Complications Associated with High-Dose Prednisolone Sodium Succinate Therapy in Dogs with Neurological Injury

 Laura A. Culbert, MS, DVM,  Dominic J. Marino, DVM,  Diplomate ACVS,  Raymond M. Baule, MD, and  Van W. Knox, III, VMD


From the Department of Surgery (Culbert, Knox), The Animal Medical Center, 510 East 62nd Street, New York, New York 10021 and the Island Veterinary Referral, PC (Merino), 2703 Hempstead Turnpike, Levittown, New York 11756 and The Division of Neurosurgery (Baule), Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania 17033.

Doctor Marino's current address is Long Island Veterinary Specialists, 163 South Service Road, Plainview, New York 11803.


 
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A retrospective study of 105 dogs with neurological injury was conducted to evaluate the type and prevalence of complications encountered when treatment consisted of a high-dose corticosteroid protocol. All dogs were treated with high-dose prednisolone sodium succinate (HDPSS) (30 mg/kg body weight, administered intravenously [IV] q 6 hrs for 36 hrs). Thirty-five (33.3%) cases developed complications including diarrhea (n= 11), melena (n= 11), vomiting (n=6), hematochezia (n=3), hematemesis (n=1), anorexia (n=1), ore combination (n=2). Most complications resolved without additional treatments after termination of the HDPSS therapy. None of the complications were considered serious, and none prolonged hospitalization. J Am Anim Hosp Assoc 1998;34:129-34.
 
 

Introduction

Neurological injury in animals can arise from many causes, including intervertebral disk disease, caudal cervical spondylomyelopathy, fibrocartilagenous emboli, congenital vertebral abnormalities, and trauma.1,2 These conditions can affect nervous tissue directly or indirectly, resulting in neurological deficits. The pathophysiology of spinal cord injury has been described as including both primary and secondary injury.3-6 Direct morphological disruption of nervous tissues and subsequent vascular changes occur immediately and are referred to as primary injury. Primary injury is characterized by early gray matter hemorrhage from microvascular disruption and edema. Edema, beginning in the central gray matter and spreading centrifugally toward the white matter, results from loss of water, protein, and electrolytes.3,7 If the edema is severe, necrosis may result in irreversible damage. Following the initial hemorrhage and edema, ischemia may proceed beyond the initial insult despite decompressive surgery. This process of secondary autolytic tissue destruction has been under investigation in recent years and is referred to as secondary injury.3,4,7 Secondary injury results from vascular changes which affect the delivery of oxygen and nutrients to the injured tissues.3,8-10Biochemical and metabolic changes occur, leading to oxygen-free radical production, lipid peroxidation, cell death, and irreversible damage.3,9,10

 Traditional therapy for spinal cord injury often included corticosteroids and originally was directed toward treating the inflammation associated with the primary injury.11 Dexamethasone, at various doses, has been used following spinal cord injury to decrease the severity of inflammation.11- 14 In 1983, Hoerlein evaluated dexamethasone use in cats with spinal cord injury and found dexamethasone to be no more effective than a placebo in improving neurological outcome. Dexa methasone is less effective than methylprednisolone sodium succinate (MPSS) at preventing lipid peroxidation,15 which is thought to play a significant role in the secondary injury phenomenon. Increasing the dose of dexamethasone to less than half of the reported equipotent high-dose protocol of MPSS (30 mg/kg body weight)16 has resulted in gastrointestinal complications in dogs and cats.13,17,18

 Various drugs have been evaluated for anti-inflammatory, cell-membrane stabilizing, or endorphin antagonizing effects in the treatment of neurological injury,19-21 and all have been found to have questionable efficacy. In recent years, drugs targeting sites in the reperfusion pathway have been evaluated to minimize the cell destruction associated with secondary injury.8,16,22,23 High-dose corticosteroids have been studied extensively to determine the effective dose and frequency of administration with regard to attenuating secondary injury.15,23-25 Methylprednisolone sodium succinate at high doses (30 to 60 mg/kg body weight) inhibits lipid peroxidation and hydrolysis; maintains tissue blood flow and aerobic metabolism; improves reversal of intracellular calcium accumulation; decreases neurofilament degradation; and enhances neuronal excitability and synaptic transmission.6,10,23-26 High-dose MPSS therapy has been shown experimentally and clinically to reduce nervous tissue damage and improve neurological outcome in patients with neurological injury.6,14-16,23,25,27-29 Prednisolone sodium succinate (PSS) is a water-soluble corticosteroid that is used more commonly than MPSS in veterinary medicine. Initial studies in mice indicated PSS is half as potent as MPSS in protecting against lipid peroxidation;29 thus, several authors have suggested doubling the recommended dose of MPSS (30 mg/kg body weight) to 60 mg/kg body weight when using PSS.30,31 A recent comparison of MPSS and PSS in cats as a spinal trauma model indicates both MPSS and PSS are equipotent with regard to their beneficial effects on injured spinal cords at 30 mg kg body weight.a

 In both veterinary and human patients, the administration of corticosteroids has been associated with various side effects (e.g., gastrointestinal ulceration, increased susceptibility to infections, pneumonia, pancreatitis, colonic perforation, and delayed wound healing).12,13,32-35Dexamethasone has been shown to increase the risk of gastrointestinal complications in dogs with intervertebral disk disease, especially when therapy lasts longer than 48 hours.12,13,31 High-dose corticosteroid therapy in patients with spinal injuries has not been accepted universally.11,33 To the authors' knowledge, no reports in the veterinary literature describe the prevalence of complications associated with high-dose corticosteroid therapy in dogs with spinal injury. The purposes of this study are to identify the types and prevalence of complications encountered with a uniform, high- dose prednisolone sodium succinateb (HDPSS) therapy protocol in dogs with neurological injury and to determine any associations with the presence of these complications.
 

Materials and Methods

The medical records of 105 dogs treated with HDPSS for neurological injury at The Animal Medical Center between June 1989 and June 1993 were reviewed. All cases were treated with intravenous (IV) PSS (30 mg/ kg body weight, q 6 hrs for 36 hrs) according to a protocol developed by the authors. High-dose prednisolone sodium succinate therapy was initiated soon after admission in all cases. Information was compiled concerning weight, age, sex, cause of injury, site of injury, neurological status, duration of clinical signs, and previous administration of corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs). At presentation, cases were grouped into six classes according to neurological status: class 1, spinal hyperpathia only; class 2, ambulatory with ataxia; class 3, nonambulatory, but voluntary motor function present; class 4, deep sensory function present, but no voluntary motor function present; class 5, complete sensory and motor function deficits; and class 6, intracranial signs. Information was recorded regarding whether cases received a myelogram or surgery and the type of surgical procedure performed. During hospitalization and on reexamination seven-to-10 days after discharge, cases were monitored for clinical signs of complications related to HDPSS therapy. Cases with complications were managed with conservative therapy (e.g., cimetidine,c misoprostyl,d and sucralfatee) at the clinician's discretion.

 The data was evaluated by chi-square ( 2) analysis; Fisher's exact test and two-sample t-test; and multiple logistic regression to determine any associations with the presence of complications related to HDPSS therapy. Differences were considered significant if p was less than 0.05.
 

Results

Of the 105 cases, 35 (33.3%) had at least one manifestation of a gastrointestinal complication, and two cases each had more than one complication [Table 1]. Gender was not associated significantly with the presence of complications between groups. The age of cases with complications ranged from four to 16 years (median, seven years), while the age of cases without complications ranged from five to 14 years (median, 5.5 years). Nineteen (35.2%) of 54 cases treated with either dexamethasone or  NSAIDs before presentation had complications.

 Causes of neurological deficits [Table 2], neuroanatomical localization [Table 3], and severity of neurological injury [Table 4] are given for cases with and without complications. Thirty- two (36.8%; p=0.09,  2 analysis) of 87 cases having myelograms and 28 (39.4%; p=0.06,  2 analysis) of 71 cases having surgery had complications related to HDPSS therapy. Distribution of surgical procedures performed in cases with and without complications is given [Table 5].
 

Discussion

Thirty-three percent of cases treated with HDPSS had some manifestation of gastrointestinal complications during this study period. The most common complications observed were diarrhea, melena, and vomiting. None of the complications could be attributed exclusively to HDPSS therapy, since some may occur in association with general anesthesia or routine hospitalization. In humans with spinal trauma, 20% of patients display gastrointestinal bleeding without regard to corticosteroid administration.36 Melena and vomiting frequently are related to ulceration in the upper gastrointestinal tract, most notably the stomach. Prior reports of gastrointestinal ulceration in dogs treated with corticosteroids for neurological injury indicate the colon (i.e., the antimesenteric portion of the left colic flexure) is the most common site of ulceration.12,13,32,37 The pathogenesis of colonic ulceration in this region is understood poorly. One theory suggests that a disruption of the autonomic control to the left colic flexure during neurological injury results in secondary motility disturbances that predispose the left colic flexure to dilatation and the deleterious effects of corticosteroids.13Neuroanatomical evaluation of colonic innervation does not support this hypothesis completely; however, it does suggest a possible mechanism for the predisposition of ulceration in this area based on colonic innervation.38

 None of the complications seen with HDPSS therapy were regarded as life-threatening, and all responded to conservative therapy. This differs significantly from reports of complications in dogs with neurological injury treated with dexamethasone The resulting colonic ulcerations caused serious, sometimes fatal complications.12,13,32,37 Increased susceptibility to infections, pneumonia, pancreatitis, ant delayed wound healing have been described in some human patients treated with high-dose corticosteroid therapy. These complications resulted in increaser morbidity, prolonged hospitalization, and increased medical costs averaging $50,000 per patient.33,34 None of the cases in this study experienced any of these serious complications or prolonged hospitalization due to their treatment. Since corticosteroid complications are a result of the relationship between potency and duration of the steroid preparation, the lower prevalence of colonic ulceration with HDPSS compared with dexamethasone may be due to pharmacological differences between the two steroid preparations. In addition, the enhanced efficacy of the HDPSS protocol in treating spinal reperfusion injury may contribute to earlier restoration of neurological function and the return of autonomic regulation.

 Prior treatment with either corticosteroid or NSAID preparations was identified in 54 cases. The types and doses varied significantly; thus, all cases with prior treatments were grouped together. Not enough case numbers were present in each category; therefore, no statistical significance could be determined in the 35% of cases treated with corticosteroid or NSAID preparations that had complications. The authors recommend close monitoring when treating dogs with HDPSS that previously received treatment with other corticosteroid preparations or NSAIDs. Furthermore, the authors do not recommend the use of subtherapeutic doses of corticosteroid preparations or NSAIDs  in dogs with neurological injury that have the potential for spinal reperfusion injury. Rather, high- dose corticosteroid therapy (MPSS or PSS at 30 mg/kg body weight) should be instituted, and the patient should be referred to a surgical specialist, if indicated.

 Thirty-two of 87 dogs having myelograms and 28 of 71 dogs having surgery had complications related to HDPSS therapy. Although these do not represent statistically significant differences, a trend can be inferred. The contribution of surgical or anesthetic hypotension to gastric ulceration in dogs treated with dexamethasone has been evaluated experimentally, and no association could be found. However, dogs without neurological injury were used in the study. The severity and location of ulcerations differed from the clinical observations of the authors and were attributed to the absence of neurological injury. The effects of surgical or anesthetic hypotension may be more significant to ischemic spinal tissue susceptible to reperfusion injury than to gastrointestinal mucosa in the genesis of gastrointestinal ulcerations. Deterioration of neurological status following anesthetic hypotension during myelography in dogs may be due to exacerbation of spinal reperfusion injury. High-dose prednisolone sodium succinate therapy is recommended by the authors in all dogs with neurological injury having anesthesia to decrease the risk of spinal reperfusion injury during anesthetic hypotension.

 An association between etiology of neurological injury or type of surgical procedure and complications could not be evaluated by statistical analysis because of low case numbers and distribution. No trends regarding cause of neurological injury or type of surgical procedure and complications were identified. No association between neuroanatomical localization or severity of neurological injury and complications was found by statistical analysis. The contribution of neu rological injury in the pathogenesis of gastrointestinal ulceration is not known; however, the severity of neurological deficits does not appear to preclude the safe use of HDPSS therapy
 

Conclusion

Injury to nervous tissue can result in irreversible damage with devastating consequences. It is essential to institute the most effective therapy, at the earliest opportunity, for the safest duration the tissues are at risk from damage due to secondary injury. Most agree the reperfusion cascade is a process of unknown duration that lasts a minimum of 24 hours. The results of this study indicate that PSS (30 mg/kg body weight, IV, q 6 hrs for 36 furs) can be used safely in dogs with neurological injury and is not associated with serious complications.

a. Hall ED. Comparison of high-dose methylprednisolone sodium succinate and prednisolone sodium succinate in acute spinal cord injury in cats. Unpublished data, The Upjohn Company, Kalamazoo, MI

b. Solu-Delta-Cortef: The Upjohn Company. Kalamazoo, MI

c. Tagamet; Smith, Kline & French Laboratories, Philadelphia, PA

d. Cytotec; GD Searle & Co., Chicago, IL

e. Carafate: Marion Laboratories. Inc., Kansas City, MO

References

 1. Braund KG, Shores A, Brawner WR. Localizing spinal cord lesions through recognition of neurologic syndromes. Vet Med 1990;7:692-702.

 2. de Lahunta A. Small animal spinal cord disease. In: de Lahunta A, ed. Veterinary neuroanatomy and clinical neurology. Philadelphia: WB Saunders, 1983:175-214.

 3. Berg RJ, Rucker NC. Pathophysiology and medical management of acute spinal cord injury. Comp Cont Ed 1985;7:646-54.

 4. Braund KG, Shores A, Brawner WR. The etiology, pathology, and pathophysiology of acute spinal cord trauma. Vet Med 1990:684-91.

 5. Calvert CA, Cornelius LM. The pharmacodynamic differences among glucocorticoid preparations. Vet Med 1990:860-5.

 6. Hall ED. The neuroprotective pharmacology of methylprednisolone. J Neurosurg 1992;76:13- 22.

 7. Tator CH, Fehlings MG. Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg 1991;75:15-26.

 8. Brown SA, Hall ED. Role of oxygen-derived free radicals in the pathogenesis of shock and trauma, with focus on central nervous system injuries. J Am Vet Med Assoc 1992;200:1849-58.

 9. Collins WF, Piepmeier J, Ogle E. The spinal cord injury problem—a review. Central Nervous System Trauma 1986;3:317-31.

10. Demopoulos HB, Flamm ES, Seligman ML, et al. Membrane perturbations on central nervous system injury: theoretical basis for free radical damage and a review of the experimental data. In: Popp AJ, ed. Neural trauma. New York: Raven Press, 1979:63-78.

11. Scavelli TD, Schoen A. Problems and complications associated with the nonsurgical management of intervertebral disk disease. In: Thacher C, ed. Problems in veterinary medicine. Philadelphia: JB Lippincott, 1989:402-14.

12. Moore RW, Withrow SJ. Gastrointestinal hemorrhage and pancreatitis associated with intervertebral disk disease in the dog. J Am Vet Med Assoc 1982;177:1443-7.

13. Toombs JP, Caywood DD, Lipowitz AJ, et al. Colonic perforation following nonsurgical procedures and corticosteroid therapy in four dogs. J Am Vet Med Assoc 1980;177:68-72.

14. Braughler JM, Hall ED. Current application of "high-dose" steroid therapy for CNS injury. J Neurosurg 1985;62:806-10.

15. Braughler JM. Lipid peroxidation-induced inhibition of gamma aminobutyric acid uptake in rat brain synaptosomes: protection by glucocorticoids. J Neurochem 1985;44:1282-8.

16. Braughler JM, Hall ED, Means ED, et al. Evaluation of an intensive methylprednisolone sodium succinate dosing regimen in experimental spinal cord injury. J Neurosurg 1987;67:102- 5.

17. Faden AJ, Jacobs TP, Patrick DH, et al. Megadose corticosteroid therapy following experimental traumatic spinal injury. J Neurosurg 1984;60:712-7.

18. Sorjonen DC, Dillon AR, Powers RD, et al. Effects of dexamethasone and surgical hypotension on the stomach of dogs: clinical, endoscopic, and pathologic evaluations. Am J Vet Res 1983; 44:1233-7.

19. Wallace MC, Tator CH. Failure of blood transfusion or naloxone to improve clinical recovery after experimental spinal cord injury. Neurosurg 1986;19:489-94.

20. Goodnough J, Allen N, Nesham ME. The effects of dimethyl sulfoxide on gray matter injury in experimental spinal cord trauma. Surg Neurol 1980;13:273-6.

21. Hoerlein BF, Redding RW, Hoff EJ, et al. Evaluation of dexamethasone DMSO, mannitol, and solcoseryl in acute spinal cord trauma. J Am Anim Hosp Assoc 1983;19:216-26.

22. Blight AR, Toombs JP, Bauer MS, et al. The effects of 4-aminopyridine on neurological deficits in chronic cases of traumatic spinal cord injury in dogs: a phase I clinical trial. J Neurotrauma 1991:8:103-18.

23. Braughler JM, Hall ED. Effects of multi-dose methylprednisolone sodium succinate administration on injured cat spinal cord neurofilament degradation and energy metabolism. J Neurosurg 1984:61:290-5.

24. Anderson DK, Saunders RD, Demedink P, et al. Lipid hydrolysis and peroxidation in injured spinal cord: partial protection with methylprednisolone or vitamin E and selenium. Central Nervous System Trauma 1985;2:257-67.

25. Braughler JM, Hall ED. Correlation of methylprednisolone levels in cat spinal cord with its effects on (Na+ + K+)-ATPase, lipid peroxidation, and alpha motor neuron function. J Neurosurg 1982;56:838-44.

26. Young W, Flamm ES. Effect of high-dose corticosteroid therapy on blood flow, evoked potentials, and extracellular calcium in experimental spinal injury. J Neurosurg 1982;57:667-73.

27. Braughler JM, Hall ED. Lactate and pyruvate metabolism in injured cat spinal cord before and after a single large intravenous dose of methylprednisolone. J Neurosurg 1983;59:256-61.

28. Bracken MB, Shepard MJ, Collins WF, et al. A randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury. New Engl J Med 1990;322:1405-11.

29. Hall ED. High-dose glucocorticoid treatment improves neurological recovery in head-injured mice. J Neurosurg 1985:62:882-7.

30. Brown SA, Hall ED. Role of oxygen-derived free radicals in the pathogenesis of shock and trauma, with focus on central nervous system injuries. J Am Vet Med Assoc 1992;200:1849-58.

31. Dewey CW, Budsberg SC Jr, Oliver JE. Principles of head trauma management in dogs and cats—Part 11. Comp Cont Ed Pract Vet 1993;15:177-93.

32. Bellah JR. Colonic perforation after corticosteroid and surgical treatment of intervertebral disk disease in a dog. J Am Vet Med Assoc 1983;183:1002-3.

33. Galandiuk S, Raque G, Appel S, et al. The two-edged sword of large-dose steroids for spinal cord trauma. Ann Surg 1993;218:419-27.

34. Bracken MB, Collins WF, Freeman DF, et al. Efficacy of methylprednisolone in acute spinal cord injury. J Am Med Assoc 1984;251:45-52.

35. Braund KG, Shores A, Brawner WR. Recovering from spinal cord trauma: the rehabilitative steps, complications, and prognosis. Vet Med 1990:740-3.

36. Hall ED, Braughler JM. Glucocorticoid mechanisms in acute spinal cord injury: a review and therapeutic rationale. Surg Neurol 1982;18:320-7.

37. Toombs JP, Collins LG, Graves GM. Colonic perforation in corticosteroid-treated dogs. J Am Vet Med Assoc 1986;188:145-50.

38. Hudson LC. Horseradish peroxidase study of the location of extrinsic efferent and afferent neurons innervating the colon of dogs. Am J Vet Res 1990;51:1875-81.


 
Table 1
Types of Complications in Dogs Treated
with High-Dose Prednisolone Sodium Succinate (HDPSS)
Complication No. of Dogs  Percentage
Diarrhea 

Melena 

Vomiting 

Hematochezia 

Combination of two or more complications 

Hematemesis 

Anorexia

 11 

11 

6 

3 

2 

1 

1

 10.5 

10.5 

5.7 

2.8 

1.9 

0.95 

0.95
None 70 66.7
Total 105 100.0
 
Table 2
Causes of Neurological Injury Versus Complications
Cause Complications No Complications Total
No. of Dogs Percentage No. of Dogs Percentage No. of Dogs Percentage
Intervertebral disk disease 31 39.2 48 60.8 79 75.2
Neoplasia 2 100.0 0 0 2 1.9
Trauma 1 7.1 13 92.9 14 13.3
Vascular 1 14.3 6 85.7 7 6.7
Caudal cervical spondylomyelopathy 0 0 3 100.0 3 2.9
Total 35 70 105 100.0
 
Table 3
Neuroanatomical Localization Versus Complications
Cause Complications No Complications Total
No. of Dogs Percentage No. of Dogs Percentage No. of Dogs Percentage
Lumbar 13 27.7 34 72.3 47 44.8
Thoracic 13 39.4 20 60.6 33 31.4
Cervical 8 38.1 13 61.9 21 20.0
Intracranial 1 25.0 3 75.0 4 3.8
Total 35 70 105 100.0
 
Table 4
Severity of Neurological Injury Versus Complications
Neurological Scale* Complications No Complications Total
No. of Dogs Percentage No. of Dogs Percentage No. of Dogs Percentage
1 0 0 8 100.0 8 7.6
2 12 38.7 19 61.3 31 29.5
3 11 34.4 21 65.6 32 30.5
4 9 45.0 11 55.0 20 19.1
5 3 25.0 9 75.0 12 11.4
6 0 0 2 100.0 2 1.9
Total 35 70 105 100.0
 

*1=spinal hyperpathia; 2=ambulatory with ataxia; 3=nonambulatory, but voluntary motor function present; 4=deep sensory function present, but no voluntary motor function present; 5=complete sensory and motor function deficits; 6=intracranial signs

Table 5
Surgical Procedures Versus Complications
Procedure Complications No Complications Total
No. of Dogs Percentage No. of Dogs Percentage No. of Dogs Percentage
Hemilaminectomy 19 38.0 31 62.0 50 70.4
Ventral cervical decompression 6 54.5 5 45.5 11 15.5
Dorsal laminectomy 2 22.2 7 77.8 9 12.7
Craniotomy 1 100.0 0 0 1 1.4
Total 28 43 71 100
 

 

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