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Keywords:

  • Congestive heart failure;
  • Dermal ulceration;
  • Diuretics;
  • Mitral valve disease;
  • pH
Abbreviations
CHF

congestive heart failure

SC

subcutaneous

Subcutaneous (SC) furosemide administration is not uncommon in the management of congestive heart failure (CHF) in dogs. The biochemical adverse effects of furosemide (eg, azotemia) are well described in companion animals, whereas nonbiochemical adverse effects are largely unreported. This report describes a dermatologic adverse effect of SC furosemide in a dog undergoing treatment of CHF.

A 10-year-old 4.4-kg neutered male dachshund was presented for tachypnea and coughing, and consequently diagnosed with CHF secondary to degenerative mitral valve disease. Initial cardiac medications included the following: furosemidea (1.42 mg/kg PO q12h), enalaprilb (0.57 mg/kg PO q12h), and pimobendanc (0.28 mg/kg PO q12h). The dog's clinical signs resolved with treatment.

Three months after the initial diagnosis and treatment, the dog was represented with a recurrence of CHF. The dose of furosemide was increased (2.27 mg/kg PO q8h). In addition, spironolactoned was administered (1.42 mg/kg PO q12h). Enalapril and pimobendan were continued as previously prescribed.

Over the next month, cardiac medications were adjusted multiple times because the dog suffered a left atrial rupture (which was treated conservatively) followed by 2 additional episodes of CHF. Enalapril was temporarily discontinued during left atrial rupture management caused by severe hypotension. When ACE inhibitor therapy could be safely reinstituted, benazeprile (0.28 mg/kg PO q24h) was substituted for enalapril. Despite high doses of oral furosemide (>10 mg/kg/d), pulmonary edema was not adequately controlled; therefore, SC furosemide administration was implemented.

The dog's evening furosemide dose (4.5 mg/kg) was changed to the SC route using an injectable formulation.f In addition, an afternoon dose of pimobendan (0.14 mg/kg PO) was added to the therapeutic regimen. Eight days later, the dog was presented again for dyspnea because of recurrent CHF. The dog was hospitalized for acute treatment of CHF for 24 hours. At the time of discharge from the hospital, the following medication adjustments were made: (1) furosemide dose and route were changed (4.5 mg/kg SC q8h); (2) hydrochlorothiazideg was administered (1.42 mg/kg PO q24h); and (3) pimobendan afternoon dose was increased (0.28 mg/kg PO).

The clinical signs resolved once more shortly after instituting these changes. Six weeks later, the client accidentally broke the glass bottle of furosemide. Because of a temporary shortage of the initial brand of furosemidef at the hospital, the client was provided with an alternate brand of injectable furosemide.h The dose and frequency of SC furosemide administration remained the same, and no other medication changes were made.

Approximately 2 weeks after the change in brand of furosemide, the dog developed multiple ulcerative dermal lesions at the sites of SC injections. All furosemide injections during that 2-week period were from a single bottle of the alternate brand of furosemide. The lesions ranged in size from 0.75 to 1.5 cm in diameter. The client also reported that the dog resented injections of the “new” brand of furosemide. The dermal lesions were suspected to be associated with the alternate formulation of injectable furosemide; therefore, this formulation was discontinued and the initial brand of furosemide substituted. During the subsequent week, no additional lesions developed and the pre-existing dermal ulcerations appeared to be resolving without specific treatment. In addition, the dog no longer resented SC furosemide injections. However, because of the recurrence of severe dyspnea associated with CHF, the dog was euthanized 1 week later. Histopathology of the dermal lesions was not performed.

Because the development of dermal lesions apparently coincided with the change in brand of furosemide, we hypothesized that differences in solution constituents, pH or osmolality were associated with the adverse dermatologic reaction in this dog. First, we contacted the distributors of both brands of furosemide. Technical support staff at Butler Schein Animal Health stated that they obtained their furosemide from Intervet Schering-Plough, and that their formulation was relabeled for distribution. Technical support staff at Intervet International GmbH stated that they prepared their furosemide at their facilities.

Next, we compared the constituents of each furosemide preparation. Several differences in the formulations became apparent: (1) the salts of furosemide differed (diethanolamine in the Intervet product versus monoethanolamine in the Butler product); and (2) pH adjustment in the Intervet product was with NaOH, and with NaOH or HCl in the Butler product. Diethanolamine salts of furosemide have a pH of 7–7.8, whereas monoethanolamine salts of furosemide have a pH of 8–9.3.[1]

Finally, to determine if the brands differed in pH and osmolality, we measured pH and osmolality of aliquots of each furosemide formulation obtained from additional bottles of each formulation (different from those used by the client). The pH of Intervet solution was 7.20, whereas the pH of the Butler solution was 8.66 at 22°C. We repeated testing on different furosemide samples from different lots and our results were replicated; the Butler formulation of furosemide had a pH of 9.05, whereas the Intervet formulation had a pH of 7.47 at 22°C. The osmolality of the 2 brands differed slightly (244 [Intervet] and 280 [Butler]), but neither was sufficiently hyperosmolar to be of clinical importance. It is important to note that all bottles of furosemide tested were different than the bottles used for the dog in this report.

Subsequent online listserve discussions among veterinary cardiologists highlighted several similar instances of dermal ulceration, or pain/discomfort with SC administration of furosemide. However, no consistent association with formulation or brand was identified in that discussion.[2]

Discussion

  1. Top of page
  2. Discussion
  3. Acknowledgments
  4. References

Diuretics are a mainstay of CHF therapy in dogs and in humans. Furosemide, a loop diuretic and sulfonamide derivative, is the standard diuretic for acute and chronic management of CHF in dogs.[3, 4] Enteral and parenteral routes of furosemide administration are widely used among veterinarians. Per os administration is most common in chronic (home-based) CHF therapy, whereas intravenous (IV) administration is most common in acute (hospital-based) therapy.[3]

Intramuscular administration is an alternative parenteral route and is often utilized in acute CHF therapy when IV administration is not possible (eg, in a dog with severe pulmonary edema that is unable to tolerate restraint for IV administration, IV catheter placement, or both).[5] Intramuscular administration is not commonly used for chronic therapy because of discomfort associated with frequent intramuscular injections.

Subcutaneous administration is an additional, off-label, parenteral route adopted and advocated by veterinary cardiologists when oral administration is no longer effective in controlling clinical signs of CHF, or where oral administration is logistically difficult, such as in some cats. Furthermore, SC furosemide administration aids in chronic therapy of Stage D heart failure (end-stage chronic valvular disease that is refractory to standard CHF therapy), because of higher bioavailability compared with oral administration.[5, 6]

Biochemical adverse effects of furosemide therapy are well established in dogs. Common disturbances include hyponatremia, hypokalemia, hypochloremia, and prerenal azotemia.[4] A cutaneous adverse effect occurred in association with chronic oral furosemide therapy in a dog.[7] The dog in that report developed alopecia, erythema, scaling, and pruritis along the dorsolumbar area. The dermatosis resolved within 7 days of discontinuing oral furosemide.

Our case report and subsequent investigation provide strong circumstantial evidence that certain preparations of furosemide, when injected SC in dogs, can result in dermal ulceration. Our biochemical analysis identified 1 formulation of furosemide as having a pH approximately 1 order of magnitude more alkaline than another formulation of furosemide, which had a neutral pH. Such an alkaline solution would be anticipated to be nonphysiological and to cause caustic injury when injected SC. Furthermore, injection of a nonphysiological solution into SC tissue results in potassium ion transport, which depolarizes nerve endings and causes pain.[8] Intravenous administration of alkaline solutions is well tolerated by animals because of the pH buffering capabilities of plasma that neutralize the pH of such solutions. Therefore, IV administration of the alkaline formulation of furosemide would not be anticipated to be problematic in animals.

Mild dermatologic adverse effects have been previously reported in a minority of human subjects receiving SC furosemide.[9, 10] Potential causes of the ulcerative dermal lesions in the dog in this report include the following: (1) an immune-mediated reaction to furosemide; (2) mechanical tissue trauma from frequent injections; (3) chemical tissue irritation caused by 1 or more components of the furosemide solution; or (4) a combination of the aforementioned factors.

Based on the findings in this case, a definitive cause of the dog's dermatologic disease cannot be determined. However, SC administration of a particular formulation of furosemide is strongly suspected based on lesion location (at the injection sites) and resolution with a change in furosemide formulation. Furthermore, the alkaline pH of the Butler formulation was notably different than the more neutral pH of the Intervet formulation in the limited number of samples we tested. It is possible, however, that the significant difference in pH between formulations was lot specific. Other lots of each brand of furosemide could have a pH different from the lots we tested. Although repeated and controlled exposure to multiple lots of both brands would be necessary to unequivocally prove causality, this approach would produce ethical issues of intentional dermal injury. Therefore, we did not pursue more rigorous experimental investigation of our hypothesis.

Our report suggests that veterinarians should exercise caution when prescribing SC furosemide to canine patients, and should consider the potential effects of furosemide formulation (eg, pH) in their choice when prescribing this route of administration.

Acknowledgments

  1. Top of page
  2. Discussion
  3. Acknowledgments
  4. References

Thanks to Richard DeFrancesco for performing osmolality measurements on furosemide samples.

Conflicts of Interest: Authors disclose no conflict of interest.

Footnotes
  1. 1

    FuroTabs, Butler Schein Animal Health, Dublin, OH

  2. 2

    Enalapril Maleate Tablets, Wockhardt USA, Parsippany, NY

  3. 3

    Vetmedin Chewable Tablets, Boehringer Ingelheim Vetmedica Inc, St Joseph, MO

  4. 4

    Spironolactone Tablets, Qualitest Pharmaceuticals, Huntsville, AL

  5. 5

    Benazepril Hydrochloride Tablets, Ranbaxy Pharmaceuticals, Jacksonville, FL

  6. 6

    Salix Injection, Intervet Inc, Millsboro, DE

  7. 7

    Spironolactone and Hydrochlorothiazide Tablets, Mylan Pharmaceuticals, Morgantown, WV

  8. 8

    Furojet, Butler Animal Health Supply, Dublin, OH

References

  1. Top of page
  2. Discussion
  3. Acknowledgments
  4. References