Hypertension in Renal Diseases and Failure. The Practical Aspect
WSAVA 2002 Congress
Dr. Claudio Brovida
ANUBI Companion Animal Hospital
Moncalieri, Italy

Introduction

Hypertension may be defined as a chronic increasing of systolic and diastolic blood pressure. Systemic blood pressure is proportional to both cardiac output and total peripheral resistance, while physiological control depends on the renin-angiotensin system, aldosterone, prostaglandin, adrenergic and neurogenic factors. Moreover, many factors may interfere with blood pressure measurement values (such as age, sex, breed, behavior or environment and in particular, the system and place of measurement.) It is generally assumed that an animal is hypertensive when systolic/diastolic evaluation exceeds 180/100 mm Hg.

Hypertension may be primary (also defined as essential or idiopathic) due to multifactorial causes, including cardiac, neurological, renal, endocrine and metabolic aspects. Hypertension is defined as secondary when it occurs as a consequence of some underlying disease: renal problems or endocrine abnormalities (e.g., hyperthyroidism, hypothyroidism, hyperadrenocorticism, pheochromocytoma, and diabetes mellitus).

Pathogenesis

Systemic blood pressure is the product of cardiac output and total peripheral resistance. Heart rate and stroke volume define cardiac output, and stroke volume depends on the inotropic function of the myocardium and extracellular fluid volume.

In the early stages of hypertension, cardiac output is increased; in later stages, it returns to nearly normal values whereas total peripheral resistance becomes secondarily elevated. Therefore, an increased total peripheral resistance is secondary to hypertension rather being the cause of hypertension. An increased stroke volume may occur in hypervolemic situations, but it is usually a consequence of increased retention of NaCl. One of the principal causes of abnormal salt and water reabsorption by renal tubules is hyperaldosteronism. Primary hyperaldodosteronism is usually related to small tumors in the adrenal glands.

The other important and effective system, related to aldosterone mechanisms, which interacts with arterial pressure control, is the renin-angiotensin system. Angiotensin II has two main effects: vasoconstriction, which occurs rapidly, and reduction of salt and water excretion, both directly and also by increasing aldosterone secretion.

Primary hypertension

In humans, about 90-95% of individuals who have hypertension is affected by essential hypertension, which is of unknown origin. Mean arterial pressure and resistance to blood flow through the kidneys are increased while the renal blood flow is decreased. The patient becomes anuric if blood pressure is lowered to normal, and total peripheral resistance is increased to the same level as the increase in arterial pressure; cardiac output is usually normal. In dogs and cats, the same situation has not yet been demonstrated and, even if primary familiar hypertension has been studied by Bovee et al. (1989), usually it was associated with and a result of other underlying diseases.

Secondary hypertension

The kidney is the main organ involved in blood pressure control, so any damage to its structure may lead to an alteration of blood pressure mechanisms. Primary renal disease is the most common cause of hypertension in animals (Ross and Labato, 1989). Sixty per cent of dogs with interstitial or tubular renal disease and 80% of dogs with primary glomerular disease are reported to be hypertensive (Cowgill and Kallet 1983, 1986). Kobayashi et al.(1990), found that 61% of cats with chronic renal failure were also hypertensive.

Endocrine disorders are also associated with hypertension. In hyperadrenocorticism, the elevated blood level of glucocorticoids increases production of angiotensinogen in the liver and a consequent activation of the renin-angiotensin-aldosterone system. In addition, the synthesis of catecholamines is increased as well as the sensitivity of the cardiovascular system to them. The increased renal sodium reabsorption and secondary water retention produce volume expansion and, consequently, blood pressure elevation. Hyperthyroidism is quite common as a cause of hypertension in cats (Kobayashi et al. 1990). Thyroid hormones, triiodothyronine (T3) and thyroxin (T4), have a direct inotropic and chronotropic effect on the heart causing high cardiac output due to tachycardia and an increased stroke volume with consequent blood pressure increase.

Hypothyroidism can cause up to 50% of the incidence of hypertension resulting from decreased vascular compliance. However, in veterinary medicine, only one case has been actually reported in the literature (Ross, 1992).

Severe hypertension is present in about 50% of dogs with pheochromocytomas (Twedt andWheeler, 1984; Feldman and Nelson, 1987) which increase secretion of catecholamines by the chromaffin cells of the tumor.

Acromegaly, due to increased secretion of growth hormone (GH), usually produces increased levels of progestogens in the dog and pituitary neoplasia in the cat. Vascular alterations, associated with secondary diabetes mellitus and increased extracellular fluid volume, are at the basis of the hypertension.

Hyperparathyroidism may also be a cause of hypertension, considering the involvement of the parathyroid hormone in calcium metabolism, renin activity and sodium secretion as well as progressive renal disease.

Diabetes mellitus produces an incidence of hypertension of 40-80% in humans (Ross, 1992). The incidence in dogs and cats is not yet defined; however, renal and vascular lesions, associated with the disease, can lead to hypertension.

Other possibilities of secondary hypertension may be associated with iatrogenic causes due to the administration of estrogen, progestogen or corticosteroids.

Blood pressure measurement

Blood pressure may be evaluated through direct or indirect measurements. In direct measurement, a needle or a catheter is inserted into an artery (usually the dorsal metatarsal artery). The use of an indwelling catheter in the artery allows more comfortable management of direct blood pressure measurement as well as removal of multiple arterial blood samples if needed. To avoid stress and pain to the patient, a local anesthetic with 0.5 ml of 2% lidocaine is administered subcutaneously. Once the catheter ( 22 G ) has been inserted, a three way Luer lock stopcock is connected to the blood pressure transducer and a saline infusion line. The catheter should be cleaned with heparinized solution periodically. The disadvantages to this method are related to the cost of the equipment, the risk of hemorrage (particularly when using a large artery such as the femoral), infections and the lack of an easy and fast way to approach the catheter insertion into the artery.

A more practical and immediate method, particularly in an emergency situation, is the use of an indirect system of pressure measurement. Various non-invasive methods are available which are based on a transducer (ultrasonic, oscillometric or photoplethysmographic) which reads the movements of the arterial wall when constricted by a cuff. The cuff can be placed on the distal forelimbs (brachial or median artery), hindlimbs (cranial or tibial artery) as well as on the tail (medial coccygeal artery).

With the oscillometric method, oscillations in the cuff pressure are recorded when the pressure in the cuff approaches that of systolic blood pressure. The oscillations increase in amplitude when the cuff pressure approximates systolic pressure, increase additionally at mean arterial pressure and decline upon reaching diastolic pressure. The coefficients of correlation of systolic, diastolic and mean arterial pressure measurements between the direct and oscillometric systems have been demonstrated to be superior to 0.90 in the dog.

With the ultrasonic method, an ultrasonic high frequency (2-10MHz) beam is produced by a piezoelectric quartz crystal. The sound waves pass throughout the tissues producing echoes of different frequencies, which are detected by another crystal. The change of frequency in the reflecting wave when it hits a moving object is called the Doppler shift. In blood pressure measurement, detected echoes in the Doppler come from the red blood cells moving in the blood vessels. Evaluation of diastolic and mean arterial pressure may be more difficult with this method. However, in comparisons among the different methods of indirect blood pressure measurements in cats, the Doppler was the most efficient, accurate, sensitive, reproducible and least expensive method. Particular attention must be given to the cuff width, which should be only 40 per cent of the limb's circumference; a larger cuff will produce falsely low values and too small a cuff will give falsely high values . An animal that is anxious or uncooperative may result in blood pressure alterations, giving higher values during the reading. For this reason, multiple measurements are necessary to confirm reproducible results, usually five (Crowe, 1995).

Normal blood pressure values

Blood pressure values may vary when using the oscillometric and Doppler techniques. In an epidemiological study performed by Bodey and Michell (1996) where more than 2000 pressure measurements were taken from 1903 dogs with the oscillometric method, systolic pressure was determined to be the most variable pressure parameter. Moreover, it depended on age, breed, sex, temperament, disease state, exercise regime and, to a minor extent, diet. The results of that study also show that blood pressure increases with age in dogs.

On a population of 1782 dogs, the following mean values have been detected (Bodey and Michell, 1996):

 Systolic arterial pressure: 133.0 mmHg

 Diastolic arterial pressure: 75.5 mmHg

 Mean arterial pressure: 98.6 mmHg

 With the Doppler system, Remillard et al. (1991) detected normal values in the dog as follows:

 Systolic arterial pressure: 150 ± 16 mmHg

 Diastolic arterial pressure: 86 ± 13 mmHg

In unsedated cats, normal blood pressure has been reported with values less than 160/100 mmHg: 123/81.2 (mean of 96.8) mmHg and 118.4/83.8 mmHg (Edwars 1990; Kobayashi et al. 1990; Lesser et al. 1992; Littman 1990); a recent study made by Santilli et al. , with the use of Doppler technique, indicates a systolic value of 138,18±23,15 in the cat (2001).

Clinical findings and their management

Actually, it is still difficult to determine the early stages of hypertension, since this diagnostic procedure is not yet routinely performed. Clinical symptoms are usually related to an advanced stage of the disease.

Ocular findings with retinal hemorrhage and retinal detachments are the most common changes. Four steps have been described for grading the disease in people and have also been applied to dogs and cats (Clerc, LaForge, 1995):

 Grade I: not applicable to dogs

 Grade II: veins and arteries with irregular diameter; venulae are compressed by arteries when they cross each other

 Grade III: grade II plus hemorrhage, exudate, retinal detachment

 Grade IV: grade III plus optic nerve head edema.

Ocular lesions may regress with systemic treatment. Vascular damage, sclerosis, and glomerular damage characterize renal lesions associated withhypertension. PU/PD, low SG of the urine and proteinuria are signs indicating renal disease. Diagnostic imaging, in particular ultrasound, can help to define small kidneys, abnormal cortical or medullar structure. In particular, evaluation of the intrarenal Pourcelot resistive index, determined by duplex Doppler estimation from the arcuate arteries of the kidney (peak systolic shift-minimum diastolic shift) / peak systolic shift), may allow the detection of renal hypertension and can be, in some cases, an element for evaluating renal function ( Rivers et al. 1997).

Ultrasound guided kidney biopsy gives a precise method of evaluation of renal vessel status as well as other renal structures in that vascular and glomerular alterations are usually associated with hypertension Vascular damage can also lead to cerebral lesions; in dogs with hypothyroidism, neurological signs are mostly a consequence of atherosclerosis related to endocrine disturbance.

The left ventricle hypertrophy is a common cardiac finding in cases of hypertension associated with low grade mitral murmurs; pulmonary crackles or muffling of heart sounds may be secondary to heart failure with pulmonary edema or pleural effusion. Ventricular hypertrophy is a consequence of the increased afterload, which produces a symmetric increase of the thickness of the ventricle wall

On the basis of the above mentioned elements, the diagnostic approach to hypertension has to distinguish symptoms that indicate underlying diseases; repeated blood pressure measurements will confirm the presence of hypertension. Renal problems may be diagnosed evaluating the complete blood count, biochemical profile, urinalysis, uroculture, urine protein/creatinine; specific endocrinological test will help to distinguish underlying diabetes mellitus (serum glucose), hyperthyroidism (T3/T4, T3 suppression), hypothyroidism (TSH stimulation test), hyperadrenocorticism (urine cortisol/creatinine ratio, low- and high-dose dexamethasone suppression tests, ACTH assay), pheochromocytoma (Regitine blocking test, clonidine suppression test, plasma/urinary catecholamines/metanephrines), hyperaldosteronism (serum aldosterone assay).

Radiographies to the abdomen and chest can help to define masses, neoplasia, abnormal kidney size, hepatomegaly, ascites. Electrocardiogram and echocardiography may help to detect left ventricular hypertrophy. Electroencephalography, CT scan or MRI will eventually give detailed information about neurological causes involved in hypertension.

Hypertension therapy

Strategic plans in the treatment of hypertension must determine whether it is primary or secondary. Different classes of drugs are used to treat hypertension with various mechanisms of action (see Table II). In veterinary medicine, human protocols have been used to treat animal hypertension, with sequential use of different drugs if the blood arterial pressure is not lower at sequential controls, which are performed at 1-2 week intervals.

Recently, attention has been focused on drugs, which reduce glomerular capillary pressure, since not all antihypertensive drugs are efficacious in reducing the progression of renal disease. Drugs, which do not normalize glomerular capillary pressure, fail in protecting the kidney from glomerulosclerosis. Hydrazine and hydrochlorothiazide are examples of this problem. In fact, both stimulate the renin-angiotensin system and increase angiotensin II levels, which then results in an increase in glomerular efferent arteriolar tone. For this reason, high glomerular capillary pressure (hyperfiltration) is maintained in spite of reduced systemic arterial pressure.

The following different specific treatments may be applied in approaching the antihypertensive regimen.

Dietary restrictions: excess of dietary sodium intake results in extracellular fluid volume expansion, which is one of the factors contributing to hypertension. Most commercial foods contain high levels of sodium (up to 1% dry matter) and reduction of dietary sodium intake has been demonstrated to reduce arterial blood pressure in dogs with renal failure. Sodium intake should be restricted to 0.1% to 0.3% of the diet (10-40mg/kg of body weight) for dogs and 0.4% for cats (Cowgill et all. 1986). A hypocaloric diet may be the treatment of choice in the case of obesity, which may be a factor in the development of hypertension.

Diuretics: diuretic therapy acts by reducing extracellular fluid volume (decreasing blood volume and cardiac output) by inducing natriuresis (reduction of total peripheral resistance).Caution should be used to avoid dehydration and worsening of renal function. The serum potassium concentration should be checked periodically when using drugs such as furosemide, which may cause potassium depletion.

alpha 1, ß blockers: Alpha blockers act against the hypertensive effect of catecholamines, decreasing total peripheral resistance, and are more effective in case of pheochromocytoma; Beta blockers reduce cardiac output, heart rate, and renin release; propranolol is the most commonly administered beta-blocker to animals. It may be associated with decreases in renal plasma flow and glomerular filtration rate; however, other drugs of the same class, like atenolol do not produce these effects. Atenolol is particularly helpful in treating hypertension associated with hyperthyroidism in cats.

Calcium channel blockers: produce inhibitors of calcium transport through slow channels in smooth muscle cell membranes; consequences are arteriolar dilatation and reduction of cardiac output. Amlodipine seems to be very effective in cats (Henik, 1997).

Vasodilators: they acts directly on smooth muscle, decreasing total peripheral resistance; angiotensin converting enzyme (ACE) inhibitors are certainly the drugs in this class which are attracting the most attention because of their efficacy and safety. Basically, they act by suppressing the renin-angiotensin system; they block the vasoconstriction produced by angiotensin II and reduce the natriuresis by suppression of aldosterone secretion. The fact that ACE inhibitors also reduce glomerular hypertension indicates that they are the drugs of choice in hypertension associated with renal disease.

Table 2. Principal antihypertensive drugs (From Hernik, 1997)

Drug

Mechanism of Action

Dosage Dogs

Dosage Cats

Diuretics:

Chlorothiazide

Inhibition of Na+ reabsorption in distal collector ducts

20-40mg/kg q 12 h PO

Furosemide

Inhibition of Cl- reabsorption in the loop of Henle

0.5-2.2 mg/Kg

q 8-24 h PO

1-2mg/Kg q12-48h PO

Hydrochlorothiazide

Inhibition of Na+ reabsorption in early distal collector ducts

1-5 mg/Kg q12 h PO

2-4 mg/Kg q 12 h PO

Spironolactone

Aldosterone antagonist in late distal collector ducts, K+ sparing

2-4 mg/Kg q 24h PO

1-2 mg/Kg q 12 h PO

Triamterene

Inhibition of Na+ reabsorption in late distal collector ducts,

K+ sparing

1-2 mg/Kg q 12 h PO

alpha blockers:

Prazosin

alpha 1 receptor antagonist

1 mg / 15 Kg q 8-24 h PO

0.5-2.0 mg/ cat q 8-12h PO

Phenoxybenzamine

alpha 1 receptor antagonist

2.5 mg / cat q 12 h increasing x 2.5mg up to a max of 10 mg / cat q 12h PO

ß blockers:

Propranolol

ß1 and ß2 receptor antagonist

0.1-0.3 mg/Kg q 8h PO

0.4-1.2 mg/Kg q 8-12h PO; 0.1 mg cat IV slowly

Atenolol

ß1 receptor antagonist

2 mg/Kg q 24h

6.25-12.5 mg/cat q 24h PO

Metoprolol

ß1 receptor antagonist

2-15 mg/cat q 8 h PO

Ca++ channel blockers:

Diltiazem

Blocks entry of Ca++ into cell, arteriolar vasodilatation.

0.5-1.5 mg/Kg q 8 h PO

1.75-2.4 mg/Kg q 8-12 h PO

Verapamil

Increases glomerular filtration and Na+ secretion

1-5mg/Kg q8h PO

Amlodipine

Blocks entry of Ca++ into cell

0.625mg/cat q 24 h PO

Vasodilators:

Benazepril

ACE inhibitor

0.25-0.5 mg/Kg q 24 h PO

0.5 mg / Kg q 24 h PO

Enalapril

ACE inhibitor

0.5 mg/Kg q 24 h PO

0.25-0.5 mg/Kg q12-24h PO

Lisinopril

ACE inhibitor

0.25-0.5mg/Kg q24h PO

Hydralzine

Direct-acting arteriolar dilator

0.5mg/Kg(initial dose) titrated to 0.5-2mg/Kg q12h PO

the same as in the dog

Sodium nitroprusside

Arteriolar and venous dilator acting as nitric oxide donor

0.5-3µg/Kg/min IV CRI

2.5-15µg/Kg/min IV CRI

CNS acting:

Acepromazine

Neuroleptic

0.5-2.2mg/Kg q8hPO

1.1-2.2 mg/Kg q12h PO

Emergency in hypertension

Hypertension may be also an emergency situation (retinal hemorrhage or detachment) that need aggressive therapy. Hydralazine and furosemide, associated with a ß blocker, can be effective if blood pressure is not lowered after the first 12 hours of therapy (Henik, 1997). Sodium nitroprusside, an arteriolar and venous vasodilators that acts as a donor of nitric oxide, given at continuous infusion rate (with an infusion pump), will provide to a rapid control of systemic hypertension. The dosage must be titrated precisely accordingly to the blood pressure continuous control.

It is important to consider that these therapies can give the risk of hypotensive crisis, with serious damage to the renal function; for such reason the continuous monitoring of blood pressure is at the basis of a successful therapy.

References

References are available on request: cbr@anubi.it

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Claudio Brovida
ANUBI Companion Animal Hospital
Moncalieri, Italy


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