Primary pulmonary causes

Primary pulmonary hypertension is a disease of unclear etiology that is characterized by abnormally high mean pulmonary arterial pressures, in the absence of a demonstrable cause. A wide variety of pulmonary and cardiac diseases can lead to secondary pulmonary hypertension. 

Until recently, d-fenfiuramine was used to control appetite, in preference to d-amphetamine, because it has a lower affinity for the catecholamine transporter and so its uptake into noradrenergic and dopaminergic neurons is much less than that of amphetamine. This is thought to explain why, at anorectic doses, this compound lacks the psychotropic effects and dependence-liability that are real problems with if-amphetamine. Unfortunately, despite this therapeutic advantage, this compound has had to be withdrawn from the clinic because of worries that it might cause primary pulmonary hypertension, valvular heart disease and even long-term neuropathy. 

It is important to resolve whether primary structural damage in the liver causes subsequent lung and circulatory effects or whether primary pulmonary blockage is the cause of the circulatory effects and liver damage. 

Toxicology. Diethylene triamine (DETA) is a skin, eye, and respiratory irritant it also causes skin and pulmonary sensitization. On the skin, DETA is a potent primary irritant causing edema and sometimes necrosis. Repeated contact with the liquid may lead to skin sensitization, and an asthmatic-type response may result from repeated inhalation of the vapors. ... 

Primary pulmonary hypertension and cardiac valve disorders have been associated with other centrally acting weight loss agents that cause release of serotonin from nerve terminals although sibutramine has not been associated with these effects in premarketing clinical studies, patients should be informed of the potential for these side effects and monitored closely for their occurrence... 

There has been a sequential comparison of inhaled nitric oxide 40 ppm with aerosolized iloprost 14— 17 micrograms in 35 adults with primary pulmonary hypertension (125). Five of the patients had minor headache and facial flushing during inhalation of iloprost, but these symptoms were short-lived and abated a few minutes after the inhalation ended. One patient had mild jaw pain after aerosolized iloprost, but again this was shortlived. There was an unexpected increase in pulmonary artery pressure in 10 patients and vascular resistance in six patients who received nitric oxide. The authors were uncertain of the cause of this increase, as nitric oxide generally behaves as a vasodilator, but they noted that... 

Morimatsu H, Goto K, Matsusaki T, Katayama H, Matsubara H, Ohe T, Morita K. Rapid development of severe interstitial pneumonia caused by epoprostenol in a patient with primary pulmonary hypertension. Anesth Analg 2004 99 1205-7. 

As of 2002, it was not known whether sibutramine caused primary pulmonary hypertension. However, sibutramine was not recommended for people with conditions including heart disease, irregular heartbeat, or a history of stroke. 

Loscalzo J. Genetic clues to the cause of primary pulmonary hypertension. N Engl J Med 2001 345 367-371. 

Habitat of Paracoccidioides brasiliensis is the soil of semitropical areas along rivers and agricultural areas in Latin America. In children, acute dissemination causes severe illness, often associated with pustules or subcutaneous abscesses. In adults (mainly males) - usually many years after an asymptomatic primary pulmonary infection - chronic disseminated disease leads to mucocutaneous lesions (ulcerating papules and pustules, subcutaneous cold abscesses, sometimes scrofuloderma-like manifestations), especially around nose or mouth in about half of the patients. Itraconazole is the drug of choice. 

Primary pulmonary diseases (e.g. primary pulmonary hypertension, pulmonary fibrosis, chronic obstructive respiratory diseases) cause chronic hepatic congestion due to chronic pulmonary heart disease, possibly leading to insufficiency. Hypoxaemia as a result of acute or chronic respiratory insufficiency can impair metabolic liver functions considerably. In 40—70% of patients with cirrhosis, hypoxaemia can be found in about 50% of cases with advanced cirrhosis, a reduced diffusion capacity for CO is detectable. Furthermore, pulmonary tissue contains a high level of glutamine synthetase, so that ammonia detoxification is possible (ultimately by perivenous hepatocytes) before the blood reaches the systemic circulation. In existing pulmonary diseases, localized ammonia detoxification is impaired. 

Anorectic drugs, which are structurally related to the amphetamines, act mainly on the satiety centre in the hypothalamus and also increase general physical activity (1). All of them, except fenfluramine, stimulate the central nervous system and can cause restlessness, nervousness, irritabihty, and insomnia. Adverse effects also occur through sympathetic stimulation and gastrointestinal irritation. Drug interactions can occur with monoamine oxidase inhibitors. Dexamfetamine, phenmetrazine, and benzfetamine can cause dependence. Some of them have been associated with cardiac valvulopathy and primary pulmonary hypertension (2). 

The most commonly observed disease process leading to death of patients with EMS was progressive polyneuropathy (disease involving the peripheral nerves) and myopathy (disease of muscles) that produced complications of pneumonia and sepsis or respiratory failure due to weakness. Two-thirds of EMS patients died of these complications. Other causes of mortality were cardiomyopathy (disorder affecting the muscles of the heart), primary pulmonary disease, arrhythmia (deviation from the normal rhythm of the heart), and stroke. 

The principal side effects of phentermine are insomnia, restlessness, and euphoria. Some patients rapidly develop toleranee to this agent, resulting in discontinuation of therapy. The combination of phentermine with fenfluramine or dexfenfluramine was as-soeiated with inereased incidences of both primary pulmonary hypertension (PPH) and ear-diae valvulopathy, but it is unlikely that phentermine alone causes these same problems. Phentermine, nonetheless, contains a warning label listing PPH and cardiac valve lesions as possible adverse events. 

Coccidioidomycosis is caused by Coccidioides immitis and is endemic in some parts of the southwestern United States. It may cause nonspecific symptoms, acute pneumonia, or chronic pulmonary or disseminated disease. Primary pulmonary disease (unless severe) frequently is not treated, whereas extrapulmonary disease is treated with amphotericin B, and meningitis is treated with fluconazole. 

Usually the cause of pulmonary hypertension can be assigned to related parenchymal lung disease, heart disease, thromboembolism, or pulmonary, vascular disease. Pulmonary hypertension is termed idiopathic (or primary), however, when it occurs in patients in the absence of associated cardiopulmonary disease and when no other apparent cause for the disease is discernible. Primary pulmonary hypertension is a very rare disease that occurs predominantly in young female patients between the ages of 20 to 40 years (Wood, 1956). It is usually progressive and fatal, with the average survival time from the onset of symptoms being 2 to 3 years (Bourdillon and Oakley, 1976). 

A number of pathogenic mechanisms have been postulated as mediating primary pulmonary hypertension however, none of these has been conclusively implicated in the development of the disease. In fact, current knowledge of the cause and treatment of primary pulmonary hypertension has been hampered by the absence of a simple, noninvasive early detection test in man and also by the absence of an acute animal model of this disease, which would allow further research into the pathogenesis of this disease. Several of the current working hypotheses for the causes of primary pulmonary hypertension are described here. 

Hypoxia. Hypoxia is undoubtedly a cause of pulmonary hypertension in patients with chronic bronchitis and emphysema or in people residing at high altitudes (Grossman and Braunwald, 1980). However, the role for hypoxia as a determinant of primary pulmonary hypertension is less clear. Support for a hypoxia-linked mechanism in primary pulmonary hypertension is the fact that this stimulus is the most effective and consistent inducer of pulmonary hypertension in all species. Hypoxia exerts its greatest effect by constricting the arterioles and precapillaries through a mechanism independent of autonomic innervation. In addition, hypoxia can cause hypertrophy and hyperplasia of the pulmonary arterial smooth muscle (Naeye, 1965). 

Venous (red) thrombi develop in areas of slow blood flow (e.g., leg veins of a bedridden patient). The clot forms rapidly and lacks the organization of the arterial thrombus. Venous occlusion occurs, but is not the primary damage caused by venous thrombi. More worrisome is the tendency of small pieces (emboli) to detach from venous thrombi and travel to pulmonary arteries. The emboh wedge into pulmonary arteries, prohibiting deoxygenated blood from entering the portion of the limg served by the embolized artery. 

Table 2). LIP was considered historically to be the cardinal form of ILD in primary SjS (1,2). However, in two more recent studies, NSIP was the most common pattern of involvement (181,205). Ito et al. evaluated 33 patients with primary SjS and histologically confirmed ILD (31 cases with SLB and 2 autopsies) (181). The histological patterns were NSIP (n = 21, 63%, including 20 cases with fibrosing disease), bronchiolitis (n = 4), primary pulmonary lymphoma (n = 4), amyloidosis (n = 2), and unclassifiable fibrosis ( = 3) (181). Remarkably, LIP was never seen, in accordance with another Asian study (207), and was present in only 16.7% in a series in the United States (205). It is likely that in earlier series, NSIP was classified as LIP and it is also possible that in some cases, lymphoma, now diagnosed from immunohistochemistry and molecular analyses, may have been viewed as LIP. With this proviso, SjS is stiU the major cause of LIP (Fig. 5A,B), accounting for half of cases (171). 

Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, 3rd, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet 2000 26 81 4. 

Health nd Safety Factors. Thionyl chloride is a reactive acid chloride which can cause severe bums to the skin and eyes and acute respiratory tract injury upon vapor inhalation. The hydrolysis products, ie, hydrogen chloride and sulfur dioxide, are beheved to be the primary irritants. Depending on the extent of inhalation exposure, symptoms can range from coughing to pulmonary edema (182). The LC q (rat, inhalation) is 500 ppm (1 h), the DOT label is Corrosive, Poison, and the OSHA PEL is 1 ppm (183). The safety aspects of lithium batteries (qv) containing thionyl chloride have been reviewed (184,185). 

Respiratory Effects. Pulmonary edema was reported in humans dying from acute methyl parathion (Wofatox) intoxication (Fazekas 1971). Edema was found in a man who died 2 hours after intoxication, and, in other cases, edema was found in others who died as long as 9 days after exposure. Broncho-constriction and hypersecretion of bronchial glands (bronchorrhea) are primary muscarinic effects of methyl parathion. The broncoconstriction, bronchorrhea, and bradycardia caused by methyl parathion are strongly conducive to pulmonary edema. 

Pulmonary hypertension develops late in the course of COPD, usually after the development of severe hypoxemia. It is the most common cardiovascular complication of COPD and can result in cor pulmonale, or right-sided heart failure. Hypoxemia plays the primary role in the development of pulmonary hypertension by causing vasoconstriction of the pulmonary arteries and by promoting vessel wall remodeling. Destruction of the pulmonary capillary bed by emphysema further contributes by increasing the pressure required to perfuse the pulmonary vascular bed. Cor pulmonale is associated with venous stasis and thrombosis that may result in pulmonary embolism. Another important systemic effect is the progressive loss of skeletal muscle mass, which contributes to exercise limitations and declining health status. 

Respiratory alkalosis is characterized by an increased arterial pH, a primary decrease in the arterial PaC02 and, when present for sufficient time, a compensatory fall in the HCOf concentration. Respiratory alkalosis represents hyperventilation and is remarkably common. The most common etiologies of respiratory acidosis are listed in Table 25-7 and range from benign (anxiety) to life-threatening (pulmonary embolism). Some causes of hyperventilation and respiratory acidosis are remarkably common (hypoxemia or anemia). 

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