Cardiorespiratory effects of isosorbide dinitrate and nifedipine in combination with nadolol: A double-blind comparative study of beneficial and adverse antianginal drug interactions

Combinations of 2 or 3 drugs are often used to treat angina pectoris, but their combined cardiorespiratory effects have not been investigated. Using a randomized, double-blind, placebo-controlled protocol, the effects of nadolol alone and nadolol in combination with isosorbide dinitrate and nifedipine were compared, in low and high doses, on antianginal efficacy, respiratory functions and arterial blood oxygen saturation (SaO₂) in 19 patients with stable angina pectoris. A complete assessment including a bicycle exercise test with the measurement of the sum of ST-segment depression in all leads (2ST) was carried out every 2 weeks. The frequency of anginal attacks and nitroglycerin consumption was reduced significantly (p < 0.001) by nadolol alone and in combination with the other drugs. Nadolol caused a slight reduction in the forced expiratory volume in 1 second, which was improved by isosorbide dinitrate and nifedipine. The ∑ST profile (basal, at peak exercise and 2 and 5 minutes after exercise) was decreased by nadolol alone and in combination with the other drugs, although the greatest reduction was achieved with large doses of nifedipine and nadolol. The rest and postexercise SaO₂ decreased after nadolol alone and in combination with isosorbide dinitrate, but recovered to pretrial values after nifedipine and nadolol. With all drug combinations, ∑ST depression was greater when the postexercise SaO₂ was < 92%, and decreased (p < 0.05) in the same patients when their postexercise SaO₂ was > 92%. Thus, isosorbide dinitrate improved antianginal efficacy of nadolol but decreased SaO₂, which was associated with an increased ∑ST depression. Nifedipine in combination with nadolol increased SaO₂ and significantly decreased ∑ST depression.     

Assessment of perhexiline maleate in angiographically proven intractable angina: A double-blind trial

We report a randomized double-blind placebo controlled trial on perhexiline. Twenty-eight patients with beta-blocker resistant intractable angina were included but only 20 of these completed the 12 week period of the trial. Perhexiline was effective in 14 patients (70 per cent) as shown by a significant (P < 0.01) decrease in glyceryl trinitrate consumption and in anginal crises. Exercise tests on a bicycle ergometer showed a significant (P < 0.01) increase in exercise tolerance and a reduction in exercise-induced tachycardia. Three patients experienced profound relief from angina and declined to have aortocoronary bypass surgery. The main side effects were tremor, dizziness, and nausea but these did not seriously incapacitate the patients.We conclude that perhexiline is a valuable drug for treating intractable angina, especially when surgery is not feasible.     

Acute central chest pain in the elderly. A review of 296 consecutive hospital admissions during 1976 with particular reference to the possible role of beta-adrenergic blocking agents in inducing substernal pain.

Two hundred and ninety-six patients were admitted to geriatric medical beds in Cardiff in 1976 with acute central chest pain. One hundred and eighty-six (63 per cent) had a confirmed acute myocardial infarction. Of the 37 per cent without evidence of cardiac infarction, 32 per cent were on beta-blocking drugs. The possible role of adrenergic blocking agents in producing acute central chest pain is discussed.     

Association of hospital admission for renal causes during childhood with renal pelvis dilatation identified during pregnancy: a prospective electronic birth cohort study

Background

Chronic kidney disease is a growing contributor to the global burden of non-communicable diseases. Early diagnosis and treatment in childhood can reduce the severity of kidney damage. It is not known whether renal pelvis dilatation (RPD) identified at the 18–20 weeks' fetal anomaly scan is a useful screening tool. We aimed to assess whether an association exists between this marker and renal hospital admissions during early childhood.

Clinical pharmacology and therapeutic application of prazosin in acute and chronic refractory congestive heart failure: Balanced systemic venous and arterial dilation improving pulmonary congestion and cardiac output

The acute and chronic cardiocirculatory effects of the oral vasodilator, prazosin, were evaluated by cardiac catheterization, forearm plethysmography, echocardiography, treadmill exercise, and symptoms in nine patients with advanced long-standing congestive heart failure due to coronary disease. Oral prazsoin (2 to 7 mg) reduced forearm venous tone from 58.9 to 18.5 mm Hg/ml (p < 0.001 and decreased forearm vascular resistance from 88.9 to 47.9 mm Hg/ml/100 g/min (p < 0.001). Concomitantly, mean systemic arterial pressure declined from 99.7 to 77.7 mm Hg (p < 0.001), left ventricular filling pressure decreased from 32.0 to 17.6 mm Hg (p < 0.001) and cardiac index was raised from 1.95 to 2.89 liters/ min/m2 (p < 0.001). These effects of a single dose of prazosin on left ventricular function were rapid in onset, maximal at 1 hour and sustained for the entire 6 hour period of observation. After two weeks of outpatient therapy with 2 to 7 mg prazosin four times daily, echographic end-diastolic dimension decreased (5.7 to 5.4 cm, p < 0.001) whereas the duration of treadmill exercise increased (209 to 317 seconds, p < 0.001). Symptoms (dyspnea, fatigue, angina) were diminished throughout the course of prazosin therapy (mean 94 days), and New York Heart Association functional class improved from 3.7 to 2.2. Thus, prazosin possesses sustained nitropruside-like balanced dilator actions on the systemic arterial and venous beds, which are effectively translated into beneficial hemodynamics of augmenting lowered cardiac output and relieving excessive left ventricular end-diastolic pressure, thereby accounting for the drug's efficacy in the ambulatory management of patients with chronic severe congestive heart failure.     

Renal failure in intracranial lesions. Evidence of function of juxtamedullary nephrons

Acute renal failure was observed in two patients with angiomatous malformations and cysticercosis of the brain. Urinary data revealed hyperosmotic urine with negative water clearance, an indication of retained urine concentration ability despite the severe degree of renal failure. Tubular necrosis of the cortical nephrons was noted at autopsy in both cases. The Juxtamedullary nephrons were rather well preserved. The findings are suggestive of a preferential decrease in renal cortical blood flow as being responsible for tubular necrosis and renal failure. The functioning nephrons were the Juxtamedullary units.     

Effect of cyclic nucleotides on mitogen. Responsiveness of lymphocytes from patients undergoing dialysis.

Lymphocytes from 10 asymptomatic patients undergoing hemodialysis and from eight control subjects were repeatedly cultured with exposure to various concentrations of cyclic nucleotides and theophylline in addition to mitogen. The blastogenic response of the patients' lymphocytes was inhibited by molar concentrations of dibutyryl cyclic AMP which had much less or no inhibitory effected on the response of the control subjects' lymphocytes. This suppressive effect was not potentiated by theophylline. Cyclic GMP enhanced the proliferative response of the patients' lymphocytes as well as that of the controls. In contrast to absolute counts per minute per culture, the suppression by dibutyryl cyclic AMP of mitogen-induced blastogenesis noted in this study clearly separated the in vitro behavior of the patients' lymphocytes from that of the controls' lymphocytes and may serve as a useful marker of cellular dysfunction in such patients.     

Effect of coffee and cigarette smoking on the blood pressure of untreated and diuretic-treated hypertensive patients

Patients with mild hypertension who habitually smoked cigarettes and consumed caffeine were examined after they abstained from caffeine and cigarettes overnight. Their mean blood pressure (147/89 mm Hg) was substantially lower than values recorded in the clinic (164/102 mm Hg) and remained so when they continued to abstain (149/94 mm Hg at two hours). Smoking two cigarettes (3.4 mg nicotine) elevated blood pressure by 10/8 mm Hg, but for only 15 minutes. Drinking coffee (200 mg caffeine) elevated blood pressure by up to 10/7 mm Hg between one and two hours. Combined coffee ingestion and cigarette smoking caused a sustained rise in blood pressure from 5 to 120 minutes to levels similar to those measured in the clinic (162/102 mm Hg at two hours). Similar results were obtained in thiazide-treated patients. The interaction of coffee and cigarettes on blood pressure, but not on pulse rate, was significant. The pressor effect of cigarette smoking and caffeine ingestion in combination may be important in the evaluation of patients with mild hypertension.     

Asplenia and abnormal neutrophil kinetics in chronic idiopathic neutrophilia

Chronic idiopathic neutrophilia is a rarely recognized finding in otherwise healthy subjects. Described here is a case, not previously reported; in which the patient also had congenital asplenia. Studies carried out to determine the mechanism for the neutrophilia are also described. The results show that the patient's neutrophilia was associated with an enlarged circulating pool of neutrophils, increased production and utilization of neutrophils and a short blood granulocyte survival. The findings differ completely from those observed in patients with chronic idiopathic neutrophilia and intact spleens. The results suggest that (1) the mechanism for neutrophilia in patients with chronic idiopathic neutrophilia varies and depends upon the presence or absence of the spleen, and (2) the spleen has a role in the control of neutrophil production, distribution and utilization.     

Bilateral diaphragmatic paralysis with hypercapnic respiratory failure: A physiologic assessment

Bilateral diaphragmatic paralysis was suspected in a patient presenting with hypercapnic respiratory failure who exhibited paradoxic (i.e., inward) abdominal movement on inspiration during tidal breathing in the supine posture; no paradoxic abdominal motion was observed at the bedside with the patient upright. Transdiaphragmatic pressure measurements established the diagnosis of diaphragmatic paralysis, although 20 cm H₂O pressure developed across the diaphragm during the latter part of a forced expiration, presumably due to the development of passive tension in the diaphragm as it was stretched near residual volume. Analysis of the relative motion of the rib cage and abdomen during breathing by the use of magnetometers confirmed the presence of abdominal paradox throughout the breathing cycle when the patient was supine, and established that paradoxic motion of the abdomen also occurred when the patient was in the erect posture but only in the latter half of inspiration. Our findings confirm that the use of transdiaphragmatic pressure measurements and magnetometry will help to quantify diaphragmatic function, that passive tension develops in the paralyzed diaphragm near residual volume and should not be confused with active contraction, and that paradoxic motion of the abdomen may be masked from the clinician when the patient is erect.     

Therapeutic application of prazosin in chronic refractory congestive heart failure: Tolerance and “tachyphylaxis” in perspective

The cardiocirculatory actions of the oral vasodilator prazosin were evaluated by cardiac catheterization, forearm plethysmography, echocardiography, treadmill exercise and symptoms in patients with advanced long-standing congestive heart failure. The administration of oral prazosin (2 to 7 mg) reduced forearm venous tone and forearm vascular resistance. Concomitantly, mean systemic arterial pressure and left ventricular filling pressure decreased, and the cardiac index increased. These effects of a single dose of prazosin on left ventricular function were rapid in onset, maximal at 1 hour and sustained for the entire 6-hour period of observation. After two weeks of outpatient therapy with 2 to 7 mg of prazosin four times daily, echographic end-diastolic dimension decreased, whereas the duration of treadmill exercise increased. Symptoms (dyspnea, fatigue, angina) were diminished throughout the course of prazosin therapy, and there was an improvement in the New York Heart Association functional class from 3.7 to 2.2. Thus, prazosin possesses sustained nitroprusside-like balanced dilator actions on the systemic arterial and venous beds, which are effectively translated into the beneficial hemodynamic effects of augmenting cardiac output and relieving excessive left ventricular end-diastolic pressure. The delayed vasodilator tolerance that occurs in 30 percent of the patients is prevented by the prior use of aldosterone antagonists and is easily treated when present. Subacute hemodynamic suppression of beneficial prazosin vasodilator actions is transient and does not preclude successful sustained prazosin therapy of severe heart failure.     

Adjunct therapy in chronic obstructive pulmonary disease

There have been several studies of acceptable design in which neither subjective nor objective benefit of physiotherapy has been demonstrated. It is possible that the subjective benefit reported in unmatched groups reflects the patients' desire to satisfy a hard-working physiotherapist. Pursed lips breathing affords immediate benefit, but the question of long-term benefit has not been examined.Despite the well documented immediate effects of intermittent positive pressure breathing (IPPB), studies in which its long-term effects have been examined have failed to demonstrate either subjective or objective benefit to patients with chronic obstructive pulmonary disease in interval. IPPB, used as a more effective method of administering bronchodilator aerosols, has been shown repeatedly not to alter significantly the response obtained with voluntary inhalation of the aerosols. Similarly there has been no demonstration that inhalation of water or saline solution, droplets or aerosol (as opposed to humidification) has any measurable effect in the chronic phase of this disease other than immediate transitory increases in airway resistance.Exercise training appears to result in definite subjective improvement in exercise tolerance and in objective indirect improvement. No consistent direct effect on any measurable pulmonary function parameters has been observed. Since most of the studies on the effects of exercise to date suffer from the lack of a control group, or at least a control period, it is not certain which of the documented alterations after exercise training are specific responses to the training; however, current evidence suggests that training is a useful adjunct to therapy. The question of altered survival has not yet been examined in a controlled fashion.The usefulness of oxygen supplementation as an aid to an exercise program and to ameliorate long-term complications such as cor pulmonale and secondary polycythemia is well documented. Decreased mortality is implied, but we found no specific studies on the effects of oxygen therapy alone upon mortality.     

Relationship between colloid osmotic pressure and pulmonary artery wedge pressure in patients with acute cardiorespiratory failure

Close relationships between progressive respiratory failure, roentgenographic signs of pulmonary opacification and decreases in the difference between colloid osmotic pressure of plasma and the pulmonary artery wedge pressure (colloid-hydrosatic pressure gradient) were demonstrated in 49 critically ill patients with multisystem failure, in patients in shock. The potential importance of this relationship is underscored by the observation that fatal progression of pulmonary edema was related to a critical reduction in the colloid-hydrostatic pressure gradient to levels of less than 0 mm Hg. More often, reduction in colloid osmotic pressure rather than increases in left ventricular filling pressure (pulmonary artery wedge pressure) accounted for the decline in colloid-hydrostatic pressure gradient. Routine measurement of colloid osmotic pressure, preferably in conjunction with pulmonary artery wedge pressure, is likely to improve understanding of the mechanisms of acute pulmonary edema.     

Successful management of severe congestive cardiac failure with enalapril

The new angiotensin-converting enzyme inhibitor enalapril (MK-421) was administered to a patient with severe congestive cardiac failure. Dramatic and sustained symptomatic and hemodynamic improvement is reported. The possible clinical significance of this agent's favorable profile is briefly discussed.     

Massive pulmonary embolism associated with a right ventricular myxoma

A 12 year old boy had a massive pulmonary embolism associated with a right ventricular myxoma. This caused complete occlusion of the main trunk of the left pulmonary artery and of a branch of the right pulmonary artery supplying the basal area of the lower lobe of the right lung. The patient died despite two surgical attempts to remove the tumor clots. To our knowledge this constitutes the first report of a massive pulmonary artery embolism associated with a right ventricular myxoma.     

Renal functional reserve in humans. Effect of protein intake on glomerular filtration rate

This study was designed to investigate the effect of protein intake on glomerular filtration rate, and to demonstrate and evaluate the functional reserve of the kidney. Normal subjects ingesting a protein diet had a significantly higher creatinine clearance than a comparable group of normal subjects ingesting a vegetarian diet. A progressive increment in protein intake in normal volunteers resulted in a significant increase in creatinine clearance. Diurnal variations in creatinine clearance were found. These daily variations correlated well with the periods of food intake. The capacity of the kidney to increase its level of function with protein intake suggests a renal function reserve. In short-term studies, the effect of a protein load on glomerular filtration rate was evaluated. Normal subjects showed an increase in glomerular filtration rate two and a half hours after protein load to a maximal glomerular filtration rate of 171.0 +/- 7.7 ml per minute. In patients with a reduced number of nephrons, renal functional reserve may be diminished or absent.     

Sustained reversal of chronic hypercapnia in patients with alveolar hypoventilation syndromes. Long-term maintenance with noninvasive nocturnal mechanical ventilation

Described in this study are eight patients with alveolar hypoventilation syndromes who presented with carbon dioxide narcosis and coma. After reversal of severe hypercapnia, all patients were discharged and maintained at home for an average period of 10 years utilizing "noninvasive" nocturnal mechanical ventilation. The use of "noninvasive" mechanical ventilation at home attempted to void the hazards of tracheostomy and the difficulties inherent in continuous daytime use of oxygen. This form of treatment has allowed these patients to continue their previously productive lives. This study represents the first published long-term follow-up regarding this mode of treatment in patients with alveolar hypoventilation.     

Successful thrombolytic therapy in two patients with renal vein thrombosis

Thrombolytic therapy was administered to two patients with angiographically documented renal vein thrombosis. One patient with bilateral thrombotic disease complicating membranous glomerulonephritis was treated with systemic streptoklnase; the second patient had unilateral renal vein thrombosis associated with chronic pyelonephritis and was treated with streptokinase and urokinase administered directly into the involved vessel. Lysis of all thrombus material was demonstrated by follow-up renal venography and was associated with a gratifying improvement of clinical well-being and laboratory function. These cases demonstrate the feasibility of dissolving renal vein thrombi of presumed recent onset and suggest that rapid lysis of the thrombus accelerates functional and clinical recovery.     

The influence of PEEP on survival of patients in respiratory failure: a retrospective analysis.

Positive end expiratory pressure breathing (PEEP) is used to decrease morbidity and mortality in patients who are hypoxemic despite breathing oxygen in concentrations potentially toxic to their lungs. We reviewed the hospital course of 78 patients whose arterial oxygen tension (PaO2) was less than 70 torr despite a fraction of inspired oxygen (FiO2) of 1.0. Only 60 per cent of these patients were treated with PEEP and their clinical illnesses and severity of cardiopulmonary dysfunction were similar to those in patients not treated with PEEP. PEEP increased the length of survival from 4.2 to 9.2 days (P less than 0.05) whereas over-all survival, defined as hospital discharge, was similar at 31 per cent with and 26 per cent without PEEP. An improvement in PaO2 and decrease in shunt fraction following a trial of PEEP portends a favorable outcome, but its continued use appears to prolong life for a few days without affecting hospital mortality. Survival appears related more to the maintenance of adequate tissue oxygenation as manifested by a high mixed venous oxygen than to improved gas exchange as reflected by an increase in PaO2.     

Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis

Forty-nine patients with progressive systemic sclerosis who had undergone extensive studies including pulmonary artery catheterization as part of an ongoing prospective study of the natural course of progressive systemic sclerosis were evaluated. The overall prevalence of pulmonary arterial hypertension in this population of patients with progressive systemic sclerosis was 33 percent, and among 10 subjects with the CREST syndrome the prevalence of pulmonary hypertension was 50 percent. The relation between pulmonary arterial hypertension documented at catheterization and abnormal results of noninvasive studies suggesting pulmonary hypertension, including physical examination, chest x-ray, electrocardiography, echocardiography, single-breath diffusing capacity, and vital capacity, was studied. Diffusing capacity was significantly lower in those patients with definite pulmonary hypertension (mean pulmonary artery pressure of 22 mg Hg or more) compared with those with a normal mean pulmonary artery pressure, and a diffusing capacity below 43 percent of predicted showed the greatest sensitivity (67 percent) of any single diagnostic test in detecting definite pulmonary hypertension. Chest x-ray suggesting pulmonary hypertension was the least sensitive of the tests evaluated, but showed the greatest specificity (100 percent) in identifying patients with pulmonary hypertension. A classification matrix based on discriminant function analysis utilizing the combination of diffusing capacity below 43 percent of predicted and chest x-ray and electrocardiographic findings correctly identified 75 percent of patients with definite pulmonary hypertension and 97 percent of patients with a normal pulmonary artery pressure, but failed to identify correctly patients with mild pulmonary hypertension (mean pulmonary artery pressure of 20 mm Hg). These findings indicate that specific noninvasive studies are helpful in assessing the likelihood of normal or definitely elevated pulmonary artery pressures in patients with progressive systemic sclerosis, but patients with mild pulmonary hypertension are not likely to be identified by these noninvasive studies.