Biomedical subjects
Publications and source records attributed to T Higenbottam.
Sixteen months after heart-lung transplantation, the FEV1 of a young woman, who had been in the terminal stages of cystic fibrosis, has risen from 16 percent (0.6 L) to 77 percent of her predicted value. Concomitant with the changes in pulmonary function, her ventilatory response to re-breathing carbon dioxide has improved, and so has her exercise tolerance. She has returned to work.
We have studied the antitussive effects of two anticholinergic agents, oxitropium bromide (200 micrograms) and ipratropium bromide (80 micrograms), and a combined beta-agonist and anticholinergic preparation containing fenoterol hydrobromide (200 micrograms) and ipratropium bromide (80 micrograms), in 16 normal and ten asthmatic volunteers in a double-blind, randomized, placebo-controlled crossover trial. Cough was induced by inhalation of ultrasonically nebulized distilled water and hypotonic saline solution. All treatments significantly reduced the cough response to inhaled distilled water aerosol when compared with placebo (p less than 0.001). There was no difference between oxitropium bromide and ipratropium bromide (p greater than 0.05), but the combination preparation displayed a greater antitussive effect than either oxitropium bromide (p less than 0.05) or ipratropium bromide (p less than 0.025). Cough frequencies in response to hypotonic 0.18 and 0.32 percent saline aerosol were lower than those obtained with distilled water (p less than 0.005) for all treatments. Asthmatic patients coughed less frequently than normal volunteers in response to all solutions when placebo was given (p less than 0.05), but there is no evidence to suggest that the response to treatment was different in the two groups. Our results suggest that inhaled anticholinergic bronchodilators alone or in combination with beta 2-adrenergic agonists might be effective in the treatment of pathologic cough.
Between April 1984 and July 1986, 14 patients underwent heart-lung transplantation at Papworth Hospital, Cambridge, England. The donors for the first five operations were brought to our hospital and the organs removed in the operating theater adjacent to that in which the recipients were prepared. Subsequently, organs have been procured from distant centers. The total ischemic time ranged from 48 to 51 minutes (mean 49.6) for the near procurement group and from 70 to 186 minutes (mean 123.6) for the distant procurement group. Our method of preservation consists of cold cardioplegic arrest of the heart with St. Thomas' Hospital solution followed by a single cold (4 degrees C) pulmonary artery flush with a solution containing 500 ml donors blood, 700 ml Ringer's solution, 200 ml 20% salt-poor albumin, 100 ml 20% mannitol, 20 micrograms prostacyclin, and 10,000 units heparin. Function of the lungs after implantation was assessed by measuring the alveolar-arterial oxygen gradient. The median alveolar-arterial oxygen gradient measured shortly after discontinuation of bypass (point 1), just before extubation (point 2), and at 1 week (point 3) were 96.0, 62.3, and 18.8 mm Hg, respectively, for the near procurement group and 91.5, 60.0, and 11.3 mm Hg, respectively, for the distant procurement group. Comparison of the two groups at the three measurement points by the nonparametric Wilcoxon test showed no significant difference (p = 0.44, 0.52, and 0.11, respectively). The two groups showed significant decline of the alveolar arterial oxygen gradient differences over the first week (p = 0.004, nonparametric Friedman test). We conclude that our method of preservation provides a satisfactory function after implantation. The alveolar-arterial oxygen gradient differences were high immediately after implantation but decreased significantly afterward.
Between April 5, 1984 and May 9, 1987, 24 patients underwent heart-lung transplantation for a variety of vascular and pulmonary diseases. Graft procurement being usually distant, the cardiopulmonary protection used was based on a simple hypothermic flush technique performed in donors prepared with prostacyclin. There was no primary graft deficiency and no intra-operative death. 17 patients are alive after a follow-up period of 1 to 41 months. The actuarial survival rate at 1 year was 77 p. 100. Late mortality was mainly due to cytomegalovirus infections. Immunosuppression relied on cyclosporine A and azathioprine with peri-operative use of antilymphocyte serum and corticosteroids. Early graft rejection episodes were treated with bolus intravenous methylprednisone. These episodes were detected from combined clinical, radiological, spirometric and histological data. Transbronchial lung biopsy was the reference examination for an objective diagnosis of lung rejection. In this series there was only one case of obliterative bronchiolitis (4 p. 100). This must be credited to the strategy used to detect rejection which seems to be the main factor of occurrence of this dangerous complication.
Haemodynamic and gas exchange measurements were made at rest, on supine exercise and on acute vasodilatation with intravenous prostacyclin in eight patients with pulmonary hypertension. This enabled an assessment of the contribution of V/Q imbalance to the abnormal gas exchange on the condition. At rest arterial oxygen tension, PaO2 (mean 8.1 +/- 1.7 kPa) and mixed venous oxygen tension, PVO2 (3.6 +/- 0.4) were reduced. The physiological shunt, Qs/Qt (15 +/- 17%) and the dead space, Vd/Vt (0.47 +/- 0.11) were elevated above normal. Exercise produced an increase in cardiac index, a fall in PVO2, no significant change in PaO2 and also no appreciable changes in the Vd/Vt and Qs/Qt. Intravenous prostacyclin increased the cardiac index and raised the PVO2 and the PaO2 but again with no significant changes in Vd/Vt and Qs/Qt. We conclude that ventilation-perfusion imbalance as shown by increased Vd/Vt and Qs/Qt, contributes significantly to the abnormal gas exchange in pulmonary hypertension. But neither index was altered by exercise or vasodilation; the latter improves the hypoxemia by increasing the PVO2 from an increase in the cardiac output.
The effect of inhibition of angiotensin-converting enzyme (ACE) on standard cough challenge was investigated in a double-blind, randomised study in sixteen normal volunteers. Captopril (25 mg) or matched placebo was given by mouth 2 h before inhalation of nebulised distilled water, citric acid, and incremental doses of capsaicin (0.5-20 mumol/l). Distilled water and citric acid challenge were not significantly changed by captopril pretreatment. However, captopril significantly shifted the dose-response curve to capsaicin inhalation. The geometric mean dose of capsaicin causing 20 coughs/min was 1.3 mumol/l for captopril and 2.8 mumol/l for placebo pretreatment (p = 0.04). Cough is a recognised side-effect of ACE inhibitors; the observation that cough challenge is changed by these drugs in normal subjects implies a role for ACE in the cough reflex, possibly by metabolism of substrates other than angiotensin I.
Combined heart and lung transplantation was used to treat seven patients with end stage lung disease. All were severely disabled, and their disease carried a poor prognosis. Six patients were well four to 33 months after transplantation. One patient died after 44 days from a primary cytomegalovirus pneumonia transmitted from the donor. All the survivors had normal exercise tolerance and greatly improved lung function. It is concluded that heart and lung transplantation is a suitable treatment for selected patients with end stage chronic lung disease.
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To determine what governs nitric oxide (NO) yields of cigarettes and to obtain a range of yields for contemporary cigarettes 17 UK, 14 US, 8 French and 1 Turkish brand were analysed using a chemiluminescent analyser and standard smoking machine. The country of origin appeared to be the major factor affecting NO yield. US and French brands exceeded UK values by 3-5 fold. Apart from a reduced NO yield in UK ventilated filtered brands, the design of a cigarette and its tar, nicotine and carbon monoxide (CO) yield had little effect on NO yield. It is argued that these international differences in NO yields reflect differences in the nitrate content of tobaccos traditionally used in manufacture in those countries over many years. Despite their probable increased lifetime exposure to NO (and by implication nitrosamine exposure) there appears to be little evidence that US and French smokers are at greater risk of lung disease than their UK counterparts.
A more widespread application of combined heart-lung transplantation (HLT) for the treatment of pulmonary vascular disease has been limited by the lack of a simple and inexpensive method for preserving donor organs for transplantation from distant hospitals. Of the 12 HLT patients treated at Papworth Hospital, the last 7 involved distant procurement of donor organs. For this, a single flush hypothermic system was used, with a Ringer's solution containing albumin, mannitol, prostacyclin, and heparin. This was preceded by a prostacyclin infusion into the donor's pulmonary artery. A retrospective comparison has been made of the post-operative pulmonary function between the HLT patients with distant procurement, those with near procurement of organs, and a group of patients who underwent coronary artery bypass graft (CABG) over the same time span. The mean ischemic time for distant-procurement patients was 110 (+/- 10) min, compared with 50 (+/- 0.5) min for near procurement. During the initial 18 hr postoperatively, the alveolar-arterial oxygen gradients (A-aDO2) for both groups of HLT patients and the CABG patients were closely comparable. Two near-procurement patients died: 1 from tracheal dehiscence, and 1 from cytomegalovirus (CMV). One distant-procurement patient died of CMV. All the others recovered fully and are alive and well at home. No patient developed a classical reimplantation response, and pulmonary function in the distant-procurement group compared closely with the CABG patients. These observations suggest that a simple single flush preservation system can effectively extend the pulmonary ischemic time so facilitating distant organ procurement.
1. The antitussive properties of bronchodilators were evaluated in a total of 47 normal volunteers. 2. Cough was induced by inhalation of ultrasonically nebulized solutions of distilled water and hypotonic saline. 3. Inhaled fenoterol hydrobromide (360 micrograms; 20 volunteers) and inhaled ipratropium bromide (72 micrograms; 14 volunteers) both significantly reduced couch compared with placebo (P less than 0.01). Oral salbutamol sulphate (4 mg; 11 volunteers) and oral pirenzepine hydrochloride (50 mg; 14 volunteers) had lesser effects. 4. Cough inhibition correlated with a small but statistically significant degree of bronchodilatation as measured by specific airway conductance (sGaw) and forced expiratory volume in one second (FEV1) in six normal subjects studied with each treatment in a placebo controlled, double blind study (r = 0.67, P less than 0.001). 5. Small reductions in airway tone are associated with a reduced cough response elicited by inhaled ultrasonically nebulized distilled water.
Primary pulmonary hypertension (PPH), in which no cause for a rise in pulmonary artery pressure can be found, is characterized by a "restriction" of the peripheral pulmonary vascular bed. Treatment is directed at the consequences of this, namely, the low cardiac output. Oral anticoagulants appear to improve prognosis, as in other low cardiac output states, by preventing intravascular coagulation. Oral vasodilators are not uniformly successful in improving cardiac output. Acute intravenous infusion of prostacyclin (PGI2) lowers both pulmonary and systemic vascular resistance in normal subjects and patients with PPH. Long-term infusion in patients with a poor prognosis, that is, with a PA saturation O2 less than 63%, has, in an uncontrolled study, improved symptoms and rate of maximal oxygen consumption (V max O2) during progressive exercise testing. Its more general use in PPH awaits controlled studies, but there is a possibility that, in addition to its vasodilator properties and the ability to impede platelet aggregation and adherence, PGI2 long term may influence the progressive nature of PPH.
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Chronic obstructive bronchitis and emphysema are two chronic lung diseases closely associated with cigarette smoking. Early pathological changes in the lung in asymptomatic smokers affect the alveoli and bronchioli, sites where surfactant production is centred. Bronchial lavage work has demonstrated a reduction of 'free' extra-cellular surfactant in smokers. In this report the interaction between the 'tar' of tobacco smoke and surfactant is described from in vitro studies. Also using an isolated rat lung model tobacco smoke 'tar' appears to increase lung compliance. These observations may help explain why young asymptomatic cigarette smokers have increased lung compliance and suggest the way in which 'tar' interacts with the lung surface.
The rapidly-adapting receptors (RARs) are strategically sited within the paracellular spaces between epithelial cells of the laryngeal and tracheal epithelium. These receptors in cats and dogs appear to respond to changes in the ionic composition of the aqueous fluid bathing the luminal surface of the airway. Studies using dogs and exposing laryngeal epithelium to solutions of differing ionic composition suggest that a reduction in [Cl-] below 75 mmol . l-1 or change in pH, less than 4 and greater than 8 together with a [K+] greater than 70 mmol . l-1 stimulates the (RARs). Coughing can be provoked in man, when breathing ultrasonically nebulized aqueous erosols, with solution low in [Cl-] or when the pH is less than 4 or greater than 8. Only a small response occurs when osmolarity is increased. The similarity of the pattern of chemical specificity of cough to stimulation of RARs suggests that, in man, changes of ionic composition of the airway surface liquid also stimulates RARs and this induces coughing.