Treatment of Congestive Heart Failure with Intravenous Nitroglycerin in Three Dogs with Degenerative Valvular Disease
ABSTRACT
We described the use of IV nitroglycerin as adjunctive therapy in three canine patients with left congestive heart failure secondary to degenerative mitral valve disease. All three dogs were admitted for signs of respiratory distress and all were determined to be in left congestive heart failure by history, exam findings, thoracic radiographs, and echocardiography. In addition to standard therapy for left congestive heart failure, IV nitroglycerin was administered as a constant rate infusion at a dose of 1–6 mcg/kg/min. No adverse events attributable to the drug were noted. This is the first reported use of IV nitroglycerin in clinical veterinary patients. Further studies are warranted to investigate the safety, efficacy, and optimal dosing of IV nitroglycerin infusions in dogs with left congestive heart failure.
Introduction
Initial therapy of congestive heart failure includes supplemental oxygen, preload reduction, and myocardial function improvement. In addition, heart rate (HR) and afterload optimization should be attempted. A cornerstone of therapy is loop diuretics, which reduce circulating volume, leading to reduced preload and therefore reduction in the formation of pulmonary edema.1 Further reduction of preload may be achieved acutely with various venodilators including sodium nitroprusside and nitroglycerin.2 The use of intravenous sodium nitroprusside or topical nitroglycerin 2% ointment for the treatment of severe left congestive heart failure has been previously described in clinical veterinary references.1–3
The efficacy of topical nitroglycerin in dogs with left heart failure is questionable. Poor absorption as a result of peripheral vasoconstriction may limit its effectiveness in the setting of heart failure. The use of topical nitroglycerin has not been evaluated in clinical patients with congestive heart failure, although there are reports of its use in research dogs.4,5 In cases refractory to standard therapy, intravenous sodium nitroprusside infusion presents an attractive therapy for acute left heart failure as it provides venodilation or preload reduction as well as arterial dilation or afterload reduction, and it is rapidly titratable.2,6 Unfortunately, sodium nitroprusside may be cost prohibitive for many clients and is often unavailable as a result of manufacturer limitations. At the time of publication, at the authors’ facility, sodium nitroprussidea is available in 2 mL vials (25 mg/mL) costing $697. Because of the limitations associated with topical nitroglycerin ointment and the high cost and supply problems with sodium nitroprusside, an inexpensive and readily available alternative vasodilator is desirable as an adjunctive therapy for patients with left congestive heart failure.
Intravenous nitroglycerinb (IV-NTG) may be an affordable alternative vasodilator with a relevant role in canine congestive heart failure. At the authors’ facility, IV-NTG is available in a 10 mL vial (5 mg/mL) costing ∼$30. To the authors’ knowledge, there are no reports of the use of IV-NTG in dogs with naturally occurring congestive heart failure, and no recommendations exist for its use in clinical canine patients, although its use is described and has been recommended in human patients.7,8 The purpose of this case series was to describe the use of IV-NTG in dogs with naturally occurring congestive heart failure in a clinical setting.
Case Report
Dog 1
A 10 yr old neutered male Chihuahua (4.9 kg) was presented to the Michigan State University (MSU) Veterinary Medical Center (VMC) for 24 hr duration of acute respiratory distress. Thoracic radiographs by the referring veterinarian 2 wk prior for coughing revealed cardiomegaly with dorsal displacement of the trachea without evidence of pulmonary edema or pulmonary venous enlargement. Furosemidec (2.55 mg/kg per os [PO] q 12 hr) and pimobendand (0.255 mg/kg PO q 12) was initiated. No clinical improvement was reported by the owners. Two weeks later, the patient was presented to the MSU VMC or 24 hr of progressive worsening respiratory distress.
On admission to the MSU VMC physical examination revealed severe tachypnea (respiratory rate [RR] 108 breaths/min) with greatly increased respiratory effort (RE), tachycardia (HR 180 beats/min), a grade 5/6 left apical systolic murmur, and bilaterally increased bronchovesicular sounds. The rest of the physical examination was unremarkable. Brief cardiac ultrasound in the emergency room subjectively showed a dilated left atrium with an increased ratio of the left atrial dimension to the aortic annulus dimension (LA:Ao). Initial Doppler blood pressure was 120 mm Hg. A peripheral capillary oxygen saturation (SpO2) measurement could not be obtained and was delayed pending further stabilization. Venous blood gas, electrolytes, and renal values were unremarkable except for hyperlactatemia (6.2 mg/dL, reference interval [RI] 0.2–3.3). Furosemide (2 mg/kg IV once) was administered at presentation and he was placed in an oxygen cage (50% inspired oxygen fraction [FiO2]). Following initial stabilization, butorphanole (0.3 mg/kg IV once) was administered and thoracic radiographs were obtained. Radiographs revealed a diffuse patchy alveolar pattern, most severe in the left caudodorsal and cranioventral lung lobes as well as left sided ventricular and atrial enlargement. Pulmonary venous congestion was not noted and was attributed to recent furosemide administration. Interpretation of the radiographs by a board-certified radiologist was consistent with a diagnosis of left congestive heart failure. Pimobendan (0.25 mg/kg PO q 12 hr) was initiated as was enrofloxacinf (10 mg/kg IV q 24 hr) as a result of the inability to rule out pneumonia based on the cranioventral pulmonary alveolar pattern. Continuous electrocardiogram revealed sinus tachycardia (HR 170–190 beats/min). No clinically significant electrocardiographic abnormalities were noted during hospitalization. SpO2 measurement at this time was 90% with supplemental oxygen (FiO2 50%).
Minimal improvement in HR or RR was noted following initial therapy. A furosemide constant rate infusion (CRI; 0.5 mg/kg/hr IV) was initiated. As a result of a lack of improvement after 4 hr of a furosemide CRI an IV-NTG infusion (2 mcg/kg/min IV CRI) was initiated. IV-NTG was diluted to a concentration of 100 mcg/mL in 5% dextrose in waterg with an initial flow rate of 1.2 mL/hr. This dilution was used for all patients in this report. The IV-NTG infusion was increased incrementally (2–6 mcg/kg/min) over 2 hr in 1 mcg/kg/min increments with 10-15 min intervals between adjustments. Doppler blood pressure remained between 100–150 mm Hg during administration of IV-NTG. Gradual improvement in RR and RE were noted over the next 24 hr. The IV-NTG infusion was discontinued abruptly after ∼16 hr as a result of improvement in the patient’s respiratory status. SpO2 measurement increased to 96% with supplemental oxygen (50% FiO2). Anxiety was presumed to be a contributing factor in tachycardia as it persisted despite improvements in RR and RE as well as SPO2. Echocardiogram performed the following day revealed mild to moderate thickening of the anterior and posterior mitral valve leaflets, dilated left atrium (LA:Ao 1.77), and hyperdynamic systolic function of the left ventricle. The furosemide CRI was discontinued several hr after the IV-NTG infusion and the patient was transitioned to oral furosemide and pimobendan. Thoracic radiographs were repeated and revealed marked improvement of all areas of lung consolidation. Recheck venous blood gas, electrolytes and renal values just prior to discontinuation of IV-NTG revealed hyponatremia (135 mg/dL, RI 143–150) and hypochloremia (102 mg/dL, RI 114–124) with no changes in in creatinine or blood urea nitrogen. Therapy with enrofloxacin was discontinued as concurrent pneumonia was considered unlikely. Supplemental oxygen was discontinued on the second day. On the third day, the patient was discharged with pimobendan as described above and torsemideh (0.25 mg/kg PO q 12 hr).
Dog 2
An 8 yr old castrated male Chihuahua (2 kg) was presented to the MSU VMC as a referral for evaluation of 24 hr of respiratory distress. When examined by the referring veterinarian, an increased RR and RE were noted along with bilaterally increased lung sounds. Thoracic radiographs were taken revealing cardiomegaly, pulmonary venous enlargement and perihilar edema suggestive of left congestive heart failure. Additional history included a 1 yr history of coughing that had progressed in the last 4 days.
At admission to the MSU VMC the dog was tachypneic (RR 80 breaths/min), tachycardic (HR 180 beats/min), had increased RE and bilaterally increased lung sounds, and a grade 3/6 left apical systolic murmur was auscultated. SpO2 measurement was 91% without oxygen supplementation, and Doppler blood pressure was recorded at 120 mm Hg. Review of the referring veterinarian’s radiographs showed perihilar edema, cardiomegaly, pulmonary venous enlargement, and an enlarged left atrium. A brief cardiac ultrasound performed by the emergency clinician subjectively showed a dilated left atrium and increased LA:Ao. Venous blood gas, electrolytes, and renal values were performed, and no abnormalities were noted. Based on these findings, treatment for left sided congestive heart failure was initiated. Furosemide (2.5 mg/kg IV single dose) and butorphanol (0.2 mg/kg IV single dose) were administered, and he was placed in an oxygen cage (FiO2 50%). Furosemide (2.5 mg/kg IV) was repeated after 1 hr then continued (2.5 mg/kg IV q 6 hr) and pimobendan (0.31mg/kg PO q 8 hr) was initiated. Doppler blood pressure at that time was 120 mm Hg, HR was 180 beats/min, and RR was 48/min.
As a result of persistent tachypnea and progressive increase in RE, an IV-NTG infusion (1 mcg/kg/min IV CRI) was initiated concurrently with the second dose of furosemide. The IV-NTG infusion was incrementally increased (1–3 mcg/kg/min) over the first hour in 1 mcg/kg/min increments with a minimum of 10 min intervals between adjustments. The decision to increase the IV-NTG dose was based on persistently elevated RR and effort. The IV-NTG infusion was continued for ∼18 hr. Serial Doppler blood pressures performed every 2 hr at minimum remained within 100–120 mm Hg during the IV-NTG infusion. RE and RR gradually improved during therapy. Approximately 18 hr after presentation tachypnea had resolved (RR 24 breaths/min) and supplemental oxygen was discontinued (SpO2 96% without oxygen supplementation). Furosemide and pimobendan doses were reduced (2 mg/kg IV q 8 hr and 0.31 mg/kg PO q 12 hr, respectively) and the IV-NTG infusion was discontinued abruptly. The patient was transitioned to oral furosemide (2 mg/kg PO q 12 hr), continued pimobendan (0.31 mg/kg PO q 12 hr), and was discharged 2 days after admission. Approximately 2 wk later, echocardiography with the MSU CVM cardiology service showed thickening of the posterior and anterior mitral valve leaflets, hyperdynamic left ventricular systolic function, and dilation of the left atrium (LA:Ao of 1.91).
Dog 3
A 10 yr old spayed female Chihuahua (1.74 kg) was presented to the MSU VMC for acutely increased RR and RE. Four months prior to presentation after referral for chronic cough echocardiogram revealed severe mitral valve regurgitation as result of valvular degeneration, with mitral valve prolapse, left atrial dilation (LA:Ao of 1.74), hyperdynamic systolic function of the left ventricle, and a suspected ruptured chordae tendinae. Thoracic radiographs at that time evaluated by a board-certified radiologist revealed no evidence of congestive heart failure. Pimobendan (0.22 mg/kg PO q 12 hr), furosemide (2.9 mg/kg PO q 8 hr), enalaprili (0.36 mg/kg PO q 12 hr), and spironolactonej (1.7 mg/kg PO q 24 hr) were prescribed. Two and a half months later, the patient was presented to the MSU CVM in acute respiratory distress and thoracic radiographs reviewed by a board-certified radiologist were consistent with left congestive heart failure. Treatment consisting of IV furosemide and sodium nitroprusside was initiated with continuation of oral pimobendan, enalapril, and spironolactone. The patient improved with therapy and was discharged with furosemide (2.9 mg/kg PO q 8 hr), pimobendan (0.2 mg/kg PO q 24 hr in the AM and 0.4 mg/kg PO q 24 hr in the PM), and spironolactone (1.1 mg/kg PO q 12 hr).
At the time of presentation, the patient was in acute respiratory distress. Tachycardia (HR 150 beats/min), tachypnea (RR 50 breaths/min), a grade 5/6 left apical systolic murmur, and bilateral pulmonary crackles were noted. The rest of the examination was unremarkable. SpO2 was measured at 89% without supplemental oxygen and 93% in an oxygen cage (50% FiO2). A blood pressure could not be obtained at that time because of the patient’s condition. Laboratory abnormalities included mild hypercapnia (44.3 mm Hg, RI 24.5–41), hypercarbia (33.9 mg/dL, RI 16–25), hyponatremia (132 mg/dL, RI 143–150), hypochloremia (90 mg/dL, RI 114–124), and an elevated blood urea nitrogen (50 mg/dL, RI 10–29). Creatinine (0.8 mg/dL, RI 0.7–1.8) and potassium (3.2 mg/dL, RI 3–4.7) were within normal limits. Furosemide (2.6 mg/kg IV once then 1.6 mg/kg IV q 6 hr) was administered followed by an IV-NTG (2 mcg/kg/min CRI) infusion. Incremental increase of the IV-NTG infusion (2–3.5 mcg/kg/min) was performed over 1 hr. Doppler blood pressure remained between 90–125 mm Hg during IV-NTG administration. No clinical evidence of hypotension including progressive tachycardia, tachypnea, or REs, lethargy, or pale mucous membranes was noted concurrently with the single blood pressure measurement <100 mm Hg. The IV-NTG infusion was continued for 8 hr during which time the HR and RR decreased (130 beats/min and 30 breaths/min, respectively). SpO2 increased to 93% without supplemental oxygen. Oral pimobendan was continued and the patient was transitioned to furosemide (2.9 mg/kg PO q 6 hr). Despite resolution of clinical signs, euthanasia was elected as a result of concerns for recurrence of congestive heart failure.
Discussion
To the authors’ knowledge, this is the first case series describing the use of IV-NTG in clinical veterinary patients. No clinically significant adverse effects of IV-NTG therapy were noted in these patients. One of the patient’s blood pressures was mildly below the normal reference range for dogs, 110–190 mm Hg.9 However, no clinical signs of hypotension were noted and a systolic blood pressure of <90 mm Hg would be more concerning for impaired perfusion and require intervention.9 Additionally all the dogs in the series had resolution of their clinical signs during therapy though this cannot be attributed to IV-NTG based on the small number of cases and their concurrent therapy for heart failure.
Currently, the American College of Cardiology, American Heart Association, Heart Failure Society of America, and European Society of Cardiology recommend IV-NTG for patients with clinical fluid over load or inappropriate response to standard oral therapy for congestive heart failure who are not hypotensive.10 In humans, the reported beneficial effects of IV-NTG in congestive heart failure include reduction of left and right ventricular filling pressures, reduction of systemic and pulmonary vascular resistance, and increased cardiac output.11 Increased cardiac output is likely as a result of reduction of afterload, myocardial ischemia, and mitral regurgitant volumes.11 IV-NTG use in has been shown to reduce preload at low doses, and afterload as well at higher doses.7 Other effects include decreased myocardial oxygen consumption, improved coronary blood flow, and increased coronary vessel diameter.7,12 Decreased endogenous nitric oxide is reported in patients with heart failure and IV-NTG may help restore these levels to more normal levels.13 Clinically IV-NTG has been shown to decrease the need for intubation and intensive care unit admission in people with acutely decompensated heart failure.14
Multiple studies of IV-NTG in dogs have shown a reduction in left ventricular end-diastolic volume, right atrial pressure, left atrial pressure, and central venous pressure indicating preload reduction.15–18 Additionally in dogs with artificially induced heart failure by chordae tendinae transection, IV-NTG was shown to decrease left atrial pressure, central venous pressure, and left ventricular end-diastolic volume.16 IV-NTG has been reported to be primarily a venodilator and have a greater effect on preload.19 This was supported in one study of anesthetized dogs where IV-NTG led to a reflex increase in peripheral resistance.15 However, several studies of IV-NTG in dogs with and without congestive heart failure have shown a reduction of afterload.16-18 IV-NTG has been demonstrated to reduce systemic vascular resistance, mean arterial pressure, and aortic pressures in dogs.16–18 In experimental dogs receiving IV-NTG decreased mean arterial pressure has been documented at a dose of 4 mcg/kg/min, although clinically relevant reduction does not occur until doses exceeding 10 mcg/kg/min.18 Further studies are required to determine its effect on blood pressure in clinical dogs with heart failure.
In a pharmacokinetic study of IV-NTG in dogs the half-life of nitroglycerin is ∼4 min; however, steady state plasma concentrations are not achieved until 60 min after infusion.20 Steady state plasma concentrations were not proportional to infusion rates; however, the relationship between steady state and infusion rate was linear.20 In the same study, active metabolites of nitroglycerin, 1,2-glyceryl dinitrate and 1,3-glyceryl dinitrate, were shown to contribute significantly to the pharmacodynamics effect of IV-NTG.20 IV-NTG should be diluted prior to infusion and must be diluted in a glass vial as it binds to plastics.21 Dilution should only be performed with 0.9% NaCl or D5W, and the recommended concentration is 100 mcg/mL, although 400 mcg/mL should not be exceeded.21 The type of administration set will affect the delivered volume as the drug may absorb into plastics.21
The most commonly reported side effect of IV-NTG in humans is headache, which may be severe and is difficult to evaluate in dogs. 22 Additional side effects include nausea, and hypotension with abdominal and chest pain being reported less commonly.22 Methemoglobinemia- and bradycardia-associated syncope have rarely been reported in humans receiving IV-NTG.22,23 No evidence of pain or nausea was documented for the dogs included in this report, and no clinically significant hypotension was recorded during nitroglycerin therapy. The development if tolerance to nitrate therapy is well documented in humans and characterized by reduction of their hemodynamic effects.22 Tolerance may develop as a result of increased catecholamines, impaired biotransformation, increased free radical production, and decreased sensitivity of guanylate cyclase.22 Tolerance is generally reported after administration for more than 24 hr and is unlikely to play a significant role in the use of nitroglycerine as an emergency therapy for congestive heart failure in dogs.22 Lastly, because preload reduction may lead to elevations in blood urea nitrogen and creatinine it would have been ideal if these values had been rechecked in the dogs of this study after IV-NTG was administered.
Conclusion
As a result of the severity of clinical signs in these three dogs, more aggressive preload and afterload reduction was considered necessary, but nitroprusside was prohibitively expensive for the owners. Based on the available experimental data, IV-NTG was considered an appropriate alternative. The dose of IV-NTG selected was based on previous experimental studies where the doses ranged from 0.3 to 40 mcg/kg/min.17,18 IV-NTG infusion was initiated at a low dose of 1 mcg/kg/min and titrated up by the attending clinician based on the patient’s clinical status. No clinically significant adverse events attributed to IV-NTG were noted in these cases, and the respiratory status of all patients improved during nitroglycerin administration. Additional studies are needed to fully evaluate the clinical efficacy and safety of intravenous therapy with nitroglycerine in dogs.
Contributor Notes
CRI (constant rate infusion); FiO2 (inspired oxygen fraction); HR (heart rate); LA:Ao (ratio of the left atrial dimension to the aortic annulus dimension); IV-NTG (intravenous nitroglycerin); MSU (Michigan State University); SpO2 (peripheral capillary oxygen saturation); RE (respiratory effort); RI (reference interval); RR (respiratory rate); VMC (Veterinary Medical Center)
