | — | 0.48 ± 0.3 | 0.34 ± 0.2 | |
| Control | 0.72 ± 0.7 | — | 0.74 ± 0.6 | — | 0.80 ± 0.7 | 0.70 ± 0.5 | ||
See Table 1 for key.
Mean ± SD values for plasma AngI, total and free cortisol, and prednisolone concentrations for the cats of Table 1.
| Sample acquisition time | |||||||
|---|---|---|---|---|---|---|---|
| Variable | Treatment group | T1 | T2 | T3 | T4 | T5 | T6 |
| AngI (ng/mL) | Prednisolone | 0.9 ± 0.5 | 2.01 ± 2.1 | 0.61 ± 0.5 | 1.33 ± 1.1 | 0.51 ± 0.3 | 1.22 ± 1.4 |
| Control | 2.44 ± 2.1 | 0.57 ± 0.5 | 0.41 ± 0.6 | 0.96 ± 1.2 | 0.44 ± 0.7 | 0.51 ± 0.6 | |
| Total cortisol (ng/mL) | Prednisolone | 65.1 ± 33.9 | 13.99 ± 20.74*† | 4.77 ± 6.12*† | 0.96 ± 1.29*† | 1.27 ± 1.67*† | 44.93 ± 22.97 |
| Control | 87.42 ± 18.34 | 62.93 ± 16.27 | 62.78 ± 25.91 | 43.32 ± 36.78 | 47.31 ± 25.02 | 67.09 ± 22.05 | |
| Free cortisol (ng/mL) | Prednisolone | 1.81 ± 1.67 | 0.89 ± 1.22 | 0.72 ± 2.28 | 0 ± 0 | 0 ± 0 | 0.78 ± 0.77 |
| Control | 2.60 ± 0.95 | 1.80 ± 0.87 | 1.73 ± 1.21 | 1.48 ± 1.84 | 1.17 ± 1.93 | 2.27 ± 1.78 | |
| Prednisolone (ng/mL) | Prednisolone | 0 ± 0 | 442.5 ± 218.8* | 2.81 ± 4.16 | 350.1 ± 261.9* | 0.5 ± 1.58 | 0 ± 0 |
| Control | — | — | — | — | — | — | |
See Table 1 for key.
For both the blood glucose concentration and serum insulin-to-glucose ratio, the percentage change from baseline did not differ significantly between the prednisolone-treated and control groups at any time (Figure 1). The mean blood glucose concentration at T6 was significantly (P = 0.041) lower than the baseline (T1) blood glucose concentration for both treatment groups (Table 1). The %ΔPV did not differ significantly between the 2 treatment groups at any time. For serum fructosamine concentration, the mean percentage change from baseline for the prednisolone-treated group was significantly greater than that for the control group at T3 (P = 0.001) and T5 (P = 0.030); however, the serum fructosamine concentration remained within the reference range for all study cats at all sample acquisition times. For the subset of cats that had blood glucose concentration measured at home, the baseline blood glucose concentration as determined by an automated biochemical analyzer did not differ significantly from the blood glucose concentration as determined by a point-of-care glucometer on study day 1 (P = 0.33), 2 (P = 0.76), 3 (P = 0.69), 8 (P = 0.53), 9 (P = 0.44), or 10 (P = 0.069).
Mean ± SD percentage change from baseline at each of 6 sample acquisition times (T1 through T6) for blood glucose concentration (A), serum fructosamine concentration (B), LVPWd (C), IVSd (D), LA:Ao (E), sodium concentration (F), potassium concentration (G), and FENa (H) for 10 cats with allergic dermatitis that were treated with prednisolone (dashed line) and 10 healthy control cats (solid line). Each prednisolone-treated cat was matched to a healthy control cat on the basis of sex, neuter status, age (± 1 year), and body weight (± 10%). Cats in the prednisolone-treated group were randomly allocated to 2 groups (A and B) and received prednisolone at 2 dosages (1 and 2 mg/kg, PO, once daily for 7 days) in a crossover study design. The order in which the 2 dosages were administered was not significantly associated with any outcome; therefore, the data for both groups were combined for all subsequent analyses. T1 (baseline) samples and data were obtained the morning of day 0 before administration of the first dose of prednisolone to the prednisolone-treated cats, and T2 samples and data were obtained 1 hour later. T3 samples were collected prior to treatment on the morning of day 7, and T4 samples and data were collected 1 hour later. T5 samples and data were collected prior to treatment on the morning of day 14, and T6 samples and data were collected on the morning of day 35. *For a given time, the mean change from baseline differs significantly (P < 0.05) between the 2 treatment groups.
Citation: American Journal of Veterinary Research 80, 8; 10.2460/ajvr.80.8.743
The mean body weight, heart rate, SAP, cardiac biomarker concentrations (cTnI and NTproBNP), and measures of left ventricular wall thickness (IVSd, LVPWd, LVMI) and diastolic function (E:A, IVRT, E:IVRT, and ratio of early diastolic mitral inflow velocity to early diastolic mitral annular motion) did not differ significantly between the prednisolone-treated and control groups at any time (Table 2). However, the mean percentage change from baseline for the LA:Ao for the prednisolone-treated group was significantly (P = 0.024) lower than that for the control group at T3 (Figure 1), whereas the mean percentage change from baseline for the LVEF for the prednisolone-treated group was significantly (P = 0.013) greater than that for the control group at T6. For the prednisolone-treated group, the mean LVIDd was significantly (P = 0.019) increased from baseline at T5, the fractional shortening was significantly (P = 0.044) decreased from baseline at T4, and the global longitudinal strain was significantly decreased (ie, became more negative) at T3 (P = 0.021) and T5 (P = 0.013). Despite the significant differences noted, all echocardiographic measurements remained within the respective reference ranges for all study cats at all data acquisition times.
The mean serum potassium concentration, FENa, and urine specific gravity did not differ significantly between prednisolone-treated and control cats at any time (Table 3). For the prednisolone-treated group, the mean serum sodium concentration was significantly (P = 0.018) greater than that for the control group at T5; the mean monocyte count was significantly increased from the mean baseline monocyte count at T3 (P = 0.039) and T5 (P = 0.014); the mean serum chloride concentration was significantly decreased from baseline at T3 (P = 0.007) and T4 (P = 0.026); the mean serum albumin concentration was significantly increased from baseline at T3 (P = 0.016) and T5 (P < 0.001); and the mean BUN concentration was significantly decreased from baseline at T2 (P = 0.047), T3 (P = 0.037), and T4 (P = 0.015). The mean total protein concentration for the prednisolone-treated group was significantly (P = 0.027) increased from baseline at T5 but significantly (P = 0.010) decreased from baseline at T6. Similarly, the mean serum cholesterol concentration for the prednisolone-treated group was significantly (P = 0.005) increased from baseline at T3 but significantly (P = 0.024) decreased from baseline at T6. The mean serum triglyceride concentration for the prednisolone-treated group was significantly increased from baseline at T3 (P = 0.021) and T5 (P = 0.036) and in fact exceeded the upper limit of the reference range (120 mg/dL) at those 2 times. For all other clinicopathologic variables, the absolute changes from baseline were minimal, and the mean values for both treatment groups remained within the respective reference ranges at all times.
For both the prednisolone-treated and control groups, the mean RBC count and Hct were significantly (P < 0.001) decreased from baseline at T3, T4, and T5. The mean hemoglobin concentration was significantly decreased from baseline at all 5 subsequent times (T2 through T6). The mean platelet (P = 0.029) and neutrophil (P = 0.008) counts were significantly increased from baseline at T4. The mean serum bicarbonate concentration was significantly increased from baseline at T3 (P = 0.043) and T5 (P = 0.047). For all those variables, all of the deviations from baseline values were minor, and all mean values remained within the respective reference ranges.
The mean plasma prednisolone concentration for the prednisolone-treated group was significantly increased from baseline at T2 (P < 0.001) and T4 (P = 0.002; Table 4). The mean plasma AngI concentration did not differ between the prednisolone-treated and control groups at any time. For the prednisolone-treated group, the mean plasma total cortisol concentration was significantly decreased from baseline and from that of the control group at T2, T3, T4, and T5; however, the mean plasma free cortisol concentration did not differ significantly from baseline or between the 2 treatment groups at any time.
Effects of prednisolone tmax and PK steady state on outcomes of interest
For the prednisolone-treated group, the mean neutrophil count and plasma AngI concentration increased and the mean body weight and global longitudinal strain decreased significantly from baseline to the PK steady state for both the 1- and 2-mg/kg dosage regimens. The mean blood glucose (P = 0.002) and NTproBNP (P = 0.023) concentrations increased and the mean serum creatinine concentration (P = 0.002) decreased significantly from baseline to the PK steady state when the 2-mg/kg dosage regimen, but not the 1-mg/kg dosage regimen, was administered. The mean NTproBNP concentration increased significantly (P = 0.010) between baseline and the prednisolone tmax for only the 2-mg/kg dosage regimen. The magnitude of all significant alterations was mild, and the mean values remained well within the respective reference ranges for both groups.
Discussion
Results of the present study indicated that short-term oral administration of anti-inflammatory dosage regimens of prednisolone (1 and 2 mg/kg/d, PO, for 7 days) to systemically normal cats caused no clinically relevant alterations in hemodynamic, clinicopathologic, or echocardiographic variables. Although statistically significant differences between prednisolone-treated and control cats were detected for some hematologic and biochemical variables, the magnitudes of those differences were small, and the mean values for those variables generally remained within the respective reference ranges for both treatment groups.
A primary objective of the present study was to assess the potential diabetogenic effects of oral administration of anti-inflammatory dosages of prednisolone to cats. For the prednisolone-treated cats of the present study, the blood glucose concentration, serum insulin-to-glucose concentration ratio, and plasma volume did not change significantly from baseline (before administration of the first dose of the drug) at any of the subsequent 5 sample acquisition times. The mean serum fructosamine concentration for the prednisolone-treated group was significantly increased from baseline at T3 (before treatment on day 7; ie, the day that the alternate prednisolone dosage regimen was initiated) and T5 (before administration of the last dose of prednisolone on day 14), but the clinical relevance of that finding is questionable because the serum fructosamine concentration remained within the reference range for all cats at all times. The mean blood glucose concentration for the prednisolone-treated group increased significantly from baseline to the PK steady state only when the highest dosage regimen was administered, but the magnitude of that increase was small, and the highest mean blood glucose concentration was 127 mg/dL (just slightly above the upper limit of the reference range [70 to 120 mg/dL]) at T3. Some cats had blood glucose concentrations that far exceeded the reference range at various times throughout the study. The 3 highest blood glucose concentrations were 239 (prednisolone-treated cat at T3), 232 (control cat at T3), and 199 (prednisolone-treated cat at baseline [T1]) mg/dL.
Those findings were generally consistent with the results of other studies21–23 that assessed the diabetogenic effects associated with oral administration of intermediate-acting glucocorticoids to cats. In cats, oral administration of methylprednisolone (1 mg/kg/d) for 8 days did not cause any significant changes in blood glucose or serum fructosamine concentration.21 However, oral administration of prednisolone (2 mg/kg/d) for 8 days caused a mild increase in blood glucose concentration (mean blood glucose concentration increased from 80 to 120 mg/dL),22 and oral administration of a higher dose of the drug (4.4 mg/kg/d) for 8 weeks caused a moderate increase in blood glucose concentration (mean blood glucose concentration increased from 78 to 137 mg/dL) in addition to an increase in serum fructosamine concentration and the development of glucosuria.23 Collectively the results of the present study and those other studies21–23 suggested that, in cats, oral administration of low doses of prednisolone (1 mg/kg/d) does not significantly affect the blood glucose concentration, but oral administration of higher anti-inflammatory and immunosuppressive doses (≥ 2 mg/kg/d) of glucocorticoids can have modest effects on glucose metabolism. Conversely, IM administration of methylprednisolone acetate (5 mg/kg), a long-acting glucocorticoid, to cats results in a profound and significant increase in mean blood glucose concentration (> 180 mg/dL) and plasma volume.4 Unfortunately, the plasma prednisolone concentrations were not reported for the cats of that study,4 so we could not compare the magnitude of prednisolone exposure between the cats of that study and the present study. Nevertheless, it appears that parenteral administration of long-acting glucocorticoids is more likely to cause clinically relevant hyperglycemia and hemodynamic alterations in cats than is oral administration of intermediate-acting glucocorticoids. Results of the present study suggested that the metabolic effects associated with oral administration of intermediate-acting glucocorticoids to cats are dosage dependent, and when those drugs are administered within the recommended anti-inflammatory dosage range, alterations in blood glucose metabolism are mild and unlikely to have any clinically relevant cardiovascular effects.
Results of the present study failed to provide any evidence of other potential mechanisms by which oral administration of anti-inflammatory dosages of prednisolone might lead to the development of heart disease or precipitation of CHF in cats. Similar to the cats treated with methylprednisolone acetate in the Ployngam et al4 study, the SAP was not increased from baseline at any time in the prednisolone-treated cats of the present study. Administration of prednisone (1.0 mg/kg/d, PO, for 14 days) to dogs results in a statistically and clinically significant increase in SAP within 7 days after initiation of treatment.5 These findings suggest that the vascular effects of glucocorticoids may be species specific. In the present study, although a brief acclimation period to the hospital environment was provided for all cats prior to SAP measurement, the duration of that period varied as did the temperament of individual cats, which might have affected the SAP measurements.
One potential mechanism by which glucocorticoids might increase SAP is activation of the RAAS, the end products of which (angiotensin II and aldosterone) are potent vasoconstrictors.24,25 Plasma AngI is a surrogate biomarker for RAAS activation, and mean plasma AngI concentration for the prednisolonetreated group of the present study did not increase significantly from baseline or differ significantly from that for the control group at any sample acquisition time. However, the mean plasma AngI concentration did increase significantly from baseline to the PK steady state for both prednisolone dosage regimens. That finding suggested that oral administration of prednisolone to cats may activate the RAAS in a manner similar to that reported in glucocorticoid-treated rats26 and dogs.27 Further research is necessary to assess whether the extent of RAAS activation induced by glucocorticoids in cats is clinically relevant because none of the prednisolone-treated cats of the present study developed evidence of sodium retention, plasma volume expansion, or systemic hypertension, all of which are expected consequences of RAAS activation.
In the present study, the mean serum potassium concentration and FENa for the prednisolone-treated group did not differ significantly from baseline or from those of the control group at any sample acquisition time, which suggested that the prednisolone dosage regimens administered had no mineralocorticoid effects in cats, a finding that was similar to cats that received methylprednisolone acetate4 and dogs that received prednisone5 of other studies. The mean serum sodium concentration for the prednisolonetreated group was significantly increased from baseline and significantly greater than that for the control group at T5, but the magnitude of that increase was small and was not accompanied by a concomitant decrease in the mean FENa. Thus, we believe that was an incidental finding. The lack of an obvious mineralocorticoid effect in the prednisolone-treated cats of the present study was somewhat surprising because prednisolone, like cortisol, has affinity for mineralocorticoid receptors.1 However, in healthy individuals, glucocorticoids typically bind to but do not activate mineralocorticoid receptors, which is the consequence of a tonic inhibitor capability conferred by the enzyme 11β-hydroxysteroid dehydrogenase.28 When the 11β-hydroxysteroid dehydrogenase enzyme becomes saturated during excessive glucocorticoid exposure or its function becomes impaired as a result of tissue hypoxia or inflammation, glucocorticoid binding of mineralocorticoid receptors activates those receptors, which results in systemic mineralocorticoid effects.29,30 Regardless, results of the present study and other studies4,5 suggested that administration of anti-inflammatory dosages of glucocorticoids does not confer clinically relevant mineralocorticoid effects in systemically normal cats and dogs.
Similar to dogs that received anti-inflammatory dosages of prednisone,5 the prednisolone-treated cats of the present study did not develop any evidence of glucocorticoid-induced cardiac remodeling. Measures of left ventricular thickness and systolic and diastolic function remained within the respective reference ranges at all evaluation times. The significant alterations in the mean LA:Ao, LVEF, and global longitudinal strain for the prednisolone-treated cats were likely incidental findings because they were observed at various times and were not consistent with an overall pattern of increasing or decreasing cardiac size or function. Moreover, concentrations of cardiac biomarkers (cardiac troponin and NTproBNP) did not differ significantly from baseline at any sample acquisition time. The mean NTproBNP concentration for the prednisolone-treated cats did increase significantly from baseline to the PK steady state when the 2-mg/kg dosage regimen was administered, which might appear to suggest that higher dosages of prednisolone could cause myocardial stretch. However, the magnitude of the NTproBNP increase was small and was not accompanied by any other echocardiographic or hemodynamic alterations, such as changes in SAP or plasma volume. Interestingly, the NTproBNP concentration was quite variable for both the prednisolone-treated and control cats despite the absence of concomitant echocardiographic abnormalities. For example, 4 prednisolone-treated cats and 1 control cat had NTproBNP concentrations that exceeded the laboratory cutoff for suspected heart disease (> 100 pmol/L) at various times, but none of those cats had echocardiographic abnormalities. Those results may simply reflect the high biological variability of NTproBNP concentration in systemically normal cats31 or the fact that approximately 8% of clinically normal cats have a false-positive test result (NTproBNP concentration > 100 pmol/L) during routine screening.32,33 Hence, NTproBNP concentration may have limited diagnostic value for evaluation of glucocorticoid-induced hemodynamic changes in cats.
In the present study, the effects of prednisolone were evaluated within 2 PK time frames (between baseline and tmax [1 hour after oral administration of prednisolone1,2] and between baseline and the PK steady state [1 week after initiation of treatment; ie, T3 and T5]). Most of the significant changes were observed between baseline and the PK steady state, which supported the notion that the biological effects of prednisolone are primarily genomic in nature and become apparent only after 3 to 4 days34 rather than acute and dependent on the peak plasma concentration of the drug.
Two prednisolone dosage regimens (1 and 2 mg/kg/d, PO, for 7 days) were evaluated in the present study. For cats, the recommended anti-inflammatory dosage range for prednisolone is 1 to 2 mg/kg/d,2 and oral administration of prednisolone at dosages of 1 and 2 mg/kg/d is reportedly effective for treatment of allergic dermatitis.1,2 Dosage regimen was not significantly associated with any outcome at any sample acquisition time but was significantly associated with some outcomes when the data were analyzed on the basis of PK time frames. Specifically, there were statistically significant (albeit not necessarily clinically relevant) increases in the blood glucose and NTproBNP concentrations between baseline and the PK steady state only when the 2-mg/kg dosage regimen was administered. Those findings suggested that some hemodynamic and diabetogenic changes consistently observed following administration of immunosuppressive doses of glucocorticoids (4 mg/kg/d)4,23 might become detectable when prednisolone is administered to cats at the high end of its recommended anti-inflammatory dosage range.
Several hematologic and biochemical variables varied significantly from baseline and between the prednisolone-treated and control cats after initiation of treatment. Those differences were expected and consistent with glucocorticoid administration. For the prednisolone-treated cats, the monocyte count and serum albumin, cholesterol, and triglyceride concentrations increased from baseline after initiation of treatment and returned to normal after the washout period (ie, by T6). Conversely, the total cortisol concentration of prednisolone-treated cats decreased from baseline at T2 through T5 and returned to the baseline concentration after the washout period. That was expected because prednisolone displaces free cortisol from glucocorticoid receptors, which leads to increased excretion of cortisol. All hematologic and biochemical changes observed in the present study were consistent with steroid administration1,35,36 and were not considered relevant factors in the development or progression of heart disease in cats. Furthermore, with the exception of the triglyceride concentration, all hematologic and biochemical values remained within the respective reference ranges for all cats at all sample acquisition times. Similar clinicopathologic trends were observed in dogs that received a short anti-inflammatory dosage regimen of prednisone (1 mg/kg/d, PO, for 14 days).5 However, the prednisone-induced changes in the dogs of that study5 routinely exceeded reference ranges, and those dogs also had increased alkaline phosphatase and alanine transferase activities and decreased chloride concentration and urine specific gravity following initiation of prednisone administration. Collectively, those findings are consistent with the supposition that cats are more resistant than dogs to the metabolic effects of glucocorticoids.1,2,5,35
Glucocorticoid administration is occasionally associated with an increase in the RBC count,1,2,35 but that was not observed in the cats of the present study. On the contrary, the RBC count, hemoglobin concentration, and Hct all decreased from baseline in both the prednisolone-treated and control cats. Those changes were most likely associated with fairly frequent venipuncture and the removal of 6 to 8 mL of blood from each cat at each sample acquisition time. Nevertheless, all RBC indices remained within the respective reference ranges at all times and none of the cats developed clinical signs of anemia.
The present study had several limitations. The calculation used to determine the number of cats required for the study was based on the ability to detect a significant and clinically relevant (≥ 20 mg/dL) change in the blood glucose concentration following administration of a long-acting prednisolone formulation; therefore, the calculation may have underestimated the number of cats necessary to detect significant changes in the other clinicopathologic and echocardiographic outcomes of interest. The prednisolone dosages used in the study (1 and 2 mg/kg, PO, q 24 h for 7 days) were chosen because they were believed to represent the most commonly used dosages for anti-inflammatory purposes in small animal medicine. Administration of higher dosages of prednisolone might have resulted in the detection of more statistically and clinically significant differences for the outcomes of interest. For example, clinically relevant diabetogenic effects were observed in cats administered immunosuppressive dosages of prednisolone (4.4 mg/kg, PO) or dexamethasone (0.55 mg/kg, PO) for 56 days.23 It is also possible that administration of anti-inflammatory doses of glucocorticoids for a long duration (> 90 days) might be necessary for the development of clinically relevant cardiovascular changes. Long-term administration of glucocorticoids can cause afferent renal arteriole sclerosis, glomerular ischemia, and glomerulosclerosis, which may result in long-term vascular changes, systemic hypertension, and secondary cardiac remodeling.37–39 Results of the present study should not be extrapolated to cats that undergo long-term corticosteroid administration, such as those with chronic inflammatory or immune-mediated diseases. Another limitation of the present study was the use of client-owned cats, which prevented standardization of subject diets, environment, and acclimation to the veterinary clinic and precluded the use of more invasive sampling methods for more intensive PK analysis. Additionally, all study cats were systemically normal and did not have any evidence of cardiac disease. Further research is necessary to determine whether cats with underlying heart disease respond differently than clinically normal cats to anti-inflammatory dosages of prednisolone (ie, have disease progression or develop CHF).
In the present study, clinically relevant hemodynamic, echocardiographic, or diabetogenic effects were not observed in systemically normal cats with allergic dermatitis that received anti-inflammatory dosages of prednisolone (1 and 2 mg/kg/d, PO, for 7 days). Thus, results suggested that short-term administration of prednisolone at anti-inflammatory dosages should be well tolerated in systemically normal cats.
Acknowledgments
Work was performed at the ISU Lloyd Veterinary Medical Center.
Supported by a Winn Feline Foundation Miller Trust Award. Financial supporters had no involvement in study design, data analysis and interpretation, or writing and publication of the manuscript.
The authors declare that there were no conflicts of interest.
The authors thank Lori Moran for technical assistance.
ABBREVIATIONS
| %ΔPV | Percentage change in plasma volume from baseline |
| Angl | Angiotensin l |
| CHF | Congestive heart failure |
| cTnl | Cardiac troponin l |
| E:A | Ratio of peak velocity of the E wave to peak velocity of the A wave |
| E:IVRT | Ratio of early diastolic transmitral flow velocity to isovolumic relaxation time |
| FENa | Urinary fractional excretion of sodium |
| ISU | lowa State University |
| lVRT | lsovolumic relaxation time |
| lVSd | lnterventricular septal thickness in diastole |
| LA:Ao | Ratio of left atrial diameter to aortic root diameter |
| LVEF | Left ventricular ejection fraction |
| LVIDd | Left ventricular internal dimension in diastole |
| LVMI | Left ventricular mass index |
| LVPWd | Left ventricular posterior wall thickness in diastole |
| NTproBNP | N-terminal pro-B-type natriuretic peptide |
| PK | Pharmacokinetic |
| RAAS | Renin-angiotensin-aldosterone system |
| SAP | Systolic arterial blood pressure |
| tmax | Time to maximum concentration |
Footnotes
AlphaTRAK blood glucose monitoring system, Zoetis Inc, Kalamazoo, Mich.
Aprotinin from bovine lung (lyophilized powder, 3–8 TIU/mg), Sigma-Aldrich Corp, St Louis, Mo.
Peninsula Laboratories International, San Carlos, Calif.
Epiq 7C Ultrasound system, Philips Healthcare, Andover, Mass.
FUS8350 X5-1, FUS8392 S8-3, and FUS8393 S12-4 transducers, Philips Healthcare, Andover, Mass.
Syngo Dynamics, Siemens Medical Solutions, Malvern, Pa.
QLAB 10, Philips Healthcare, Andover, Mass.
R software, version 3.5.1, R Foundation for Statistical Computing, Vienna, Austria.
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