„Slow Kill” – adulticide protocol in heartworm treatment! Can we use it? When to use it? How to use it?

13549281_10207110414020766_1752592814_oTodor Kalinov DVM

 

veterinary clinic “Vitalis”, Plovdiv, Bulgaria

drkalinov80@gmail.com

 

 

 

Heartworm disease is caused by Dirofilaria immitis. The disease is widely distributed throughout Europe. Species susceptible to infection are dogs, wolves, foxes, coyotes, cats, ferrets, muskrats, sea lions, and humans. The parasite is transmitted by over 70 species of mosquitoes.

Adult heartworms reside in pulmonary arteries and in cases of severe infections in the right ventricle. Mature female parasites produce microfilariae and release them into the circulation. The feeding female mosquitoes ingest these microfilariae, and they undergo two molts, L1 – L2 – L3, over an 8 to 17 dаy period. This process is temperature-dependent (at least 18 C are needed). The L3 are infective and are transmitted by the mosquito to the hosts. In the subcutaneous, adipose, and skeletal muscle tissue L3 molt to L4 for 1 to 12 days and L4 molts to S5 – immature adults, for 2 to 3 months. The Immature adults enter the vascular system, migrating to the heart and lungs, where final maturation and mating occur. Under optimal conditions, completion of the life cyclе takes 184 to 210 days.

The adult worms cause the following through mechanical, immune-induced, and through toxic substances: inflammation and proliferation of the pulmonary arteries, pulmonary thromboembolism, pulmonary hypertension, and right-sided heart failure. Clinical signs of the disease are weight loss, exercise intolerance, lethargy, poor condition, cough, dyspnea, syncope, abdominal distention.1

According to the guidelines of the American Heartworm Society2 treatment of the heartworm infection consists of doxycycline 10 mg/kg BID for 28 days, monthly use of macrocyclic lactones, and melarsomine at days 60, 90 and 91.

In other publication3, the authors suggest administration of melarsomine on day 30 , 60 and 61, to make the protocol shorter, and to better comply with the owner’s financial resources.

 

In certain circumstances, melarsomine dihydrochloride could be contraindicated, unavailable, or not affordable to the owners. In this situation the practicing veterinarian could use the so-called “Slow kill” or “Soft kill” protocol.  It consists of the use of macrocyclic lactones in prophylactic doses with and withоut doxycycline to kill adult heartworms4–6. In most of the studies, the results are not satisfactory. L. Venco et al.6 used ivermectin – 6mcg/kg, monthly and had 100% microfilaricidal efficiency after 7 months, and 71% adulticidal efficiency after 24 months. The authors do not recommend this treatment regime in patient with clinical, radiographic or echocardiographic signs. G. Grandi et al.4 used doxycycline – 10 mg/kg/sid for 30 days and ivermectin-pyrantel – 6mcg/kg-14mg/kg every 15 days. By day 90 one hundred percent of the dogs became negative for microfilariae, and 72.7% became antigen-negative by day 300.

The study of Savadelis et al.7from 2017 had results similar to melarsomine treatment for a relatively short period of time. They used topical moxidectin 2.5%+imidacloprid 10% monthly with combination of doxycycline 10mg/kg/bid for 30 days. All treated dogs became negative for microfilariae at day 21. Ten months after the beginning the adulticidal efficacy was 95.6%. Hence, the conclusion of the authors is that this treatment regimen is a relatively quick, reliable and safe option to treat canine heartworm infection as compared to other treatment regimens involving macrocyclic lactones, when the approved drug melarsomine dihydrochloride is unavailable, contraindicated or declined by an owner unable to afford the more costly treatment or concerned about the potential side effects”.

I used this protocol numeral times with very good results. Most of the dogs were with class 4 heartworm disease and caval syndrome. Probably the most severe case was a 10-year-old Bulgarian shepherd dog. At presentation, the dog was cachectic, could not walk, did not eat for several days, and had ascites. Blood work revealed slight leukocytosis, neutrophilia, and thrombocytopenia, slightly increase in ALAT, ASAT, BUN, decrease in albumin, and the test for HW antigens was positive. Echocardiographic examination revealed severely dilated right atrium and right ventricle, with heartworms in the tricuspid valve region(video 1).

photo2

photo 2

The left atrium and ventricle were collapsed due to severe pulmonary hypertension. Of course, in this situation surgical extraction of the worms is the first choise8, but this option was declined by the owners. So we started treatment with doxycycline 10 mg/kg/sid, moxidectin+imidacloprid topically, and sildenafil 1mg/kg/bid. Several days after the start of the treatment the dog was in better condition, and on the echocardiographic examination we found that the left ventricle is relatively dilated, compared with the previous exam, the number of worms in the tricuspid valve region was subjectively lower. However, on m-mode, the systolic motions of Interventricular septum and left ventricular free wall was weak(photo 2). Therefore we suggested that the dog has subclinical dilated cardiomyopathy, which contributed to the development of the caval syndrome. We added pimobendane – 0.25mg/kg/bid and benazepril – 0.5 mg/kg/bid and prednisolone – 0.5mg/kg/sid to the therapy for thromboembolism prophylactic. On the next control examination, the dog was feeling better, there were no heartworms in the right atrium and ventricle and in the pulmonary artery(photo 3,4).

photo4

photo 4

photo3

photo 3

photo 5

photo 5

After a month from the diagnosis we stopped the doxycycline and continued with other pimobendane, benazepril, topical moxidectin+imidacloprid, sildenafil, and prednisolone – 0.5 mg/kg/48h. After two more months we gradually stopped the prednisolone. Six months after diagnosis the antigen test for heartworms was negative. The dog still had severe pulmonary hypertension, exercise intolerance and coughed occasionally. We continued treatment with pimobendane, benazepril and sildenafil and monthly moxidectin+imidacloprid for heartworms prophylactic. The dog lived for two more years and died from noncardiogenic reasons. I have similar results with two other large-breed dogs, also with caval syndrome, with complete resolution of clinical signs and withdrawal of all drugs, only continuing with moxidectin+imidacloprid for heartworm prophylactic. A small-bred dog developed severe pulmonary hypertension and tricuspid valve granuloma after the third month probably due to damages of the tricuspid valve from heartworms(photo 5), and untreatable right-side heart failure. Soon after the dog was euthanized.

The “slow kill” protocol is arguably more suitable for large and giant breed dogs, where the surgical extraction is more challenging, and the treatment with melarsomine is more expensive. In caval syndrome, the worms could be moved back in the pulmonary artery with a combination of pimobendane and sildenafil. Sildenafil is a phosphodiesterase 5 inhibitor, and pimobendane is a phosphodiesterase 3 inhibitor. The combination leads to more profound reduction in pulmonary artery pressure. The pimobendane has positive inotropic effect, hence the combination of improved myocardial function and lower pulmonary artery pressure helps in movement of the heartworms from right heart in pulmonary artery9(photo 6, 7 – before and after administration of pimobendane and sildenafil).

photo 6

photo 6

photo 7

photo 7

In small and medium dog breeds the surgical extraction, when possible, is the best choice, however, do not exclude the use of macrocyclic lactones and melarsomine.

In conclusion, when we treat a dog with dirofilariosis, we should first rely on the American heartworm society guidelines2. When we decide to use the Slow kill protocol, the macrocyclic lactone of choice is topical moxidectin. It has a unique pharmacokinetic, establishing a peak several days after application, long half-life about 28 days, and steady-state levels after four monthly applications, ensuring constant and high exposure of the parasites to the drug10,11. Of course doxycycline is also mandatory for adulticide therapy. Last but not least, we always have to think of the patient, we have to treat the patient rather than the disease, and to ensure good quality of life to them.

Rupture of the atrial septum in dog with degenerative mitral valve disease

13549281_10207110414020766_1752592814_o

Dr Todor Kalinov

Dr Todor Kalinov

ZaraVet- city of Plovdiv, Bulgaria

Introduction

Degenerative mitral valve disease (DMVD) is the most common cardiologic disorder in canine population. It has been estimated to account for 75% to 80% of canine cardiac disease1. It is common in small breed dogs, but also can be encountered in large breeds like german shepherd and other . The disease characterizes with thickening and enlarging of the mitral leaflets, elongation of chrdae tendineae and mitral regurgitation. Histopathologic  features are expansion of extracellular matrix with glycosaminoglycans and proteoglycans; valvular interstitial cell alteration; and attenuation or loss of the collagen-laden fibrosa layer2. Because of the mitral regurgitation the usual course of this disorder represents volume overloud of the left atrium and left ventricle , eccentric hypertrophy of the left ventricle , dilation of the left atrium ,and  left sided congestive heart failure . Increased pressure in left atrium and pulmonary veins leads to pulmonary edema . Often complication is so called passive pulmonary hypertension , consequence of increased pressure in pulmonary veins. Really rare complication is left atrial rupture .

 

Case presentation

fig 1

Fig. 1

fig 3

Fig.3

fig 2

Fig.2

Richka is 12 years old mixed breed dog with history of DMVD , threated only with enalapril . She was admitted in our clinic for cardiologic examination, because recently increasing in coughing and exercise intolerance. During the examination she was tachypneic , normal mucous membrane color , alert and responsive .She had increased heart rate. Auscultation revealed right and left apex systolic heart murmurs. The abdomen was swollen with palpable fluid thrill. We have made echocardiographic examination, with the patient on left and right lateral recumbency, with all parasternal views according to the accepted standards. We found eccentric hypertrophy of the left and right ventricles, left and right atrial dilation, thickening and prolapse of the mitral valve. Doppler examination shows mitral and tricuspid regurgitation with pressure gradient of 162 mmHg and 62 mmHg respectively (figures 1,2,3) . Abdominal echography revealed ascites. So we diagnosed degenerative mitral valve disease with secondary pulmonary hypertension. We prescribed following: pimobendan – 0.25 mg/kg/bid , furozemid – 4.0 mg/kg/bid , spironolactone – 1.0 mg/kg bid enalapril – 0.5 mg/kg/bid , sildenafil – 1.0 mg/kg/tid.

Week later on control examination Richka was better, ascites resolved , mitral and tricuspid regurgitation was with gradient 125 mmHg and 43 mmHg respectively. So we decreased the dose of furosemide to 2.0 mg/kg/bid, and the other drugs were continued with the same doses.

fig 4

Fig 4

fig 5

Fig 5

fig6

Fig 6

fig 7

Fig 7

fig 8

Fig 8

Several months later the owners noticed again swelling of the abdomen and the dog collapsed after exercise. When they came in the clinic Richka was tachypneic with cyanotic mucous membrane. On auscultation we have found 5/6 systolic murmur on the right haemithorax with palpable precordial thrill. Electrocardiography revealed sinus tachycardia – 156 bpm , with premature supraventricular and multifocal ventricular complexes (fig 4). We have made roentgenography in right lateral (fig 5) and dorsoventral (fig 6) position. There was generalized cardiomegaly with dilation of the pulmonary vessels. On echocardiographic examination we have found eccentric hypertrophy of the left and right ventricles, paradoxical motion of the ventricular septum (fig 7), mitral and tricuspid regurgitation with gradient – 118 mmHg and 42 mmHg respectively. Abdominal ultrasonography showed ascites with no collapse of the caudal vena cava with respiration (fig 8). Despite the medications and lower then before pulmonary pressure in this dog the signs of right heart failure were predominant. Because of that and the palpable precordial thrill on the right side we suggested right to left intracardiac shunt. The presence of ventricular septal rupture is less possible, so we decide to search for rupture of the atrial septum. On the right parasternal 4 chambers view modified for better visualization of the right and left atrium with atrial septum, we have found rupture of the septum in the region of the fossa ovalis with left to right shunt.

 

 

 

Video 1 and 2 are same loops with and without colour Doppler demonstrating the defect and shunt of the blood. In this region very often because of the echo dropout on 2d image can be seen a hole in the atrial septum. To be sure that this is a real defect we decided to make a bubble contrast study. We injected 10 ml of agitated saline in v.cephalica antebrachii thru i.v. catheter.  When there is right to left shunt the microbubbles are seen in left atrim, left ventricle or arterial circulation – usually the abdominal aorta. But in left to right shunt the goal of the bubble study is to notice contrast washout during right atrium passing of the bubbles. Video 3 and 4 show right parasternal short axis view of the base of the heart with cranial vena cava. We can see the entrance of the contrast and the following washout like a flame because of the left to right shunting of the blood.

 

 

In this situation sildenafil makes the pulmonary pressure lower and facilitate the shunt from high pressure left atrium to low pressure right atrium. So we decided to use pulmonary hypertension properly and make the dose of sildenafil lower – 1 mg/kg/24 h. with presumption that higher right ventricle and right atrium pressure will make the amount of the shunt lower. 72 hours after this change the ascites resolves and the condition of the dog became better. On the time of the written of the article Richka is about half year on this medications with sildenafil once per day and no changes in other medications and the only clinical sign is exercise intolerance.

 Discussion

Rupture of the atrial septum is really rare complication of mitral valve disease. Most commonly the rupture occurs in caudal weaker part of atrial wall. In a study of Buchanan JW from 30 dogs only in 4 was found rupture of the interatrial septum with signs of right heart failure3. In another study from the same investigator from 50 dogs 7 have acquired ASD4. The еtiology for rupture of the left atrium is uncleаr , but probably is related with the high pressure in the left and right atrium and the so called jet lesions from the mitral and tricuspid regurgitation. Usually the mitral regurgitation jet is toward lateral wall of the left atrium like in this case (video 5). Tricuspid regurgitation jet was directed to interatrial septum so probably contributed to rupture of the septum. The thin fossa ovalis is weak and suitable place for this kind of lesions. In human medicin rupture of the septum is reported after blunt chest trauma , most often accompanied with rupture of the tricuspid valves 5,6. The proposed reason is that compressivе force occurred during isovolumic contractiоn with maximally dilated ventricles and closed atrioventricular valves5. In humans  right ventriсle is right behind the sternum , and this predispоse it to injury. In those cаses when there is rupture of the tricuspid valve and massive regurgitation , the increased pressure in right atrium leads to rupture of the septum and right to left shunt. In canine patients with degenerative mitral valve disease after the rupture of caudal atrial wall and following haemopericardium the clinical signs are collapse and sudden death. After rupture of the atrial septum the predominant signs are of right heart failure. In this case the right atrium and ventricle serves as a low pressure “sink” for severely dilated left atrium.

There are several publications about echocardiographic diagnosis of acquired atrial septal defect and rupture of the atrial septum with haemopericardium3,4. The bubble contrast study has been validated in veterinary echocardiography for diagnosis of congenital and acquired intra and extra cardiac defect and shunt7,8. In this case we have demonstrated the usefulness of so called contras washout – result of bubbles free blood entering contrast rich compartment.

In conclusion in any dog with degenerative mitral valve disease and predominated signs of right heart failure we have to look echocardiographically for atrial septal rupture. More we scan , more we find , and more we learn.

 

Patent Ductus Arteriosus in adult dog

 

13549281_10207110414020766_1752592814_o

Todor Kalinov, DVM, Zaravet veterinary clinic

Todor Kalinov, DVM, Zaravet veterinary clinic, city of Plovdiv, Bulgaria, e-mail drkalinov80@gmiail.com

INTRODUCTION

 

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Fig 2

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Fig 1

Patent Ductus Arteriosus(PDA) is one of the most frequently encountered congenital heart disease in dogs , ranging in prevalence from about 25 to 32 % from reported malformations 1 , and lest frequently in cats – about 11 % .  The ductus arteriosus is normal foetal structure  that  shunts blood from  pulmonary artery to aorta 2. Before the birth , it divers approximately 80 to 90 % of the right ventricular output back to the left side of the circulation. After parturition and the onset of breathing , pulmonary vascular resistance falls, flow in the ductus reverses , and the resulting rise in arterial oxygen tension inhibits local prostaglandin release causing constriction of the vascular smooth muscle within the vessel wall and functional closure of  the ductus arteriosus3.

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Fig 4

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Fig 3

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Fig 6

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Fig 7

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Fig 5

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Fig 8

The ductal wall usually contains a loose branching pattern of circumferential smooth muscle in normal pups. The increasing genetic liability to PDA represents extension of the noncontractile wall structure of the aorta to an increasing segment of the ductus arteriosus, progressively impairing its capacity to undergo physiologic closure1.

In typical cases because of the lower pressure in pulmonary circulation there is continuous flow thru the ductus arteriosus from aorta to pulmonary artery. Clinical impact from this is volume overload of the structures in the shunt pathway : the main pulmonary artery, lungs, left atrium, left ventricle, and back to the ascending aorta up to the level of the ductus4. In that shunt direction the dogs show signs of left-sided congestive heart failure – exercise intolerance, coughing, eventually pulmonary edema. In rare instances when the ductus still wide after birth, the flow is really enormous and this leads to increase in pulmonary vascular resistance and change in direction of the shunt, so-called Eisenmengers physiology and reversed PDA . This pattern of pulmonary hypertension and reversed (right to left) shunting usually develops within the first few weeks of life3. Clinical signs in reversed PDA are shortness of breath, differential cyanosis – pink mucous membranes in cranial part of the body and cyanosis in caudal membranes, polycythemia , pelvic limb weakness, collapse, and seizures. The changes in pulmonary vasculature are irreversible and closure of the PDA is not suggested.

Many dogs with left to right PDA do not show any clinical signs, but if left heart failure has developed in first year of life, up to 65 % would die if left untreated. In most of the dogs clinical signs are apparent before the third year of age. The appearance of signs in older dogs is unusual2.

 

CASE PRESENTATION

 

Buky was 7 years old springer spaniel admitted in our clinic with severe respiratory distress. He had history of heart murmur noted on routine examination , several episodes with increasing respiratory rate, and one presyncopal event with rear limb weakness. All clinical signs were apparent past several months.

The dog breathed with open mouth, mucus membranes were cyanotic , respiration rate increased, and on auscultation we have founded continued heart murmur, and crackles on the both side of the thorax. On the X-ray there was severe generalized cardiomegaly, pulmonary overcirculation with dilation if the pulmonary arteries and veins, interstitial to alveolar lung pattern (Figure 1 – L/L projection, Figure 2 – D/V projection). We have applied initial therapy for congestive heart failure with:

Furozemide – 4mg/kg/hour i.v.

Pimobendan – 0.25mg/kg p.os.

Enalapri – 0.5mg/kg p.os.

Sodium nitroprusside – i.v.  constant rate infusion

Oxygen – via mask .

After several hours there was a reduction in respiratory rate, and efforts and an ECG and echocardiography were made.

ECG findings :

Sinus tachycardia – 163 bpm

Wide and tall P wave – suggestive of left atrium enlargement

Tall R wave – suggestive of left ventricular enlargement (Figure 8)

Atrial premature complexes (Figure 3)

Ventricular  premature complexes(VPC) with origin in left ventricle (Figure 4)

Fusion beats – intermediate morphology between normal complexes and VPC (Figures 5, 6, 7).

 

ECHOCARDIOGRAPHY

 

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Fig 9

11 (1)

Fig 11

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Fig 10

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Fig 12

We have made echocardiography at left and right lateral recumbency of the patient with all parasternal  views according to accepted standards. From the exam we have found severe left heart volume overloud with eccentric hypertrophy of the left ventricle. Left atrium was dilated with rightward excursion of the atrial septum. Left ventricle was dilated with thin free wall and interventricular septum, dooming of the septum to the right ventricle, and reduced systolic motion of the free wall and the septum (video 1).

 

 

 

Left atrium and aorta  was measured on right parasternal short axis view at the heart base and the ratio LA/AO was estimated with results showing at Figure 11. Normal LA/AO ratio have to be < 1,6. Main pulmonary artery was dilated compared to aortic root (video 2)

 

, and blowing of the pulmonary valve was noted (Figure 12).

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Fig 14

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Fig 13

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Fig 15

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Fig 16

On Color Doppler exam there was mild mitral regurgitation with central jet , probably because the dilation of the mitral annulus (Figure 13), and in pulmonary artery was noted typical for PDA continuous flow (video 3).

 

 

With  CW Doppler the aortic flow velocity was measured 2,19 m/s , with normal speed les then 2.0 m/s. In pulmonary artery CW Doppler show typical continuous bidirectional flow (Figure 14).

On the  basis of this findings the dog was diagnosed with Patent Ductus Arteriousus with left to right shunt. Because of the dramatic structural and functional changes in heart, the already developed left heart failure and increased anesthetic risks the owners refused surgical ligation of the ductus. At the time of the diagnosis in our country we did not have the chance for transcatheter coil embolisation. So the only opportunity was to treat congestive heart failure with medications. We have prescribed :

Pimobendan – 0.25 mg/kg/12 h. p.os

Enalapril – 0.5 mg/kg/12 h. p.os

Furozemid – 1.0 mg/kg/12 h. p.os

Spironolacton  – 1.0 mg/kg/12 h. p.os

Supplements with L carnitine, taurine, and coenzyme q10.

The dog was very well after the beginning of the therapy and had only exercise intolerance. After about 1 year he had improvement in some echocardiographyc parameters of systolic function – normal fractional shortening, normal pre ejection period, normal ejection time, but the left atrium was bigger then year ago (Figures 15, 16, 17).

 

 

 

Video 4 – right parasternal  four and five chamber view year after diagnosis ,

 

 

 

 

 

 

video 5 – modified left parasternal short axis view of heart base with color Doppler of the pulmonary artery showing continuous flow with small turbulent jet in opposite direction.

COMMENTS

 

The treatments for Patent Ductus Arteriosus are surgical ligation or transcatheter device closure. Because of the technical factors and price in our country no one does make device closure but in many clinics surgical procedure can be done with great success. In this case the owners decline surgery, but mine opinion is also that the dog was not appropriate candidate for operation. Despite the fact that in most cases there is dramatic improvement in clinical status and cardiac function after surgical closure, the age ,the already developed  heart failure, and concurrent heart disease, affect negatively survival period after PDA closure5. In adult dogs one of the major surgical complications is haemorrhage due to ductus friability2. Mitral valve endocardiosis is also an important factor affecting the survival period. On video 1 and 4 we can see the slight thickening and prolapsed mitral valve leaflets, so I supposed that the dog had degeneration of the mitral valve. Conduction instability of the heart is another reason for anesthetic complications. Actually the dog has died suddenly during routine walk without any other signs, about two years after the diagnosis,  so malignant arrhythmia can be the reason. Despite this facts in most of the literature, the authors suggest closure of the PDA, even in adult dogs, only important contraindication for not closing is right to left shunt.

CONCLUSION

It is not known why some animals with PDA do not show any signs until adulthood. One of the reasons could be the small diameter of the ductus. In human medicine the maintenance of normal pulmonary vascular resistance is important factor for survival of the older patients2. It is certain that the adult dogs with congenital heart diseases are more then we expect, and always  when we examine adult animal for some heart disease, we have to think not only for degenerative valve disease and cardiomyopathies but also for congenital and inherited problems. And of course rare things do happen everyday.