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Keywords:

  • Canine;
  • Glucose metabolism;
  • Glycolysis;
  • Lactate metabolism

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgments
  8. References

Background: Glucocorticoids affect carbohydrate and lactate metabolism.

Hypothesis: Administration of prednisone to healthy dogs will result in clinically relevant hyperlactatemia.

Animals: Twelve healthy adult Beagle dogs.

Methods: Prospective, controlled experimental study. Twelve healthy adult Beagles were divided into 2 groups (3 of each sex per group). One group served as control. The other group received 2 treatments: low, 1 mg/kg prednisone PO q24h for 2 weeks; high, 4 mg/kg prednisone PO q24h for 2 weeks. A washout period of 6 weeks separated the treatments. Blood samples were drawn for whole blood lactate measurement on day (D) 0, D4, and D14 and measured in duplicate.

Results: Compared with the control group, low and high groups had significantly higher blood lactate concentrations at D4 and D14. There was no difference at D0. There was no effect of time within the control group. In the low and high groups, blood lactate concentration was increased at D4 and D14 versus D0. Blood lactate concentration was greater in the high group than the low group at D14 only.

Conclusions and Clinical Importance: Dogs treated with prednisone experience statistically significant increases in blood lactate concentrations, which can result in type B hyperlactatemia. In such cases, improving tissue perfusion, treatment for the commonest form of hyperlactatemia (type A) would be unnecessary.

Abbreviations:
D0

day 0

D4

day 4

D14

day 14

With the advent of handheld lactate meters, measurement of blood lactate concentration is becoming common in the veterinary practice. There are 2 stereoisomers of lactate, an l form and a d form. The l form is the predominant form produced by mammalian cells and the stereoisomer that most laboratory and handheld lactate meters measure.1–3 As such, it is the more clinically relevant form of lactate measured in veterinary medicine and the form referred to throughout this paper. Extensive reviews on both the l and d stereoisomers are available in the veterinary and human literature.1–4

In the majority of cases, blood lactate concentration is measured to help identify and treat type A hyperlactatemia because of states of decreased oxygen delivery, in particular hypoperfusion. However, other causes of hyperlactatemia exist, including type B hyperlactatemia, which is not associated with states of hypoperfusion. To the authors' knowledge, type B hyperlactatemia has not been extensively studied in veterinary medicine.1 Although the lactate molecules derived from type A and type B lactic acidosis are identical and cannot be differentiated based on biochemical analysis, it is important to identify the origin of hyperlactatemia because clinical management of the 2 conditions differs. Whereas all causes of hyperlactatemia require identification and correction of the underlying cause, treatment of type A hyperlactatemia usually requires aggressive fluid therapy and the administration of hemoglobin carrying or transport solutions whereas treatment of type B hyperlactatemia often does not.

Because glucocorticoids have known effects on carbohydrate and lactate metabolism, therapeutically appropriate doses of glucocorticoids could result in clinically relevant type B hyperlactatemia.5,6 In some instances, patients receiving glucocorticoids also may have an underlying disease state associated with hypoperfusion and type A hyperlactatemia. Immune-mediated hemolytic anemia is a common disease of dogs requiring high-dose glucocorticoid therapy that also may be associated with hypoperfusion as a result of red blood cell destruction, vomiting, decreased fluid intake, as well as decreased oxygen delivery because of anemia. In cases of hemolytic crisis, blood lactate measurement may be useful to help guide decisions regarding the need for blood products and aggressive fluid therapy because severe hemolysis has been associated with anemic hypoxia, anaerobic metabolism, and metabolic acidosis.3,7 Determining if glucocorticoids could result in hyperlactatemia, regardless of red blood cell counts and hypoperfusion, is important to guide appropriate decisions regarding blood transfusion and fluid therapy. The aim of this study was to determine if PO administered prednisone could result in an increase in blood lactate concentration (type B hyperlactatemia) in healthy dogs.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgments
  8. References

Twelve neutered, healthy adult Beagles (median weight 11.7 kg; range, 9.3–15 kg) were divided into 2 groups of 6 dogs (3 of each sex per group). All dogs had physical examinations, biochemistry profilesa and CBCsb performed before starting the study. One group of dogs served as a control group and received placebo pill pocketsc once daily for 2 weeks. The other group received 2 treatments: low, 1 mg/kg prednisone PO q24h for 2 weeks; high, 4 mg/kg prednisone PO q24h for 2 weeks. These doses were chosen to reflect a high anti-inflammatory dosage of prednisone and a high immunosuppressive dosage of prednisone, respectively. All prednisone treatments were administered within pill pockets. A washout period of 6 weeks separated the treatments. All dogs had physical examinations performed at the start of each treatment period, once daily during the 2 weeks of placebo or prednisone administration, and once weekly during the washout period. All physical examinations were performed by an experienced veterinarian (LR). Animals were cared for according to the principles outlined by the Canadian Council on Animal Care Guide to the Care and Use of Experimental Animals. All procedures were approved by the Ethics Committee for the Utilization of Animals for the University of Montreal. The dogs were housed under identical conditions in an environmentally controlled room. They were fed a commercial dry diet and had free access to water. Blood was collected directly into 3 mL lithium-heparinized tubesd by jugular venipuncture and a 21-g butterfly needle attached to a vacutainer system.e In cases of technical delay in collecting blood or slow (>15 seconds) filling of the collection tube, the sample was discarded and the contralateral jugular vein used. Lactate then was measured in duplicatef within 5 minutes of blood collection on Day (D) 0, D4, and D14 for all study groups. Blood lactate concentrations were considered increased if they were ≥ the established reference value of 2.5 mmol/L in dogs.1 Data were analyzed with a general linear model for repeated measures and post hoc t-tests with Bonferroni's correction. P values < .05 were considered significant. Results are reported as mean ± SD.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgments
  8. References

Physical examinations, biochemistry profiles, and CBCs were within reference limits for all dogs. All dogs drank and ate well throughout the entire study. One dog on D0 in each of the low and high groups, and 1 dog on D4 in the control group required a second attempt to draw blood from the opposing jugular vein. The corresponding lactate concentrations in these dogs were 0.5, 1.2, and 0.3 mmol/L, respectively. In all 3 of these dogs, the 2nd attempt was successful. All of the dogs in the control group had blood lactate concentrations <2.0 mmol/L throughout the study. On D0, all dogs in the low and the high groups had blood lactate concentrations <2.0 mmol/L. On D4, 5 dogs in the low group and 5 dogs in the high group had blood lactate concentrations ≥2.5 mmol/L. On D14, 3 dogs in the low group and all 6 dogs in the high group had blood lactate concentrations ≥2.5 mmol/L. Compared with the control group, low and high groups had significantly higher blood lactate concentrations at D4 (P < .0001 and P < .0001, respectively) and D14 (P= .007 and .0001, respectively). There was no difference between treatment groups at D0 (low, P= .65; high, P= .14; see Table 1). There was no effect of time within the control group (P > .29). Within the low and high groups, blood lactate concentration was increased at D4 (P < .0001) and D14 (P= .003 and .0001, respectively) as compared with D0 (see Table 1). In the low group, blood lactate concentration was greater at D4 than D14 (P= .02). Blood lactate concentrations was greater in the high group than the low group at D14 only (P= .001). Mean heart rates (± SD) in the control group were 99.3 (± 12.8), 109.3 (± 28.9), and 110.7 (± 13.5) for D0, D4, and D14, respectively. Heart rates for the low group were 89.2 (± 14.9), 89.7 (± 12.9), and 84.7 (± 5.0), and in the high group were 111.3 (± 7.8), 108.0 (± 8.0), and 100 (± 4.1) for D0, D4, and D14, respectively. Mean heart rates were significantly lower at D0 in the low group compared with the high group (P < .05). At D14, mean heart rates were significantly lower in the low group compared with the control group (P < .01). There was no statistical difference in mean heart rates within any of the groups for D0, D4, and D14.

Table 1.   Mean ± SD for blood lactate (mmol/L) in healthy dogs receiving placebo (control), low (1 mg/kg) or high (4 mg/kg) doses of prednisone PO q24h for 14 days.
TreatmentDay 0Day 4Day 14
  1. Identical letters within columns denote significant differences. Identical numbers within rows denote significant differences. A P value < .05 was considered significant.

Control0.5 ± 0.30.4 ± 0.4a,b0.9 ± 0.5c,d
Low0.7 ± 0.213.4 ± 0.9a,12.3 ± 1.5c,e,1
High1.0 ± 0.62,33.1 ± 0.7b,24.3 ± 0.7d,e,3

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgments
  8. References

Healthy dogs treated with anti-inflammatory and immunosuppressive doses of prednisone (1.0–4.0 mg/kg PO q24h) had statistically significant increases in blood lactate concentrations within 4 days of starting therapy. These changes exceed the normal reference ranges of blood lactate reported in healthy dogs (< 2.5 mmolL1) and may be misinterpreted by the attending clinician. Because none of the dogs in this study showed signs of hypoperfusion based on daily physical examinations, glucocorticoid-treated dogs likely developed type B hyperlactatemia (not associated with hypoperfusion or other causes of decreased oxygen delivery). The effects of lower dosages of glucocorticoids, the time to onset of hyperlactatemia and the long-term effects of glucocorticoids on blood lactate concentrations in dogs requires further study.

Steroids have known effects on carbohydrate metabolism5,6 and people with Cushing's syndrome or those receiving 17-hydroxycorticosteroids have significantly increased blood concentrations of lactate and pyruvate.5 In addition, those patients found to have increased lactate concentrations in association with Cushing's syndrome had concentrations return to normal after subtotal adrenalectomy.5

Increased lactate concentrations after glucocorticoid administration are because of a marked increase in gluconeogenesis from protein.8 This increased gluconeogenesis subsequently is associated with an increased rate of glucose production and utilization. Enhanced utilization of glucose in turn is believed to account for increased formation of lactate and an increased concentration of lactate in the blood.8 The specific site of action of glucocorticoids may involve hormonal inhibition of the conversion of pyruvic acid to acetyl CoA, which results in decreased pyruvic acid oxidation and subsequent accumulation of lactic and pyruvic acids (because lactic acid appears to be largely oxidized rather than repolymerized to glycogen). Additionally, glucoroticoids may enhance amino acid utilization and conversion to pyruvate. Lactate concentrations would be expected to increase as pyruvate concentration increases.5

In conclusion, administration of prednisone to dogs at anti-inflammatory and immunosuppressive dosages (1–4 mg/kg PO q24h) results in clinically relevant hyperlactatemia. This hyperlactatemia is most likely type B in origin. Given that therapy for type A and type B hyperlactatemia varies, it is important to carefully interpret hyperlactatemia in patients that may be hypoperfused and concurrently receiving glucocorticoids, because the increase in lactate concentration may be the result of type A or type B hyperlactatemia, or a combination of both.

Footnotes

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgments
  8. References

aSynchron CX 5, Beckman Coulter, Fullerton, CA

bCell-Dyne 3500, Abbott, Illinois, IL

cPill Pockets Central Sales Ltd, Brampton, ON, Canada

dMonoject, Tyco Healthcare Group LP, Mansfield, MA

eVacutainer Brand Blood Collection Set, Becton Dickinson and Company, Franklin Lakes, NJ

fNOVA Statprofile M; Nova Biomedical, Waltham, MA

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgments
  8. References

Approval for this study was granted by the Ethics Committee (CEUA) of the Université de Montréal.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnotes
  7. Acknowledgments
  8. References