Serum immunoreactive erythropoietin in children with cyanotic and acyanotic congenital heart disease.

Serum immunoreactive erythropoietin (siEp) was measured in 27 cyanotic and 21 acyanotic children with congenital heart disease, age 4 months to 10 years. The geometric mean value was 9 mIU/mL for each group with 95% range from 3 to 26 mIU/mL and 4 to 22 mIU/mL for the cyanotic and acyanotic subjects, respectively. The levels are similar to those found in normal adults using the same assay system. Three cyanotic subjects showed increased siEp values. One was anemic relative to his hypoxemia, and the other two showed signs of increasing hypoxia. There was a significant negative correlation between siEp and arterial oxygen content. However, siEp did not correlate significantly with hemoglobin, hematocrit, PaO2, or SaO2. Despite normal siEp levels, the cyanotic children showed compensatory erythropoiesis with significantly elevated hemoglobin and hematocrit levels, which did correlate inversely with PaO2 and SaO2. Arterial oxygen content was also significantly higher in the cyanotic subjects (p less than 0.02). The cyanotic children seemed to display the same pattern as observed in man and animals exposed to prolonged hypobaric hypoxia, where after an initial rise in erythropoietin values the levels fall to normal, while increased erythropoiesis is sustained.

The effect of human antiendotoxin monoclonal antibodies on endotoxin-induced lung injury in the rat.

A model of endotoxin-induced lung injury was developed in the rat. We found that 24 h after intravenously administered endotoxin (3 mg/kg) there was increased clearance of the isotope 99mTcDTPA from the lung to blood, increased neutrophils in the lung in bronchoalveolar lavage, and increased levels of products of peroxidation of lipids and nucleic acid in the serum. Using this model, we evaluated the effect of pretreatment of rats with a human monoclonal antibody specific to the core glycolipid that is common to all endotoxins. We found that pretreatment prevented the increased clearance of 99mTcDTPA from the lung, as well as the increase in lipid peroxidation products in the serum. The antibody did not prevent increased neutrophil accumulation in the lung. The findings suggest that the administration of human antiendotoxin monoclonal antibodies prior to endotoxemia may prevent some of the changes in the lung associated with endotoxin.

Sequential changes in lung metabolism, permeability, and edema after ANTU.

Lung injury and pulmonary edema were induced in rats after intraperitoneal injection of 10 mg/kg alpha-naphthylthiourea (ANTU). The time course of development of lung injury was assessed by the clearance of 99mTc-diethylenetriamine pentaacetate (99mTcDTPA) from the lung into the blood, the pharmacokinetics of tritiated prostaglandin E2 [( 3H]PGE2) in the isolated perfused lung, and by increase in the weight ratio (wet-to-dry) of lung. Two hours after ANTU administration, the clearance of 99mTcDTPA was significantly faster than in untreated animals and implied an increase in permeability of the alveolar-capillary barrier. This change preceded the increase in wet-to-dry weight ratio of lung, which was not significant until 5 h after ANTU administration. The pharmacokinetics of [3H]PGE2 were significantly altered after ANTU and these changes persisted beyond the time when both lung weight ratio and 99mTcDTPA clearance had recovered to normal values. We conclude that both 99mTcDTPA clearance and PGE2 pharmacokinetics change in ANTU-induced lung injury but with different time courses. In the progressive phase of lung injury due to ANTU, the early change in clearance of 99mTcDTPA suggests that an increased permeation of the alveolar capillary barrier by this small molecule precedes pulmonary edema due to an increased colloid permeability of the barrier. Abnormal metabolism in the pulmonary microvasculature persists when the permeability defect and edema have recovered.

Regional respiratory clearance of aerosolized 99mTc-DTPA: posture and smoking effects.

We studied 10 healthy nonsmokers and 8 healthy smokers, in both the upright and supine position, to investigate whether regional differences in respiratory clearance of technetium-99m-labeled diethylenetriamine pentaacetic acid 99mTc-DTPA (RC-DTPA) existed and to assess the influence of posture and smoking on the regional RC-DTPA. RC-DTPA was assessed by the lung clearance rates (%/min) of aerosolized 99mTc-DTPA (0.8 micron MMD; 2.4 GSD), using data corrected for recirculating radioactivity, in the upper (zone 1), middle (zone 2), and lower (zone 3) posterior lung fields. In nonsmokers, RC-DTPA in zone 1 was faster than in zone 2 or 3 in both the upright (P less than 0.001) and supine positions (P less than 0.0). No effect was produced by changes in posture on the regional RC-DTPA. In smokers, RC-DTPA was increased in all zones compared with the nonsmokers (P = 0.004), with a further increase in RC-DTP in zone 1 in the upright posture compared with the other regions (P less than 0.001). We conclude that in nonsmokers regional RC-DTPA is faster in zone 1 than in other zones, and this is not related to recirculation of radioactivity; posture does not modify the regional RC-DTPA of nonsmokers; smoking increases RC-DTPA in all zones and more in zone 1 in the upright posture.

Cigarette smoke induced changes in rat pulmonary clearance of 99mTcDTPA. A comparison of particulate and gas phases.

The rat model was developed to study the effects of cigarette smoke on pulmonary clearance of 99mTcDTPA. The method developed was sufficiently noninvasive to allow frequent repeat measurements to be made with a high degree of reproducibility. Animals exposed twice daily to 90 puffs of dilute whole cigarette smoke for 7 days showed an increase in 99mTcDTPA clearance from the lung which returned to normal within 3 wk of stopping exposure. Filtration of the smoke to remove all the particulate matter abolished the changes.

Some short-term effects of changing to lower yield cigarettes.

The rate of clearance from the lung of the hydrophilic tracer molecule 99mTc DTPA was used to investigate the short-term effects on lung epithelial function when smokers switched to cigarettes with lower yields of tobacco smoke constituents. Two separate studies were performed. In the first study, subjects smoked conventional mid- and low-tar cigarettes. The second study used two specially manufactured cigarettes with similar tar and nicotine yields, but differing carbon monoxide yields. Neither study demonstrated any significant improvement in 99mTc DTPA clearance. The yields of carbon monoxide determined under standard machine smoking conditions implied that there would be a 44 percent reduction in exposure to carbon monoxide when subjects switched from smoking conventional mid-tar to low-tar cigarettes. However, measurements of carboxyhemoglobin showed that the smokers compensated for the lower yields and their exposure was reduced by only 11 percent. Similarly, in the second study, the subjects reduced their exposure by 7 percent instead of the expected 44 percent. Urine nicotine/cotinine excretion measurements in this study indicated that there was no complimentary increase in nicotine absorption suggesting the possibility that subjects may be able to regulate their intake of individual components of the cigarette smoke. Thus, the unexpected result from this study was the finding that cigarette smokers could, in some way, regulate their intake of smoke from cigarettes of different composition so as to maintain a constant exposure of smoke constituents.

Changes in permeability of the alveolar-capillary barrier in firefighters.

The effect on alveolar-capillary barrier permeability of chronic exposure to a smoke produced by the partial combusion of diesel oil, paraffin, and wood was examined. An index of permeability was determined from the rate of transfer from the lung into the blood of the hydrophilic, labelled chelate 99mTc diethylene triamine penta-acetate (MW 492 dalton). The results of this test were expressed as the half time clearance of the tracer from the lung into the blood (T1/2 LB). The study was carried out at the Royal Naval Firefighting School, HMS Excellent. Permeability index was measured on seven non-smoking naval firefighting instructors who had worked at the school for periods of longer than two and a half months. Tests of airway function and carbon monoxide transfer factor were performed on four of these seven instructors. The results of the permeability index showed a T1/2 LB of 26 min +/- 5 (SEM) which differed significantly from that of normal non-smokers. By contrast all other lung function tests had values within the predicted normal range.

The effect of surgery with cardiopulmonary bypass on alveolar-capillary barrier function in human beings.

We measured the rate of clearance of technetium 99m-labeled diethylenetriamine pentaacetate (99mTcDTPA) (molecular weight, 492 daltons) from the lung into the blood (T1/2LB) in 9 patients before and after operation with cardiopulmonary bypass (CPB). Two hours postoperatively, T1/2LB fell from 49.3 +/- 13.6 minutes (mean +/- standard deviation) to 24.0 +/- 12.8 minutes (p less than 0.001). In addition, alveolar-arterial oxygen tension difference P(A-a)O2 had increased from 73 +/- 28 mm Hg to 164 +/- 37 mm Hg (p less than 0.001). The rates of clearance of 99mTcDTPA had returned to preoperative times by 7 days after operation, although there was still a significant (p less than 0.05) elevation in P(A-a)O2. Postoperative respiratory failure developed in 1 patient. The only abnormality of lung function detected preoperatively was an increased clearance rate for 99mTcDTPA (T1/2LB, 18 minutes). This study has shown an increased clearance from the lung of a low-molecular-weight molecule following operation with CPB. This finding should allow a more rational approach to elucidating the mechanisms of injury to the gas-blood interface in the lung following this type of operation.

Warming blood before transfusion. Does immersion warming change blood composition?

The practice of warming blood for transfusion by immersion in a water bath has been studied. Blood, 3 days after collection, with CPD-adenine anticoagulant, was warmed at 25 degrees C, 37 degrees C and 45 degrees C for up to 2 hours. The procedure was repeated after 2 and 4 weeks' storage at 4 degrees C. Only trivial biochemical and morphological changes resulted from warming. Within these limits, immersion warming of blood appears to be a reasonable alternative to using a blood-warming coil. Other aspects of immersion warming are discussed.

The effect of nicotine on pulmonary epithelial permeability in man.

We examined the effect of nicotine on pulmonary epithelial permeability in man. Nicotine was administered from a chewing gum base given over a seven-day period. An index of pulmonary permeability was derived from the rate of clearance from the lung into the blood of 99mTcDTPA (diethylenetriamine pentacetate). In five nonsmoking volunteers there was no change in permeability for the seven-day study period. This lack of effect of nicotine alone was in striking contrast to the increase in epithelial permeability observed in five nonsmoking subjects who took up cigarette smoking.

A simple separator to generate half micron aqueous particles for lung imaging.

An aerosol of a radionuclide may be used for ventilation imaging as an alternative to radioactive rare gases. For good-quality images as few particles as possible must be deposited in the trachea and bronchi, which means that no, or very few, particles should have aerodynamic diameter of more than 2 micron. We have developed a separator to modify the output of an Acorn jet nebuliser. It reduced the proportion of particles in the aerosol with aerodynamic diameters of more than 2 micron from 60% for the unmodified output of the nebuliser to only 6%; it consisted of a cylinder of perspex with two compartments containing inert spheres, either stainless steel or glass, of diameter 3 mm (the first compartment contained two layers of spheres, and the main section was packed with spheres). To examine the efficiency of the separator system for routine clinical use we compared the images produced and the deposition of the particles in the modified aerosol (using 99TcmDTPA) with the distribution of ventilation of 81Krm in eight subjects. Despite the theoretical differences between the behaviour of a gas molecule and of a particle in the respiratory tree, the images produced using the modified aerosol delivery system were as good as those produced with 81Krm in normal subjects. In abnormal subjects the images produced were only distinguished following the calculation of a penetration index.

Fluid and electrolyte homeostasis during prolonged exercise at altitude.

The combined effect of exercise and altitude on fluid and electrolyte homeostasis was studied over 13 days on six male subjects eating a diet with constant sodium and potassium content. During the first 4 and last 4 days subjects were semisedentary at an altitude of 900 m. In the middle 5 days subjects exercised by hill walking for about 7 h daily at altitudes between 2,678 and 3,629 m. There was a retention of sodium (mean of 202 mM by the end of the exercise-altitude period) and a small retention of water (mean of 0.49 liters). Plasma volume increased by 0.76 liters and packed cell volume fell from a mean of 44.5 to 41.8%. There was no change in plasma sodium concentration. The retention of sodium implies an expansion in the extracellular space of 1.44 liters at the expense of the intracellular space, which decreased by a calculated 1.05 liters. These changes are similar to those resulting from comparable exercise at sea level and opposite to the effect of altitude on resting subjects.

Effect of prolonged exercise at altitude on the renin-aldosterone system.

The combined effect of exercise and altitude on the renin-aldosterone system was studied in six male subjects on a fixed diet. After 4 control days at rest and at low altitude, subjects ascended to 3,100 m and took about 7 h exercise daily for 5 days. There followed a 4-day recovery period at low altitude. Daily blood samples were taken for estimation of plasma renin activity (PRA), plasma aldosterone concentration (PAC), and angiotensin converting-enzyme (ACE) activity. Results showed a maximal rise in PRA and PAC with exercise at altitude maximal on the first 2 days. ACE activity fell by 23% at altitude. Compared with similar exercise at sea level, the rise in PAC was comparable but the rise in PRA was four times greater, indicating a marked decrease in PAC response to PRA. It is suggested that this loss of sensitivity of PAC to PRA is mediated by the measured reduction in ACE activity.

Abnormality of an index of alveolar-capillary barrier permeability associated with respiratory tract infection in the rat.

The study investigated the role of subclinical respiratory tract infection in producing an abnormality of lung function assessed by measuring an index of the permeability of the blood-gas barrier to 99mTcDTPA. Pasteurella pneumotropica was grown from throat swabs taken from 9 female rats age 10 weeks at the time of the experiment and housed under conventional husbandry conditions for 4 weeks previously. There was a significant association between the amount of bacteriological growth and an abnormality of the index of permeability. In contrast to this finding, there was no bacterial growth and no abnormality of function found in 12 female rats age 6 weeks, kept under strict barrier-maintained conditions. This finding emphasises the need for great care to be taken in the husbandry of animals used in scientific research.

Carboxyhaemoglobin and pulmonary epithelial permeability in man.

The effect of cigarette smoke exposure on pulmonary epithelial permeability was studied in 45 smokers and 22 non-smokers. An index of cigarette smoke exposure was obtained from the carboxyhaemoglobin concentration (HbCO%). Pulmonary epithelial permeability was proportional to the half-time clearance rate of technetium-99m-labelled diethylene triamine pentacetate (99mTc DTPA) from lung to blood (T1/2LB). The relationship between T1/2LB and HbCO% was hyperbolic in form and the data could be fitted to the quadratic formula (formula; see text) where the parameters a0, a1, and a2 represent respectively the asymptotic T1/2LB value at large carboxyhaemoglobin values and the slope and shape of the curve. The values of these parameters were a0 4.4 (2.6), a1 = 77.8 (15.5), and a2 -25.5 (9.7) (SE). This is the first demonstration of a dose-response relationship between carboxyhaemoglobin and an increased permeability of the lungs in man and provides a technique for identifying the roles of carbon monoxide and other cigarette smoke constituents in causing increased pulmonary epithelial permeability.

Sodium balance, fluid homeostasis and the renin-aldosterone system during the prolonged exercise of hill walking.

1. The effect of 5 consecutive days of hill walking on electrolyte balance, fluid homeostasis, plasma renin activity and plasma aldosterone concentration was studied in five male subjects. 2. The 5-day exercise period was preceded by a 4-day control period and followed by a 4-day recovery period. Throughout the 13-day study subjects ate a fixed diet. 3. After 5 days of exercise subjects had retained a mean of 264 mmol (SD 85) of sodium. Plasma sodium concentration remained constant at 142.0 mmol/l (SD 5.4). This indicates an expansion of the extracellular space by 1.84 litres. 4. By the end of the exercise period there was a positive water balance of about 0.9 litre. Thus there was a net movement of 0.94 litre of fluid from the intracellular to the extracellular space. 5. Packed cell volume decreased from a mean of 43.5% to 37.9% after 5 days of exercise, indicating that about 0.9 litre of the extracellular fluid entered the vascular compartment. The remaining fluid may be responsible for the significant increase in lower leg volume. 6. During the exercise period plasma aldosterone concentration and plasma renin activity rose, and there was a highly significant correlation between these values and the sodium retention. There was also a significant correlation between sodium retention and the increase in leg volume, which suggests that oedema may be the result of prolonged exercise of this type.

Pulmonary epithelial permeability is immediately increased after embolisation with oleic acid but not with neutral fat.

Pulmonary fat embolism occurs frequently after trauma but its functional significance is often unclear. To obtain direct evidence of lung damage caused by fat embolism we have measured changes in permeability of the alveolar-capillary interface. A permeability index was derived from the half time clearance from lung to blood (T1/2LB) of 99mTcDTPA introduced into the lung in a 1 ml bolus. Three groups of rabbits were studied. Baseline T1/2LB. did not differ significantly between groups. After intravenous injection of saline placebo in one group and of 300 mg/kg triolein in another group there was no change in permeability index. After intravenous injection of 100 mg/kg oleic acid in the third group there was an immediate change in T1/2LB from a monoexponential baseline 280 +/- 20 min (SEM) to a multiexponential curve which was resolved into two components, one with a T1/2LB of 3.2 +/- 0.6 min (SEM) and the other 39.5 +/- 7.6 min (SEM). Statistically significant changes in alveolar-arterial PO2 difference, dynamic compliance, chest radiography, and postmortem lung water accompanied the changes in T1/2LB in this group. There were no significant changes in these variables in the placebo or triolein group. Histological studies of the lung tissue of these animals using the osmic acid stain for fat showed no fat in the placebo group, extensive fat embolisation which was densely stained in the triolein group and much less densely stained fat in the oleic acid group. Measurement of the permeability of the alveolar-capillary interface provides direct evidence of lung damage after oleic acid embolisation. There were no functional changes in animals with extensive embolisation with triolein.

Rapid improvement in abnormal pulmonary epithelial permeability after stopping cigarettes.

A new, non-invasive method of measuring pulmonary epithelial damage in man was compared with traditional tests of small-airway function. Pulmonary epithelial permeability was expressed as the half-time clearance from the lung into blood of (99m)Tc-diethylene triaminepenta-acetic acid ((99m)Tc-DTPA) deposited predominantly in the alveoli from an inhaled aerosol.Recovery from abnormal pulmonary permeability was recorded after stopping smoking for 21 days in a group of young symptomless cigarette smokers. Before stopping smoking there was a significant correlation between half-time lung clearance of (99m)Tc-DTPA and carboxyhaemoglobin concentration (r=0.69; p <0.05). There was no correlation between carboxyhaemoglobin value and closing volume, the only other abnormal test of airway function. Twenty-four hours after stopping smoking the mean half-time lung clearance of (99m)Tc-DTPA had increased significantly (p <0.001) from a baseline of 15.8 min (SEM 1.3 min) to 25.5 min (SEM 2.5 min). The mean half-time clearance continued to increase to a maximum of 35.5 min (SEM 3.1 min) at seven days, but was significantly less than the reported half-time clearance for non-smokers (59 min, SEM