Effect of amiloride on contractility of rat cardiac muscle exposed to chronic hypercapnia and acute acidosis.

Papillary muscle preparations from rats with normal arterial oxygen and carbon dioxide tensions and from rats which had been maintained with normal oxygen tension but with hypercapnia for 28 days (FICO2 = 5%) were subjected to acute hypercapnia with or without amiloride, a competitive inhibitor of the Na+/H+ pump. Acclimatisation to hypercapnia reduced the slope of the line relating log tension against the extracellular pH from 0.96(SEM0.06) to 0.71(0.07) (p less than 0.02). Amiloride increased the slope in unacclimatised muscle to 1.39(0.09), p less than 0.001 and in muscles acclimatised to hypercapnia to 1.03(0.13), p less than 0.05. The slope in acclimatised muscles was significantly less steep than in unacclimatised muscle (p less than 0.05). The sarcolemmal Na+H+ exchanger is important in the protection of rat cardiac muscle against acute respiratory acidosis.

The effect of noradrenaline on the ability of rat papillary muscle to resist an acute respiratory acidosis.

We have studied the effect of an increase in extracellular calcium and of noradrenaline on the ability of rat right ventricular papillary muscle in vitro to resist an acute fall in extracellular pH (pHe) produced by a rise in superfusate PCO2. We found a steep linear relationship, slope 0.86(SEM 0.06), r = 0.94, between a plot of logarithmic change in tension against pHe for control muscles (superfusate containing 1.8 mmol.litre-1 calcium). An increase in extracellular calcium (3.6 mmol.litre-1) increased absolute tension but did not alter the slope significantly. Increasing concentrations of noradrenaline (6.3 x 10(-8) to 6.3 x 10(-6) M) progressively reduced the slope of the tension/pHe plot from 0.82(0.05) to 0.35(0.07), p less than 0.001. Noradrenaline improved the ability of rat papillary muscle to resist an acute acidosis by a mechanism independent of changes in calcium concentration.

Increased resistance to acute respiratory acidosis in isolated cardiac muscle following chronic hypoxia-induced hypertrophy.

OBJECTIVES: Hypertrophied myocardium is more sensitive to ischaemic dysfunction and damage. The objective of this study was to determine the effect of respiratory acidosis on cardiac muscle function following hypoxia-induced right ventricular hypertrophy, and to ascertain the role of Na(+)-H+ antiporter, which is known to be associated with cell growth. METHODS: Wistar rats were maintained at 10% O2 for 1 or 4 weeks. Experiments were performed on right ventricular papillary muscles stimulated at 1 Hz, and developed tension was recorded. The effect of respiratory acidosis was examined by equilibrating the perfusing solution with increasing levels of CO2, and the role of the Na(+)-H+ antiporter was determined by preincubation with the inhibitor 5-(N,N-hexamethylene) amiloride (HMA). Data were analysed by comparison of the slope of the semi-log plot of normalised tension against pH. RESULTS: Right ventricular hypertrophy was apparent after both 1 and 4 weeks of hypoxia. Respiratory acidosis reduced developed force in preparations from all groups, but the relationship between log tension and pH in the 4-week hypoxia group was less steep than in controls (4-week hypoxia 0.736 (0.057); control 0.947 (0.067); P < 0.01). In the 1-week hypoxia group however the relationship was steeper (1.243 (0.090); P < 0.01). HMA increased the slope in all groups, and under these conditions the control and 4-week hypoxia groups were not significantly different (control 1.134 (0.080); 4-week hypoxic 1.083 (0.087); P > 0.05). CONCLUSIONS: The increased resistance to respiratory acidosis of hypertrophied cardiac muscle following 4 weeks of hypoxia was abolished by HMA. This implies that it is related to increased activity of the Na(+)-H+ antiporter. The mechanism underlying the decreased resistance to acidosis following 1 week of hypoxia is unclear, but is unlikely to involve the Na(+)-H+ antiporter.

Single-dose etoposide in combination with vincristine and doxorubicin in the treatment of small-cell lung cancer (SCLC).

From July 1980, 104 consecutive patients with previously untreated small-cell lung cancer (SCLC) received vincristine 1.4 mg/m2, doxorubicin (Adriamycin) 40 mg/m2, and Etoposide (VePesid) 300 mg/m2 intravenously (as a single infusion) every 3 weeks. The overall response rate (complete response plus partial response) was 58%. In 47 patients with limited disease the response rate was 66% with 21/47 (45%) complete responders. Treatment was delivered on an outpatient basis. Toxicity was mild, and in 455 rapid infusions of etoposide, there have been no adverse reactions.

Does inhalation of pentamidine in the supine position increase deposition in the upper part of the lung?

To assess the effect of posture on the distribution of nebulized pentamidine isethionate deposition in the lung, ten patients with AIDS were studied. Two nebulizer systems, System 22 Mizer (MedicAid) and Respirgard II (Marquest) were modified by adding 40 cm of corrugated tubing (volume 150 ml) to allow the patients to be studied in both the sitting and supine posture. Modification of the nebulizers caused a reduction in lung deposition in the sitting position for the System 22 Mizer but increased deposition in the Respirgard II compared with the unmodified apparatus. The ratio of upper to lower zone deposition (corrected for 133Xe distribution) was increased in the supine position for both devices (p less than 0.01). The best upper zone deposition was achieved with the unmodified System 22 Mizer in the sitting position. Respirgard II had the lowest nonpulmonary deposition and the lowest incidence of adverse effects. The supine position was associated with a redistribution of deposition to the upper zones. To attempt to reduce upper zone recurrence of Pneumocystis carinii pneumonia, the supine posture is suggested for less efficient nebulizer devices, ie, the Respirgard II, but for more efficient systems, ie, System 22 Mizer, the sitting position is probably suitable. This postulate needs to be confirmed by a clinical trial.

An outbreak of multi-drug-resistant tuberculosis in a London teaching hospital.

We describe the epidemiology and control of a hospital outbreak of multi-drug-resistant tuberculosis (MDR-TB). A human immunodeficiency virus (HIV)-negative patient with drug-sensitive tuberculosis developed MDR-TB during a period of unsupervised therapy. She was admitted to an isolation room in a ward with HIV-positive patients, but the room, unbeknown to hospital staff, was at positive-pressure relative to the main ward. Seven HIV-positive contacts developed MDR-TB. The diagnosis in the second patient was delayed, partly because acid-fast bacilli in his sputum were assumed to be Mycobacterium avium-intracellulare. All the available Mycobacterium tuberculosis isolates were indistinguishable by molecular typing. Nearly 1400 staff and patient contacts were offered screening, but the screening programme detected only one of the cases. Despite therapy, the index patient and two of the contacts died. HIV-positive patients are more likely than others to develop tuberculosis after exposure, and the disease may progress more rapidly. In these patients the possibility that acid-fast bacilli may represent M. tuberculosis must always be considered. Patients with tuberculosis (suspected or proven) should not be nursed in the same wards as immunosuppressed patients, and should be isolated. MDR-TB cases must be isolated in negative-pressure rooms. Hospital side-rooms may be positive-pressure as a fire safety measure; infection control teams must be aware of the airflows in all isolation rooms, and must be consulted during the design of hospital buildings. Good communication between infection control teams and clinicians is important, and all medical and nursing staff must be aware of the principles of management of patients with proven or suspected tuberculosis and MDR-TB.

Disposition of intravenous 123iodopentamidine in man.

This study compared the disposition of the radiopharmaceutical [123I]iodopentamidine with that of pentamidine after intravenous infusion by measuring plasma concentrations of each using scintilation counting and high-performance liquid chromatography (HPLC), respectively. There was rapid hepatic uptake and biliary excretion of the 123I label. Distribution kinetics of the 123I label were similar to those of pentamidine, but its elimination half-life (41 +/- 27 h) was longer than that of pentamidine measured by HPLC (11 +/- 8 h). [123I]iodopentamidine distribution reflects that of pentamidine, but elimination of the radiopharmaceutical appears slower.

The place of lung 99mTc DTPA aerosol transfer in the investigation of lung infections in HIV positive patients.

Pneumocystis carinii pneumonia (PCP) is the most common cause of pneumonia in HIV antibody positive patients, but other pneumonias remain important, i.e. streptococcal and mycobacterial infections. A definitive diagnosis relies on obtaining samples from the lung either noninvasively (induced sputum), or invasively (bronchoalveolar lavage, transbronchial or open lung biopsy). We have used the noninvasive technique of nebulized 99mTc DTPA transfer, to assess patients with PCP (n = 30) and other lung infections (n = 20) to see whether this test will distinguish between the various infections. The presence of a biphasic, rapid transfer curve indicates severe extensive alveolar damage and is seen in PCP or legionella pneumonia. The mean transfer time (T50 +/- SEM) for patients with PCP (whether smokers or nonsmokers) was 2.1 +/- 0.2 min, and for two of the patients with legionella 3.2 min. In PCP effective treatment causes the transfer to slow (mean T50 22.7 +/- 3.3 min, n = 24) and become monoexponential. Other causes of these changes in transfer are discussed. The other pneumonias (streptococcal, mycobacterial, and staphylococcal) did not result in biphasic curves or very rapid times, their T50 values are indistinguishable from cigarette smokers. In this patient group the DTPA transfer is a useful noninvasive investigation with a very rapid, biphasic curve indicating a high probability of PCP.

Functional images of lung 99Tcm-DTPA aerosol transfer in smokers and nonsmokers.

The large amount of information from dynamic 99Tcm-DTPA lung can be simplified and rendered easily interpretable by the use of functional images. Eight such images have been devised: a maximum count image, a minimum count image, a time of maximum count image, a time of minimum count image, percentage maximum change image, a T50 image, a standard error image and a correlation coefficient image. These images enable the distribution of aerosol after inhalation, the reliability of the calculated T50 value and movement artefacts to be easily identified. They also allow rapid assessment of the distribution of T50 values in the lungs which may be particularly useful in segmental lung disease.

Regional lung epithelial leakiness in smokers and nonsmokers.

In order to measure regional lung 'leakiness' we have adapted a method developed by Jones et al., to correct for background in the estimation of regional lung transfer of DTPA. It is clear from our study that the half time transfer values (T50) alter from the apex to the base of the lungs in both smokers and nonsmokers. The mean apical T50 values are 56.0 and 56.7 min for the right and left lung respectively in nonsmokers and 12.5 and 12.6 min in smokers. The basal T50 values are 77.5 and 76.9 min for the right and left lung respectively in nonsmokers and 24 and 24.2 min in smokers. These figures suggest that cigarette smoke affects all lung regions and that the transfer values in the apices are more rapid than in the bases in both smokers and nonsmokers.

Lung 99Tcm-DTPA transfer: a method for background correction.

A method to correct for background in lung DTPA transfer has been developed for use with a large field of view gamma camera. The method gives comparable values of T50 to those obtained by Jones et al. The correction factors vary from apex to base; therefore to allow intersegmental T50 comparisons each segment should be corrected for background using its own correction factor.

Disposition of nebulized pentamidine measured using the direct radiolabel 123I-iodopentamidine.

The pulmonary deposition of nebulized pentamidine (300 mg, Respirgard II nebulizer) was measured in seven human immunodeficiency virus (HIV)-positive men using a new radiopharmaceutical, 123I-iodopentamidine. Mean total pulmonary deposition was 15.3 mg or 5.1% of the initial nebulizer dose. Further studies in two of the patients showed that at 24 h, 87% of deposited 123I was retained in the lungs. Small amounts of activity (expressed as a percentage of the initial nebulizer activity) were also detected over the thyroid (0.4%), bladder (1%) and gut (0.7%). The ratio of 123I activity to pentamidine concentration was similar in the nebulizer solution and urine. These results suggest that 123I-pentamidine may be sufficiently stable in vivo to be used to study the biodistribution of inhaled and parenteral pentamidine in humans.

Does 99Tcm human serum albumin alter the characteristics of nebulized pentamidine isethionate?

Nebulized pentamidine has been used as therapy for Pneumocystis carinii pneumonia. The lung dose delivered using different nebulizer systems and doses of pentamidine from 50-600 mg is unknown. To measure this a marker which does not alter the characteristics of the nebulized pentamidine solution must be found. We have assessed the aerosol characteristics of four jet nebulizers (System 22, System 22 Mizer, Optimist, Respigard II) and one ultrasonic device (Pulmosonic) using two concentrations of pentamidine isethionate (50 mg and 300 mg) in 3 ml of solution. The jet nebulizers were operated at a flow rate of 6 l min-1, a rate suitable for home use. These measurements were repeated with 99Tcm labelled human serum albumin (HSA) added to the solutions. A linear relationship between 99Tcm-HSA activity and pentamidine concentration was demonstrated by using a nine stage cascade impactor. The Respigard II and Optimist produced the best results in terms of particle size (96% less than 5 microns), but the addition of the tracer to the latter led to a smaller particle size range and a reduction in the amount of aerosol present at the mouthpiece. The Mizer system had 52% of particles less than 5 microns, the Pulmosonic 46%. The Respigard II had a total output of 8.7 mg for the 50 mg concentration and 30.9 mg for the 300 mg concentration. The System 22 produced corresponding outputs of 18.0 mg and 67.1 mg with 54% of the aerosol particles less than 5 microns.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute oxygen therapy.

Tissues require oxygen for survival. Its delivery depends on adequate ventilation, gas exchange and distribution in the circulation. Many causes of hypoxaemia can be corrected by adding oxygen to the inspired air but response is variable and must be measured.

Domiciliary oxygen therapy.

Domiciliary oxygen is prescribed widely and often with benefit. However, patients with chronic lung disease, in whom its efficacy is proven, continue to be denied adequate assessment and treatment. It is time to ensure that this expensive treatment is given to those who will benefit in a manner that maximizes the improvement in the quality of life.

Contractility of papillary muscle from rats exposed to 28 days of hypoxia, hypercapnia, and hypoxia with hypercapnia.

The effects of chronic respiratory failure (hypoxia and hypercapnia) on the contractile properties of cardiac muscle are not established. A study was performed of the isometric contractile properties of isolated papillary muscle removed from rats exposed in a normobaric environmental chamber to 28 days of hypoxia (fractional inspired oxygen (FIO2) 10%, fractional inspired carbon dioxide (FICO2) less than 1%), hypercapnia (FIO2 21%, FICO2 5%), and hypoxia with hypercapnia (FIO2 10%, FICO2 5%). Rats exposed to both hypoxia and hypoxia with hypercapnia developed selective right ventricular hypertrophy. Exposure to hypercapnia alone did not alter right ventricular weight. No change in right ventricular papillary muscle contractility per unit muscle mass was observed as measured by maximum active tension, maximum rate of rise or fall of tension, or time to peak tension. Rat cardiac muscle adapts successfully to the altered acid-base environment and increased work load associated with prolonged exposure to hypoxia and mild hypercapnia.