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Issue Eightly One – July 2014
standards of
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CLINICAL CASE MANAGEMENT NEWSLETTER
The Calgary Animal Referral & Emergency Centre Animal Hospital
standards of
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Issue Eightly One – July 2014
Pulmonary Artery Hypertension
Dr. Lisa Shearer BSc., DVM, DACVIM (SAIM), DVSc.
Definition and Pathophysiology
Pulmonary artery hypertension (PAH) is uncommonly a primary/idiopathic disorder or more
frequently a complication/consequence of a variety of common diseases occurring in small
animal veterinary patients. Due to the wide variation in clinical presentation of PAH and the
frequent need for referral for availability of specialized equipment for diagnosis, it is often
underdiagnosed or diagnosed late in the progression of the disease. Early diagnosis and
appropriate therapy may lead to improvement in prognosis.
Normal pulmonary vasculature is comprised of a network of low pressure, low resistance but
high capacitance blood vessels. Blood from the right ventricle drains into the pulmonary
artery, subsequently into the pulmonary capillary bed and then drains into the pulmonary
veins to return oxygenated blood to the left atrium. The normal pressures in the pulmonary
artery are approximately as follows: systolic 18-25mmHg; mean 10-15mmHg; and diastolic
6-10mmHg. The pressure within the pulmonary system is affected by the pulmonary venous
pressure, right ventricular output and pulmonary arterial resistance. In general, PAH can be
further classified arbitrarily based on the severity of systolic pulmonary arterial pressures as mild
(30-50mmHg), moderate (51-75mmHg) or marked (>75mmHg). PAH arises due to vascular
changes such as imbalances between pulmonary arterial vasodilators and vasoconstrictors
(favoring vasoconstriction), smooth muscle and endothelial proliferation and thrombosis.
Clinical Presentation for PAH
The signalment for patients with PAH is highly variable as it can be seen in any age, breed or
sex of dog or cat. In light of the propensity for Terrier breeds to develop primary pulmonary
disease, these breeds may be overrepresented. Clinical signs observed by the owners can
also be highly variable ranging from no specific observations to severe clinical signs. Dogs
with mild-moderate PAH often do not show clinical signs. Dependent on the underlying
etiology for development of PAH, the onset of clinical signs can be acute (e.g. with
pulmonary thromboembolic events) or more chronic (e.g. with chronic lung pathology).
Clinical signs that can be noted (also may be difficult to differentiate from the primary
pulmonary pathology) include lethargy/exercise intolerance, dyspnea/tachypnea, cough,
syncope and ascites (if right sided heart failure present). Physical examination features would
include a cardiac murmur most associated with mitral and/or tricuspid valve insufficiency,
splitting of the second heart sound (due to delayed pulmonic valve closure associated with
moderate-severe PAH), pulmonary crackles/wheezes and occasionally cyanosis. Clinical
and physical examination findings will also be dependent on the underlying pathology
resulting in the PAH.
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Classification of PAH
The World Health Organization (WHO) outlined classification of PAH in humans in 2003. Similar
classifications apply to our small animal patients and therefore PAH in small animals can be
categorized into 5 groups based on underlying etiology:
1. Pulmonary Arterial Hypertension (e.g. idiopathic/primary/familial, congenital systemicto-pulmonary shunts, etc.)
2. Pulmonary Venous Hypertension – PAH associated with left heart disease (e.g. mitral
valve disease, myocardial disease, other)
3. PAH associated with chronic alveolar hypoxia (e.g. chronic small airway disease,
pulmonary fibrosis, neoplasia, chronic pneumonia, tracheobronchial diesease, high altitude
disease, etc.)
4. PAH caused by thromboembolic disease (e.g. heartworm disease or secondary to
another underlying disease associated with hypercoagulability such as IMHA, neoplasia,
heart disease, hyperadrenocorticism, DIC, sepsis, etc.)
5. Miscellaneous (e.g. compressive mass lesions, etc.)
Diagnosis
Although no specific laboratory findings are diagnostic for PAH, a minimum database is
recommended. Complete blood count may reveal a stress leukogram or increased numbers
of nucleated RBCs/polycythemia as an indicator of chronic hypoxia. Serum biochemical
profile results are often non-specific but may be an indicator of other underlying diseases.
Similarly, urinalysis findings are often non-specific. A coagulation panel is also recommended.
The presence of increased fibrin-degradation products (FDPs) or D-dimers may be seen.
Potentially more importantly, due to the high negative predictive value of these tests, a
negative FDP or D-dimer measurement makes thromboembolic disease highly unlikely.
Other ancillary non-specific testing of benefit would include arterial blood gas analysis, a
heartworm test (if travel history is supportive) and thoracic radiographs (may be normal with
acute pulmonary thromboembolism or may reveal evidence of the underlying etiology).
For a definitive diagnosis of PAH, invasive cardiac catheterization of the right heart and
pulmonary artery is considered the gold standard. However, in light of the cost of this
procedure, need for specialized training/equipment, the often-unstable condition of the
patient (given the need for anesthesia), this procedure is rarely performed in veterinary
medicine. In lieu of cardiac catheterization, echocardiography has become a widely used
modality for the diagnosis of PAH given it’s reasonable affordability and noninvasive nature.
To diagnose PAH, the speed of the regurgitant signal across the tricuspid valve in systole
or, the pulmonic value in diastole is measured. This then allows derivation of an estimate
of the pulmonary artery pressure in systole and diastole, respectively by the conversion of
this speed to a pressure gradient across the valve in question using the modified Bernoulli
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equation (pressure gradient = 4V2). If known, the right atrial pressure is then added to this
value to yield the most accurate prediction of the pulmonary artery pressure (right atrial
pressure is not often measured in small animals and is instead approximated at 5mmHg). A
diagnosis of PAH via echocardiography relies both on patient co-operation and skill of the
operator and it must be acknowledged that the pulmonary artery pressure determined is
always an underestimation of the true value. Other cardiac changes (e.g. right ventricular
free wall and interventricular septal thickening secondary to pressure overload, dilation of
the main pulmonary artery and paradoxic motion of the interventricular septum) may also
be seen.
Once PAH is diagnosed, further evaluation to determine the underlying etiology for
development of this complication is recommended and may include other advanced
procedures such as bronchoscopy, bronchoalveolar lavage/bronchial brushing, nuclear
scintigraphy, pulmonary biopsy, etc.
Treatment
Prevention is worth a pound of cure! Early detection and management of conditions that
are known to possibly lead to PAH is the most effective approach. In some cases, if the
underlying cause and the PAH are detected early, then reversal of the PAH may be possible.
In cases presenting in distress with decompensated PAH, oxygen therapy should be provided
irrespective of the underlying etiology as oxygen is a pulmonary arterial vasodilator.
PAH is a multifactorial disorder. Therefore therapy has two primary goals. Firstly, treatment
should be aimed at treatment/reversal of the underlying cause if possible. This is obviously
dependent on the diagnosis but may include therapies such as surgical correction of
congenital vascular anomalies (e.g. left-to-right PDA), treatment of congestive left sided
heart failure, treatment of thromboembolic disease (both the inciting cause and prevention
of further thrombus formation), specific therapy for heartworm disease and specific therapy
for various pulmonary conditions (e.g. anti-inflammatories, antibiotics, bronchodilators,
other).
The second goal of treatment for PAH (if severe) is specific therapy to target the complication
of pulmonary hypertension directly. In humans a variety of different therapies for PAH have
been attempted; however, in dogs, the only therapy evaluated for specific treatment of
PAH is sildenafil. Sildenafil (Viagra), is a highly selective phosphodiesterase type V inhibitor.
It results in pulmonary vasodilation by increasing pulmonary vascular concentrations of
cGMP which ultimately increases the activity of endogenous nitric oxide. Treatment with
sildenafil appears to be well tolerated in dogs and although normalization of the pulmonary
artery pressure in cases with severe PAH is not achieved, owner perception of quality of
life is reportedly improved. The major downside to this therapy is its expense. Pimobendan
(Vetmedin), is a phosphodiesterase III inhibitor leading to increases in both cAMP and cGMP
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concentrations, increased activity of nitric oxide and subsequent pulmonary vasodilation.
This medication in severe cases can be used in conjunction with sildenafil; however, it is
important to exclude conditions that would be contraindications to pimobendan therapy
prior to initiation of therapy. Other therapies that have been attempted in humans include
calcium channel blockers (only effective in 10% of humans and not believed to be of use in
small animals), prostacyclin analgues (very expensive and not currently used in veterinary
patients), endothelin receptor antagonists such as Bosetan (very expensive and not widely
available). Lastly, owners should be instructed to limit stress and strenuous exercise.
Prognosis
Monitoring of patients receiving therapy for PAH involves serial echocardiograms to evaluate
for any reduction achieved in the pulmonary artery pressure. Trending of systemic blood
pressure should also be performed to avoid hypotension in patients receiving vasodilators.
If pulmonary parenchymal disease is documented, then serial thoracic radiographs may be
warranted to help evaluate response to therapy..
Prognosis for patients with PAH is likely dependent on three factors: (1) the severity of the PAH;
and (2) the primary etiology and it’s reversibility; and (3) the chronicity (e.g. have structural
changes to the heart already occurred). Kellum and Stepien (JVIM 2007) retrospectively
evaluated a group of 22 dogs with PAH treated with sildenafil. This study documented survival
times in the range of 8 to 734 days and that if the dog survived the first week of therapy,
then there was a 95% probability of surviving to 3 months, 84% for 6 months and 73% for 1
year after initiation of therapy. However, it should be noted that this study documented no
significant reduction in the pulmonary artery pressures but rather, a perceived improvement
in quality of life and clinical condition were noted. As such, it appears that treatment with
sildenafil has a positive effect on the survival and clinical condition of dogs with PAH.
References
1. Pulmonary Hypertension and Pulmonary Thromboembolism. In: Textbook of Veterinary Internal Medicine: diseases of
the dog and cat (7th edition). Ettinger SJ, Feldman ED (eds). Saunders, St. Louis, 2010.
2. Kellum HB, Stepien RL: Sildenafil citrate therapy in 22 dogs with pulmonary hypertension. J Vet Intern Med, 2007;21:12581264.
3. Johnson L, Boon J, Orton EC: Clinical characteristics of 53 dogs with Doppler-derived evidence of pulmonary
hypertension: 1992-1996. J Vet Intern Med 1999;13:440-447.
4. Bach JF, Rozanski EA, MacGregor J, et al: Retrospective evaluation of sildenafil citrate as a therapy for pulmonary
hypertension in dogs. J Vet Intern Med 2006;20:1132-1135.
5. Glaus TM, Soldati G, Maurer R, Ehrensperger F: Clinical and pathological characterisation of primary pulmonary
hypertension in a dog. Vet Rec 2004;154:786-789.
6. Glaus TM, Hassig M, Baumgartner C, Reusch CE: Pulmonary hypertension induced in dogs by hypoxia at different
high-altitude levels. Vet Res Commun 2003;27:661-670.
7. Simonneau G, Galie N, Rubin LJ, et al: Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:5S-12S.
8. Nelson OL, Andreasen C: The utility of plasma D-dimer to identify thromboembolic disease in dogs. J Vet Intern Med
2003;17:830-834.
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