Surfactant protein B deficiency caused by a novel mutation involving multiple exons of the SP-B gene.

BACKGROUND: Inability to produce surfactant protein (SP)-B causes fatal neonatal respiratory disease. Homozygosity for a frameshift mutation (121ins2) in the gene encoding SP-B (SFTPB) is the predominant but not the exclusive cause of disease. OBJECTIVES: To report a novel mutation in the SFTB gene. METHODS: We analyzed tracheal aspirates, lung tissue obtained by in vivo lung biopsy and DNA from a newborn infant with lethal respiratory failure. RESULTS: DNA analysis revealed a large homozygous genomic deletion encompassing exon 7 and 8 of SFTPB gene, a mutation we described as c.673-1248del2959. The parents were both heterozygous carriers. Analysis of the SP profile in tracheal aspirates and lung tissue by immunohistochemistry, routine and electron microscopy supported the diagnosis of SP-B deficiency and suggested that this large mutation might lead to abnormal routing and processing of proSP-B and proSP-C. CONCLUSIONS: This report shows that SP-B deficiency can also be caused by a multi exon deletion in the SFTPB gene and this finding emphasizes the importance of using modern DNA analysis techniques capable of detecting multi exon deletions.

Stimulation of ventilation by normobaric hyperoxia in exercising dogs.

In order to describe the factors which, during hyperoxic exercise, can counteract the chemoreceptor-mediated inhibition of ventilation by O2, minute ventilation (VE) and the pulmonary gas exchange were studied breath-by-breath in four dogs running on a treadmill (5 km x h(-1)) for 10 min during and following exposure to O2 of different durations. We found that a brief inhalation of O2 applied during the steady state of the VE response provoked a reduction in VE by 6.5 +/- 0.9 l x min(-1) whereas hyperoxia applied 2 min before the onset of exercise and maintained for 2.5 min during the running tests had a significantly weaker effect on VE (-1.8 +/- 0.2 l x min(-1), P < 0.05). The rise in pulmonary CO2 output (VCO2) during the prolonged O2 exposure was less than in normoxic exercise leading to a deficit of CO2 eliminated by the lungs of 181 ml. The return to air breathing provoked a rise in VE, which reached within 73 s a much higher level than the control tests (22.9 +/- 3.6 vs. 19.5 +/- 2.2 l x min(-1), P < 0.05); VE then subsided to control levels with a long exponential decline. The CO2 deficit during O2 breathing, was fully compensated after recovery in air within 6 min. No stimulatory effect on ventilation was observed at rest at the cessation of a similar exposure to O2 despite a higher end-tidal PCO2 (+4 +/- 1 mmHg) than in exercise. In conclusion, the stimulatory effect of O2 during exercise can be clearly revealed after recovery in air and seems to operate through a more complex mechanism than that thought to be involved at rest. We propose that the changes in CO2 stores in the exercising muscles could contribute to O2-induced stimulation during exercise, possibly through stimulation of muscle afferents responding to local circulatory changes. Finally, the observation that during continuous dopamine (DA) infusion (5 microg x kg(-1) x min(-1)) the VE response to recovery in air was only a slow decrease, suggests that the arterial chemoreceptors potentiate O2-induced hyperventilation, or that the vascular actions of DA counteract part of the effects provoked by CO2 accumulation in the exercising muscles.

[Value of pulmonary gas exchange study during exercise in the diagnosis of a muscular glycogenosis]. / Apport de l'étude des échanges gazeux respiratoires au cours de l'exercice dans le diagnostic d'une glycogénose musculaire.

BACKGROUND: The diagnosis of muscular glycogen storage disease is usually difficult to demonstrate as symptoms normally consist of muscular cramps and exercise intolerance. Informations obtained from the study of the pulmonary gas exchange during exercise in a young patient with a glycogen storage disease are reported. CASE REPORT: The ventilatory and gas exchange responses to a cyclo-ergometer exercise were studied in a 17-year-old girl during a ramp-like test (5 W/min). The temporal profile of CO2 production (VCO2) response was clearly abnormal: VCO2 was always lower than oxygen consumption throughout the test, reflecting the lack of lactate buffering by the bicarbonates due to the absence of lactate production. The respiratory ratio was still around 0.75 at the peak of the test. In contrast, responses were perfectly normal in the other members of the family, allowing rejection of the diagnosis of glycogen storage disease without any blood sampling. CONCLUSION: This case illustrates the benefit of studying pulmonary gas exchange during exercise for a non-invasive diagnosis of muscular glycogen storage disease and detection of the disease in the other members of family.

Laryngeal reflex apnea is blunted during and after hindlimb muscle contraction in sheep.

This study was carried out on seven chloralose-anesthetized sheep and was designed to investigate the role of muscular afferent fiber stimulation on the duration of reflex apnea triggered by laryngeal stimulation (LS). In six animals, injection of distilled water onto the laryngeal mucosa provoked a 15.7 +/- 1.0 s (mean +/- SE) apnea associated with a rise in systemic blood pressure (+7 +/- 0.8 Torr). Electrically induced contractions (EIC) of the hindlimb muscles doubled the metabolic rate and ventilation and reduced the duration of the apnea produced by LS to 7.4 +/- 1.0 s (P < 0.01). Apnea duration was still reduced during the first minute after the cessation of EIC (7.2 +/- 1.1 s, P < 0.01) but returned to control after a 5-min recovery period (16.7 +/- 1.6 s). The apnea triggered by LS was also reduced during EIC when the venous return was impeded by occluding the inferior vena cava (5.2 +/- 1.1 s, P < 0.01), despite a profound hypocapnia (20.7 +/- 0.3 Torr). The duration of apnea was not significantly affected (14.2 +/- 1.4 s) by breathing a 6% CO2-14% O2 in N2 gas mixture that roughly mimicked the alveolar gas composition when the apnea turned off. These results suggest that chemical drive has a negligible role in the fast reinitiation of breathing after LS during muscular stimulation. Stimulation of muscle afferent fibers does, however, appear to be a potent source of ventilatory reflexes capable of counteracting the inhibition of breathing resulting from laryngeal stimulation. Conversely, it is postulated that any reduction in somatic afferent traffic during this type of reflex apnea, including that resulting from the LS-induced systemic vasoconstriction, may delay the termination of apnea.

Papaverine injection into the hindlimb circulation stimulates ventilation in sheep.

To test the hypothesis, previously suggested by Huszczuk et al. (1993), that distention of the peripheral microvascular network could, per se, stimulate ventilation, the ventilatory effects of papaverine-induced muscular vasodilation were studied in ten anaesthetized sheep. Because systemic action of papaverine may involve the arterial baro- and chemoreceptors, the animals were surgically prepared for a reversible isolation of the hindlimb circulation. Papaverine injection (1-2 mg/kg) into the arterial inflow of the isolated limbs provoked a 13 +/- 6 sec-delayed increase in VE by 1.8 +/- 0.2 L min-1 (p < 0.01) with a concomitant decrease in peripheral vascular resistance and no decrease in the systemic arterial blood pressure. Identical control injection into a jugular vein prior to the hindlimb circulatory separation yielded an increase of VE by 4.95 +/- 0.58 L min-1 with a latency of 21 +/- 2 sec and a coinciding moderate decrease of the systemic arterial pressure. The present data suggest that papaverine injection into the hindlimb circulation can stimulate ventilation independently of its possible effects on the arterial baro- or chemoreceptors, supporting the hypothesis that muscular vasodilation could contribute to the control of breathing through a neural link.

Vascular distension in muscles contributes to respiratory control in sheep.

It has recently been proposed that afferent fibers from skeletal muscle could sense the state of the microvascular circulation, linking ventilation to the degree of peripheral perfusion or vascular distension (Huszczuk et al., Respir. Physiol., 91:207-226, 1993). Ventilatory and circulatory responses to manipulation of peripheral vascular pressures in the hind limbs of anaesthetized (sodium thiopental) sheep were examined. Inflatable balloons were placed at the caudal ends of the abdominal aorta and the vena cava (Vc). Aortic (Ao) occlusion induced a consistent normocapnic decrease in minute ventilation (VE). In contrast, VE increased significantly during vena cava obstruction, leading to hypocapnia. Small changes in systemic blood pressure were observed (+7 mmHg for Ao occlusion and -12 mmHg during Vc obstruction). Moreover, inflation of the caval balloon superimposed on a previously established Ao occlusion, preventing venous drainage of anastomotic inflow, resulted in a significant rise in distal vascular pressures with trivial changes in systolic blood pressure. This led to a gradual rise of VE, despite further reduction of the CO2 flux to the lungs. The subsequent deflation of the aortic balloon, exposing the hindlimb vasculature to aortic pressure, resulted in an even more profound hypocapnic hyperpnea. The concurrent arterial blood pressure changes were too small to possibly involve the ventilatory component of the arterial baroreflex. We therefore hypothesize, that perfusion-related afferent signals within the muscles could contribute to respiratory homeostasis by maintaining ventilation of the lungs commensurate with the circulatory state of the muscular apparatus.

Extracorporeal circulation in European Economic Community (ECC in EEC): 1979-1989.

This study determines the evolution of ECC in EEC. After recollecting the great stages of ECC since its routinely use in open heart surgery, the study situates its position in the entire world taking into account several indexes like the Gross National Product (GNP) and its evolution, the life expectancy and some other factors either technical or economical. Only a coarse analysis could be done for Europe due to an unsteady evolution. A more detailed analysis has been achieved for France thanks to a greater number of data. In such a study the major difficulty is to estimate the relevance and consistency of data which can change very quickly and are provided either by companies or by other organization.

EC CO2R: oxygenator or hemodialyzer? An in vitro study.

In respiratory support of patients with acute respiratory distress syndrome (ARDS), the extracorporeal CO2 removal (EC CO2R) technique should be the earliest and easiest procedure so as to have the lowest blood flow rate. Extracorporeal circulation (ECC) can be achieved using an oxygenator for CO2 removal under the dry form (dissolved CO2) or a hemodialyser for CO2 removal under the wet form (bicarbonates). This study investigated different methods allowing an increase in CO2 transfer, using liquid flow rates up to 0.330 l/min. The experimental set-up employed heated (38 degrees C) aqueous polyelectrolytic solutions mimicking the venous blood (pH 7.20, PCO2 53 mmHg). Four in vitro methods were tested: Series I: a DIDECO D702 oxygenator without blood (= liquid) acidification, Series II: D702 oxygenator with inlet HCl acidification, Series III: a HOSPAL H10-10 hemodialyzer without dialysate alkalinisation, Series IV: H10-10 hemodialyzer with NaOH dialysate alkalinisation. Maximum gas flow in the oxygenator and dialysate rate in hemodialyzer were 5 and 0.55 l/min respectively. For the four series the CO2 transfer (TCO2) (mean +/- S.E. ml/min) and pH out were: [table: see text] The difference between the four series was statistically significant (t-test). Acidification using the oxygenator increased CO2 transfer by 80%, but CO2 elimination was better with hemodialysis.

[CO2 elimination via extracorporeal circulation in respiratory assistance: artificial lung or kidney? Experimental study]. / Circulation extracorporelle (CEC) d'élimination de CO2 en assistance respiratoire: poumon ou rein artificiel? Etude expérimentale.

In the context of a respiratory assistance protocol dissociating oxygenation of the blood from elimination of carbon dioxide, it is possible to rest the lungs which are used for oxygen exchange by diffusion via functional zones. CO2 is eliminated via extracorporeal circulation. In order to simplify this method, the authors investigated the optimal conditions for this elimination at flow rates similar to those used for haemodialysis (0.33 l/min). This study was designed to evaluate the in vitro elimination of CO2 obtained by a membrane artificial lung with and without "doping" by acidification (10 ml/min of 0.01 N HCl) of the blood inlet compared with that obtained with a haemodialysis machine with and without alkalinisation (0.5 ml/min of 0.5 N NaOH) of the dialysate inlet. The results obtained showed that haemodialysis with an alkaline bath ensured CO2 elimination 36% superior to that of the artificial lung associated with acidification.

[Use of extracorporeal circulation oxygenators (CEC) in the European Economic Community (EEC)]. / Utilisation des oxygénateurs en circulation extra-corporelle (CEC) dans la Communauté Economique Européenne (CEE).

This study analyses the growth of CPB in the EEC. The study situates its position in the world taking into account several indexes such as the Gross National Product and its growth the life expectancy and other technical or economic factors. Only a broad analysis could be performed for Europe to the irregular development of CPB. A more detailed analysis was performed for France thanks to a greater number of data. In this type of study the most important problem is to estimate the relevance and consistency of the data provided either by companies or by other organizations because they can change very quickly.

Monitoring of blood gases during extracorporeal circulation with an artificial lung.

During cardiopulmonary bypass, the heart-lung machine and the patient's gas exchange systems (uptake and elimination) form an undissociable couple. Changes in one of the components lead to corresponding changes in the other. In the artificial lung, like in the natural lung and peripheral tissues, gas exchanges depend on several parameters: blood inlet conditions, blood flow rate, temperature, composition of the gas mixture used for ventilation, blood tissue perfusion, O2 consumption, etc. The perfusionist's primary objective is to obtain from the artificial lung adequate O2 delivery to and CO2 removal from the tissues. This paper discusses the main parameters which must be taken into account and analyses the main sensors currently available for in-line measurement of blood gases.

Metabolic CO2 removal by dialysis: THAM vs NaOH infusion.

New methods of respiratory support are needed to reduce the high mortality rate of acute respiratory failure. To simplify the procedures of extracorporeal CO2 elimination under apneic oxygenation, one approach is to replace the membrane lung by a hemodialyzer and to administer an alkali, since hemodialysis requires a lower blood flow rate than blood-gas exchange. This study compared the effectiveness of trishydroxymethyl aminomethane (THAM) and NaOH in this procedure. Twelve male Anglo-Poitevin dogs (25 to 33 kg) were anesthetized, curarized and mechanically hypoventilated (VE = 41% of the control value). After not less than 15 min, a venovenous shunt was used for dialysis with blood flow of 7-10 ml. min.-1kg-1 for at least 8 hours. The dialysate contained no acetate, bicarbonate or lactate, but was alkalinized to a pH of 8-9 by the addition of NaOH. A solution of THAM (0.5 N) was infused into the right heart at the rate of 0.30 ml.min.-1kg-1 in six animals, and NaOH (0.15 N) was infused in the other six at the rate of 0.80 ml.min-1kg-1. The injected volumes were compensated for by an equivalent amount of ultrafiltration. Elimination of CO2 (mean TCO2 = 2.3 ml.min.-1kg-1) was the same with both methods and the difference for the electrolytes and acid-base equilibrium was only very small. However, hemolysis was six times greater with NaOH than with THAM. Despite ultrafiltration, a similar marked weight gain was observed from the second hour of the experiment in the NaOH series, but only after 7 hours with THAM. It thus appears that hemodialysis combined with alkalinisation is still too complex a procedure to be safely applied in acute or chronic pulmonary failure.

CO2 removal with hemodialysis and control of plasma oncotic pressure.

CO2 removal by hemodialysis, associated with systemic alkalinization, is the simplest method of metabolic CO2 elimination. In this experimental work, the authors investigated the efficacy of this protocol in modifying an alkaline perfusate by addition of dextran 40. The results, unlike those of preceding experimental series without dextran, disclosed no significant change in weight, hemodynamic variables, electrolyte concentrations or osmotic or oncotic pressures after 12 hours. Sixty-five percent of metabolic CO2 was eliminated with a bypassed blood flow rate of only 8% of cardiac output.

Cardiorespiratory function and pathological findings in heart-lung block reimplanted after hypothermic preservation.

A good result from the heart-lung transplantation depends on the quality of the preservation of cardiopulmonary transplants. To determine the functional and pathological status of the heart-lung block after preservation for several hours, we performed 10 heterologous heart-lung transplantations in Beagle dogs (weight 13.5 kg) under extracorporeal circulation. Weight and length compatibility between donor and receiver was ensured. Measurements of hemodynamics, lung mechanics and blood gases were performed in the donor and in the receiver before the transplantation, and in the receiver after heart-lung reimplantation. Histological studies were carried out by biopsy on the heart and on the lung of the donor before removal, at the beginning of the preservation at low temperature, after 3 h of ischemia in cold, and every hour after recirculation in the heart-lung block. Myocardial preservation was conducted with cold cardioplegia at 4 degrees C (Ringer lactate solution with high potassium). Lung preservation was achieved by injecting a Euro-Collins solution at 4 degrees C, with addition of dog plasma, into the pulmonary artery; during the whole ischemic phase, the lung parenchyma was maintained at 0 degrees C, and inflated at a 10 cm H2O pressure. After transplantation, we observed that cardiac output was low in all cases, with normal or subnormal pulmonary arterial pressure. Dynamic lung compliance was very low immediately after transplantation, and increased when restarting the circulation, but deteriorated again after several hours. At the same time alveolo-arterial O2 pressure difference and arterio-alveolar CO2 pressure difference progressively increased, due to the extensive gas exchange impairment.(ABSTRACT TRUNCATED AT 250 WORDS)

[Experimental chronic paraquat poisoning. Functional and histopathological pulmonary changes]. / Intoxication chronique expérimentale au paraquat. Modifications pulmonaires fonctionnelles et histopathologiques.

An experimental model of pulmonary interstitial fibrosis was attempted in beagle dogs by intravenous administration of weak doses of paraquat. After various trials, the final protocol involved the intravenous injection of 2 mg/kg repeated every eight days for three weeks, and then every 15 days. On the 70th day, areas of localized interstitial fibrosis were observed (less than 10% of the surface of the tissue sections) in an otherwise healthy parenchyma. There was no marked hepatic or renal lesion. The evolution of the inflammatory and toxic processes was followed by the changes: 1) in the animal's weight (drop in weight after the injection of paraquat), 2) in blood gases (essentially drop in PaO2 and in SaO2), 3) in ventilation and respiratory exchanges (increase of VE and ventilatory frequency, decrease of Duco2), and 4) in static pulmonary compliance (distinct fall after injection). All these modifications showed a close relationship to the pattern of the paraquat injections. They receded 15 days after the last injection and reappeared after a new injection. The pulmonary hemodynamic study carried out only at the beginning of the experiment and before the animal was killed showed only a few anomalies (reduction of the average pressure of the right atrium).

Pentose pathway in pulmonary fibrosis due to chronic paraquat poisoning.

In 14 beagle dogs, paraquat was infused in fractional doses to produce pulmonary fibrosis while avoiding fatal liver and kidney lesions. Activity of the three enzymes of the pentose pathway: glucose-6-phosphate dehydrogenase (G-6-PDH), glutathione reductase (GR) and glutathione peroxidase (GSH Px), which supply reduced equivalents against oxidant agents, were measured in the mediastinal lobe of the lung. After a single low dose (2-3 mg/kg body weight), GR and GSH Px activities were reduced. After repeated paraquat doses, pentose pathway enzyme activities were higher than after a single low dose; however, they did not significantly exceed the normal values as determined in control dogs. The activities of G-6-PDH, GR and GSH Px correlated with the total paraquat dose and with the extent of pulmonary fibrosis measured with an electronic image analyzer. The activity of pulmonary lactate dehydrogenase, which was also reduced after a single low dose of paraquat, did not show the same correlations.

[Hemodynamic effects of normovolemic hemodilution]. / Les effets hémodynamiques de l'hémodilution normovolémique.

After reviewing data from the literature concerning the effects of normovolaemic haemodilution on cardiac output and regional flow rates, the authors illustrate these concepts by a personal study involving the haemodynamics of 10 subjects undergoing operation in normovolaemic haemodilution. Removal of blood was compensated simultaneously by modified liquid gelatin in electrolytic solution (Plasmion) until the haematocrit was 0.30. Measurements were performed before haemodilution in patients in a steady state (anaesthetised, intubated, normoventilated), at the end of haemodilution, at the end of the operation, then 4 hours after recovery. There was no variation in blood pressure and heart rate, showing that normovolaemia was maintained. At the end of haemodilution, cardiac index increased from 3.10 to 3.84 l.min-1.m-2 (0.0517 to 0.0638 l.s-1 . m-2) (p < 0.005); stroke volume increased from 70 to 83 ml (p < 0.005); systemic resistance fell from 1585 to 1262 dynes. s.cm-5 (158.5 to 130.4 kPa.s.l-1) (p < 0.005); arterial oxygen content decreased from 191.1 to 152.1 ml.100 ml-1 (8.535 to 6.793 mmol.l-1) (p < 0.005), whilst oxygen transport was unchanged. These various haemodynamic measurements showed no significant changes at the subsequent times when they were measured, values remaining close to those obtained at the end of haemodilution. The results confirm the fact that norvolaemic haemodilution is accompanied by a fall in systemic vascular resistance with an increase in cardiac output. Regional circulations are thus improved. Since oxygen transport is unaffected, the oxygenation of peripheral tissues is ensured normally.