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RAYNAUD'S AND MYCOPLASMAL PNEUMONIA Raynaud's Phenomenon. A second syndrome, occurring in fewer than 5 per cent of mycoplasmal pneumonia patients, is Raynaud's phenomenon. This consists of painful blanching of the distal parts of fingers and toes upon exposure to cold and may occur whether or not the patient has a history of Raynaud's phenomenon unrelated to mycoplasmal infection. The pathogenesis of this complication in M. pneumoniae infection is unknown. However, it is tempting to hypothesize that high titers of cold hemagglutinins could play a role by creating minute thrombi in the microcirculation of the distal extremities when exposed to cold. Patients with sickle cell disease may have particularly severe symptoms when they contract mycoplasmal pneumonia. In the presence of extremely high titers of cold agglutinins (1:20,000), gangrene of the distal parts of finders and toes in these patients has been reported. RAYNAUD'S DEFINITION. Raynaud's phenomenon is a syndrome manifested by attacks of pallor and cyanosis of the digits in response to cold or to emotion. As the attack abaters these color changes are replaced by redness. When the disorder is primary, it is called Raynaud's disease, when it is secondary to another disease or cause, it is called Raynaud's phenomenon ETIOLOGY AND INCIDENCE. Raynaud's disease is the most common cause of Raynaud's phenomenon, accounting for 60 per cent of patients with this disorder. The cause of Raynaud's disease is unknown. Although it can begin at any age, it becomes clinically manifest most commonly between the ages of 20 and 40 years. Raynaud's disease is much more common in women than in men. Two theories have been advanced to explain its occurrence. Raynaud believed that it is caused by increased sympathetic nerve activity. However, measurements of the sympathetic nerve traffic in the median nerve failed to show differences between patients with Ray- naud's disease and normal individuals. Lewis discovered that attacks of Raynaud's phenomenon could be induced after interruption of the sympathetic nerves, He concluded that the cause of the disorder was a fault in the arterial wall that rendered the vessels hyper-responsive to the vasoconstrictive effects of cold. He ascribed the vasospastic attacks to spasm of the digital arteries as a result of this hypersensitivity. Little is known about the defect in the vessel wall, which renders the vessel hypersensitive to cold. The circulation of the digits of p' attests with Raynaud's 'disease is not hypersensitive to infused norepinephrine. Also, determination of the arterio- venous concentration differences of norepinephrine and epinephrine across the hand showed that there was no excessive release of catecholamines from the hands of patients with Raynaud's disease. More recently, accelerated destruction of platelets and release of agents such as serotonin or thromboxane A2 have been proposed as causing vasoconstriction in some patients with Raynaud's phenomenon. It is not known whether platelet destruction is the cause of spasm in such patients or a consequence of it. In a recent study, 26 per cent of patients with the variant type of angina pectoris were found to have migraine, and 24 per cent were found to have Raynaud's phenomenon. This suggested that some patients with Raynaud's phenomenon may have a generalized defect that predisposes arteries in many regions to vasospasm. An association of Rayhaud's phenomenon with idiopathic pulmonary hypertension has also been reported. This association may reflect a very high level of peripheral vascular tone secondary to the severe reduction in cardiac output. Secondary Raynaud's phenomenon is observed frequently as a manifestation of the diseases listed in Table 57-1. In the presence of arterial obstruction, vasoconstrictive stimuli that normally do not cause clinical manifestations result in more severe reduction in blood flow and may cause Raynaud's phenomenon. Raynaud's phenomenon is very often associated with connective tissue diseases; it is particularly frequent in scleroderma. Almost all patients with scleroderma develop Raynaud's phenomenon at some time during the course of illness. A distinctive syndrome consisting of calcinosis, Ray- naud's phenomenon, abnormal esophageal motility, sclero- dactyly, and telangiectasia (CREST syndrome) is recognized. Raynaud's phenomenon may be the presenting manifestation in connective tissue diseases and may precede the appearance of other manifestations by several years. The presence of 'abnormal nail fold capillaries in patients with Raynaud's phenomenon has predictive value for the future development of scleroderma. Structural changes in the vessel wall that limit flow and increase the sensitivity to vasoconstrictive influences appear to account for the frequent occurrence of Raynaud's phenomenon in these diseases. Vascular injury may also result from repetitive minor occupational trauma or from a severe exposure to cold, as in frostbite. Consequent hyper- sensitivity to cold causes Raynaud's phenomenon. Neurogenic lesions cause Raynaud's phenomenon because of irritation of sympathetic nerves and consequent vasocon- striction. Intense or sustained vasoconstriction caused by drugs may also result in Raynaud's phenomenon, as in 3 to 6 per cent of patients taking beta-adrenergic receptor-blocking drugs. Propranolol is the main offender. These drugs block a beta-adrenegic vasodilation mechanism in the digits and may also enhance the vasoconstrictive effects of norepinephrine. Intramuscular aggregation or coagulation of blood elements may obstruct the vessels and cause ischemia and Raynaud's phenomenon. PATHOPHYSIOLOGY. The pallor during the attack of Raynaud's phenomenon is explained by intense vasoconstriction or spasm of the digital arteries. This results in severe reduction in blood flow. In a later stage of the attack, the vasoconstriction becomes less severe, and the capillaries and veins are partially filled with blood whose hemoglobin be- comes markedly deoxygenated. This accounts for the cy- anosis. Upon rewarming, cyanosis is replaced by an intense red color associated with reactive hypoxemia. Between attacks, blood flow to the digits is usually reduced, especially in patients who have trophic changes, but may be normal in some patients. In those patients without trophic changes, blood flow to the hand during maximum vasodilation is the same as in normal individuals, but it is severely reduced in those with trophic changes, a reflection of structural changes in the blood vessels. TABLE 57-1. CAUSES OF SECONDARY RAYNAUD'S PHENOMENON 1. Occlusive arterial disease a. Arteriosclerosis obliterate b. Buerger's disease c. Arterial embolism d. Vasculitis e. Arterial thrombosis 2. Connective tissue diseases a. Scleroderma b. Rheumatoid arthritis c. Systemic lupus erythematosus 3. Vascular injury a. Repetitive minor occupational trauma,
CLINICAL MANIFESTATIONS. The onset of Raynaud's disease is usually gradual. The patient notices an occasional mild and short-lasting attack during winter. Over succeeding years, the severity and duration of the attacks may increase. A wide variation in severity is present. Most commonly, the attacks are provoked by exposure to cold. In some patients, attacks are also precipitated by emotion. The attacks may be terminated by rewarming, or they may abate spontaneously. Between attacks, in a warm environment, the patient is asymptomatic, and physical examination shows no abnormalities. Some patients, however, complain of chronically cold hands and feet, and they may have cold fingers with cyanosis on examination. In a typical attack of Raynaud's phenomenon, the digits become pale. Usually, all digits are affected symmetrically. The pallor is sharply demarcated at the level of the metacarpophalangeal joints, a reflect-ion of spasm of the digital arteries. At a later stage during the attack, pallor is replaced by cyanosis. The patient may have feelings of coldness, numbness, and occasionally pain. Upon rewarming the cyanosis is replaced by intense redness, and the patient may feel tingling or throbbing. Most commonly, only the hands are affected. Frequently, both hands and feet are affected. Rarely, the nose, cheeks, ears, and chin are affected also. Atypical attacks are not infrequent. In these, the involvement of the digits may be asymmetric, with only one or two digits being affected. In some cases, only a portion of the digit is affected. In these instances, the most severely affected portion of the digit is the most distal one. Thus, one may see pallor of the fingertip or of the terminal phalanx of one digit. In other cases, more than one phalanx may be involved. In severe, progressive cases, trophic changes may occur after a few years of involvement. The hair may disappear from the dorsal aspect of the digits. The nails grow more slowly and become brittle and deformed. The skin becomes atrophic, thin, and tight (sclerodactyly). Ulcerations may develop at the fingertips or around the nail bed. These heal slowly and may become infected. They are extremely painful, especially at night. When they heal, they leave characteristic smalls pitted scars. DIAGNOSIS.
The diagnosis of Raynaud's phenomenon can usually be made on the basis
of the history of vasospastic attacks in the digits, precipitated by
cold and relieved by warming. In atypical cases or when the patient's
description of the attack is not clear, provocation of an attack may
be helpful. This may be done by immersing the hands in water at a temperature
of 10 to 15 degrees C. Whole-body exposure to cold is more successful
in provoking attacks. A negative result does not exclude Raynaud's phenomenon.
In typical cases, Raynaud's phenomenon is easily distinguished from
acrocyanosis, but when involvement is atypical, the differentiation
may be more difficult. Distinguishing features include the following;
The color changes in Raynaud's phenomenon are episodic, whereas in acrocyanosis
they are sustained. Pallor is not a prominent feature of acrocyanosis.
Cyanosis is the more typical color change, whereas in Raynaud's disease
digital pallor is characteristic. In Raynaud's disease, only the digits
are involved, whereas in acrocyanosis the color changes usually involve
the whole hand or foot and sometimes even more proximal portions of
the limbs. In Raynaud's disease the skin of the palms is usually dry,
whereas in acrocyanosis it is wet and clammy with sweat. Finally, acrocyanosis
rarely causes trophic changes and ulcerations. Obstruction of major arteries from arteriosclerosis, angiitis, embolism, or thrombosis may lead to color changes in the digits that simulate Raynaud s phenomenon. The distinction is made by the demonstrate of changes in arterial pulses and by the fact that the color hinges in these disorders are likely to be confined to one limb rather than be symmetric. Arteriography, which demonstrates the arterial lesion, is helpful, However, secondary Raynaud's phenomenon may be superimposed upon any of these diseases. In Raynaud's phenomenon, Doppler velocity studies show patent arteries and sharply peaked blood flow velocity patterns in the digits. Arteriography shows normal major arteries and diffuse spasm of the digital arteries. The distinction of Raynaud's disease from secondary Raynaud's phenomenon is based mainly on the exclusion of disorders known to cause secondary Raynaud's phenomenon. The exclusion of obstructive arterial disease is discussed above. Connective tissue disorders, particularly scleroderma, are excluded by the absence of arthralgias or arthritis, alterations of esophageal motility, and the absence of a pulmonary oxygen diffusion defect. The presence of a normal sedimentation rate and the absence of circulating autoantibodies, such as antinucleor antibodies, provide additional reassurance. A careful occupational history is necessary to exclude Raynaud's phenomenon secondary to minor repetitive trauma. A history of drug ingestion or exposure to chemicals is helpful in identifying drug-induced Raynaud's phenomenon. Neurologic disorders can be recognized by their somatic neurotoxic manifestations. Thoracic outlet compression syndromes can be excluded by the appropriate maneuvers. The presence of intramuscular agglutination or coagulation of the blood ele- ments may be suspected if, in the presence of cyanosis, the blood cannot be expelled from vessels by pressure, and when there are isolated areas of redness as the attack abates during rewarming. Confirmation is obtained by demonstrating the cold agglutinins or cryoglobulins in the patient's blood. PROGNOSIS. The prognosis of patients with Raynaud's disease is good. There is no mortality associated with the disease and morbidity is low, it is generally limited to loss of portions of digits as a result of ulcerations. In approximately 50 per cent of patients with Raynaud's disease, the disorder improves and may disappear completely after several years. In only a fraction of 1 per cent of patients is amputation necessary. Approximately 15 per cent of patients with Ray- naud's phenomenon eventually develop a connective tissue disorder, particularly scleroderma. The prognosis in secondary Raynaud's phenomenon depends on the course of the primary disorder. In scleroderma, the prognosis is unsatisfactory, particularly when the disease has caused digital ulcerations. TREATMENT. Management of patients with Raynaud's phenomenon must be tailored to the individual needs of the patient, taking into consideration the frequency and severity of the attacks (Table 57-2). Al1 patients benefit from reassurance and protective measures against exposure to cold. The patients should limit the duration of exposure to cold to the greatest extent possible. They should wear heavy clothing, protecting not only the hands and feet but also the face and trunk, especially when there is a cold wind, this is important because exposure to cold of other portions of the body may reflexed induce vasoconstriction in the digits and precipitate Raynaud's phenomenon. When prolonged exposure to cold is unavoidable, the use of electrically powered or solid fuel-powered hand and foot warmers is advisable. These patients should be taught to recognize and terminate attacks by returning promptly to a warm environment, placing their hands in warm water, or using a warm-air hairblower to warm their hands rapidly. Smoking causes cutaneous vaso- constriction; therefore, tobacco smoking is contraindicated in Raynaud's phenomenon. The use of induced vasodilation by placing the hands in warm water (43 C) has been reported to raise skin temperature and minimize the severity of attacks of Raynaud's phenomenon. Biofeedback to teach patients to raise skin temperature voluntarily has been shown to limit the duration and frequency of vasospastic attacks, but its effect is nonspecific because it is also seen in control patients who received no such treatment and in those in whom biofeedback is used to teach relaxation. The simple measures outlined below usually suffice for patients with infrequent or mild attacks. When Raynaud's phenomenon is more frequent or more severe, and especially when it has resulted in trophic changes or ulcerations, these measures need to be supplemented by drugs. The aim of drug therapy is to induce vascular smooth muscle relaxation, thereby relieving spasm, raising resting blood flow, and limiting the degree of ischemia during attacks. The drugs most frequently used in treating patients with Raynaud's phenomenon are shown in Table 57-3. For most patients, the drug of choice is a calcium antagonist. Nifedipine* has been found to be effective in several well-controlled, double-blind studies. The drug is administered at a dose of 10 to 20 mg three or four times daily. Diltiazemz* at a dose of 60 mg three or four times 'daily, may be substituted, if nifedipine is not well tolerated or if it causes side effects. In one study of very severely affected patients, verapamil was found not to be effective. Reserpine* is the best-studied drug among the group that interferes with the function of the adrenergic nervous system. It is administered by mouth in eses of 0.1 to 0.5 mg daily. In cases in which ulcerations ha e developed, it may be given intra-arterially in a dose of 0.5 to 1 mg, dissolved in saline and administered into the brae ial or radial artery by slow infusion over several minutes. The drugs in this group may also be administered by means of tourniquet-controlled intravenous injection (Bier's block). The administration by the last two routes gives a much higher local concentration and largely avoids systemic side effects. In controlled trials, nitroglycerine ointment or topical prostaglandin E2* (PGE2) has been found effective in Raynaud's phenomenon. The topical application of these drugs is advantageous because their local relaxant action is not counteracted by reflex vasoconstriction, secondary to changes in blood pressure that may occur when they are given systemically. Prostaglandin E1* (PGE1) or prostacyclin* (PGI2) administered intravenously has a beneficial effect in patients with Raynaud's phenomenon. These drugs can be given by constant intravenous infusion in a dose of 6 to 10 ng per kilogram per minute for a few hours or up to three days. It is reported that the beneficial effect outlasts this therapy by several weeks. A novel but effective way of inducing vasodilation in the digits is via the iatrogenic induction of hyperthyroidism by the administration of sodium liothyroninef (triiodothyronine), 75 u.g daily. The resultant hypermetabolism elicits thermoregulatory reflex cutaneous vasodilation. The combination of triiodothyronine and reserpine has been found to be most effective. Preganglionic sympathectomy to eliminate vasoconstrictor tone may have a beneficial immediate result, but the long- term results are disappointing. The duration of benefit is limited by regeneration of the nerves. If sympathectomy is contemplated, it is advisable to try sympathetic blockade with local anesthetics to verify a beneficial result. A recently devised technique that involves surgical stripping of the palmar and digital arteries to bring about a local sympathectomy may also be tried, but its results have not been fully evaluated. TABLE 57-2. TREATMENT OF RAYNAUD'S PHENOMENON Frequency and severity of Vasospastic Attacks -- |
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