Department of Anaesthesiology, Erasmus University Rotterdam, Rotterdam, The Netherlands
Accepted for publication: 12 June, 2000
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Abstract |
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Br J Anaesth 2000; 85: 7526
Keywords: models, respiratory distress; ventilation, mechanical; lung, surfactants; lung, lavage
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Introduction |
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Exogenous surfactant improves lung function in the respiratory distress syndrome (RDS) of the premature newborn, giving better gas exchange, lung mechanics and outcome.8 Since hypoxia and poor lung mechanics in ALI are also caused by a lack of active surfactant, the efficacy of surfactant replacement in ALI is being studied experimentally and clinically.9 10 11 Surfactant therapy in adults is expensive and the large amount of surfactant that is needed is difficult to obtain. If protein influx could be reduced in ALI patients, the surfactant dose could be reduced so that surfactant replacement would be practicable.
We considered the hypothesis that the improvement in lung function after surfactant replacement would be better if ventilation with a high PEEP were used to decrease alveolar protein influx. We therefore ventilated surfactant-depleted rats with a high or a low PEEP, and then assessed gas exchange and lung mechanics in response to surfactant treatment.
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Methods |
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In the remaining animals, acute lung injury was induced by repeated bronchoalveolar lavage (BAL) (32 ml kg1) with warm saline (37°C).12 Lavage was repeated as often as necessary to produce a PaO2 <13 kPa at a PIP of 26 cm H2O and a PEEP of 6 cm H2O. Within 10 min after the last lavage, the animals were randomized to two study groups (eight animals in each group). In the first group, mechanical ventilation according to the open lung concept was applied. In this strategy, collapsed alveoli are recruited by applying a high PIP and kept open with a high PEEP, and PaO2 can be kept >65 kPa.3 In the present study, we used identical ventilator settings. First, the lungs were opened by increasing PIP to 40 cm H2O and PEEP to 20 cm H2O, and the I:E ratio was set at 1:1. After 23 min, PIP was decreased to 35 cm H2O and PEEP to 18 cm H2O, and arterial blood gas samples were taken. Ventilator settings remained unchanged for the remainder of the study period. In the second group, which served as ventilated controls, ventilator pressure was increased by 2 cm H2O (PIP/PEEP 28/8 cm H2O). These ventilator settings were based on results from a previous study using this model, which found that at these settings PaO2 remained stable at a low value of about 13 kPa for 4 h at an FIO2 of 1.0, indicating that large parts of the lungs remain collapsed and protein transfer into the alveoli is increased.3 In the present study, both ventilated groups were treated with surfactant at a dose of 120 mg kg1 after 4 h of ventilation. The surfactant used was isolated from minced pig lungs, processed as described previously.13 The freeze-dried material was suspended in warm saline to a concentration of 40 mg ml1 and given into the trachea after the animals had been disconnected from the ventilator. The surfactant suspension was given as a bolus followed by a bolus of air (12 ml kg1), directly into the endotracheal tube via a syringe, and this was followed immediately by reconnection to the ventilator. After administration of surfactant, ventilation was continued for 15 min with the previous ventilator settings. This short interval was chosen because maximal improvement of lung function by exogenous surfactant occurs 25 min after administration, and because the inactivation of surfactants by proteins occurs instantaneously.
Arterial blood gas samples were taken before lavage, after lavage, hourly for 4 h after lavage, and immediately and 15 min after surfactant administration. The samples were analysed for PaO2 and PaCO2 with an electrochemical blood gas analyser (ABL 505; Radiometer, Copenhagen, Denmark).
At the end of the experiment, the animals were killed with an overdose of pentobarbital. Static pressurevolume curves were recorded using conventional techniques. Total lung capacity was defined as lung volume at inflation with a distending pressure of 35 cm H2O (TLC35). Maximal compliance (Cmax) was defined as the steepest part of the deflation limb of the pressurevolume curve. After the pressurevolume recordings, BAL was performed five times with salineCaCl2 1.5 mmol litre1. The active surfactant component in the BAL fluid was separated from the non-active surfactant component by differential centrifugation followed by subsequent phosphorus analysis, and the ratio of non-active to active components (small aggregate:large aggregate ratio=SA:LA ratio) was calculated as described by Veldhuizen and colleagues.14 The protein concentration of the BAL fluid was determined using the Bradford method15 (Bio-Rad, Munich, Germany).
Statistical analysis was performed with the Instat 2.0 biostatistics package (GraphPad, San Diego, CA, USA) under Windows 95. For blood gases, intergroup comparisons were analysed using the alternative (Welch) t-test, while intragroup comparisons were analysed using repeated measures analysis of variance (ANOVA). All other data were analysed with ANOVA. If ANOVA resulted in P<0.05, a TukeyKramer post-test was performed. All data are reported as mean (SD) and P<0.05 was considered statistically significant.
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Results |
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Tidal volume after lavage was similar in the two ventilated groups: 10.2 (0.6) and 10.9 (0.7) ml kg1 for the high-PEEP and control groups respectively.
The protein concentration of BAL fluid was significantly greater in both ventilated groups than in healthy control animals (Fig. 2). However, in the ventilated control group protein concentration was significantly greater than in the high-PEEP group.
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Discussion |
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In the ventilated control group, TLC35 and Cmax were lower than in the healthy controls. In the high-PEEP group this difference was not found (Table 2 and Fig. 3). Surfactant has the unique ability to reduce surface tension at the airliquid interface in the alveoli and to reduce alveolar radius, thus improving lung distensibility and alveolar stability. Plasma proteins decrease the ability of surfactant to decrease surface tension.6 We suggest that the poor response of lung mechanics in the low-PEEP group after administration of surfactant was caused by the greater degree of protein transfer into the alveoli in this group. These results are consistent with previous results obtained in this model, in which mechanical ventilation with high PEEP decreased protein transfer into the alveoli and improved lung mechanics.3 7
An important factor in decreasing protein influx is probably the prevention of damage to the alveolar epithelium by reducing the shear forces from repeated alveolar collapse.4 PEEP can also shift fluid from the alveoli to the interstitium by decreasing the pressure gradient across the alveolarcapillary membrane.16 Furthermore, there is evidence that PEEP prevents the loss of surfactant from the alveoli. This will prevent an increase in surface tension, which could increase protein influx from capillary to alveolus.5
Before administration of surfactant, PaO2 was >66 kPa in the high-PEEP group, indicating that the ventilator settings were sufficient to open up the lungs and keep them open; this confirms previous experience (Fig. 1).3 7 The decrease in oxygenation after surfactant administration is attributable to the bolus of liquid in which the surfactant was suspended, which partially filled the alveoli, causing a decrease in diffusion.9
No differences were found between the ventilated groups in non-active and active surfactant aggregates (SA:LA ratio). This supports the report of Veldhuizen et al., who showed that the conversion of LA into SA depends on alveolar area cycling and time.17 Alveolar cycling is determined by tidal volume, which was similar in the two ventilated groups.
An important factor in successful treatment with surfactant in RDS of the premature infant is giving the surfactant shortly after birth, to reduce the time in which proteins can transfer into the surfactant-deficient alveoli. In the adult ALI patient, where the surfactant deficiency is secondary to lung injury, protein concentration in the alveoli is increased.18 Mixing exogenous surfactant with plasma proteins decreases the ability of surfactant to improve gas exchange, and larger amounts of surfactant are necessary to overcome the inhibitory effects.6 This study shows that surfactant therapy can be improved by attenuating the increase in protein transfer into the alveoli. It has been suggested that a decrease in alveolar protein concentration, for example by lobe-wise lung lavage, could improve the effect of exogenous surfactant on pulmonary function.19 Our study suggests that if the lungs are kept open with a high PEEP during the ventilation period before surfactant treatment, the efficacy of surfactant treatment can be improved. Because the inhibition of surfactant by proteins is dose-dependent, a reduction in protein influx during mechanical ventilation before surfactant administration is important, as it could reduce the surfactant dose, reduce costs and improve outcome in ALI.
In conclusion, the improvement in lung function after surfactant treatment in experimental ALI is better if a high PEEP is used to decrease alveolar protein influx. Clinical studies are necessary to assess the effects of high PEEP in ALI patients who might benefit from surfactant therapy, in increasing the efficacy of surfactant replacement and improving the outcome.
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Acknowledgements |
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Footnotes |
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References |
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2 Lachmann B, Jonson B, Lindroth M, Robertson B. Modes of artificial ventilation in severe respiratory distress syndrome: lung function and morphology in rabbits after wash-out of alveolar surfactant. Crit Care Med 1982; 10: 72432[ISI][Medline]
3 Hartog A, Vazquez de Anda GF, Gommers D, Kaisers U, Verbrugge SJC, Lachmann B. Comparison of exogenous surfactant therapy, mechanical ventilation with high end-expiratory pressure and partial liquid ventilation. Br J Anaesth 1999; 82: 816
4 Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 1998; 157: 294323
5 Verbrugge SJC, Böhm SH, Gommers D, Zimmerman LJI, Lachmann B. Surfactant impairment after mechanical ventilation with large alveolar surface area changes and effects of positive end-expiratory pressure. Br J Anaesth 1998; 80: 3604
6 Lachmann B, Eijking EP, So KL, Gommers D. In vivo evaluation of the inhibitory capacity of human plasma on exogenous surfactant function. Intensive Care Med 1994; 20: 611[ISI][Medline]
7 Hartog A, Vazquez de Anda GF, Gommers D, Kaisers U, Lachmann B. In surfactant deficiency application of the open lung concept prevents protein leakage and attenuates changes in lung mechanics. Crit Care Med 2000 (in press)
8 Robertson B. Pathology and pathophysiology of neonatal surfactant deficiency (respiratory distress syndrome, hyaline membrane disease). In: Robertson B, van Golde LMG, Batenburg JJ, eds. Pulmonary Surfactant. Amsterdam: Elsevier, 1984; 384418
9 Lachmann B, Fujiwara T, Chida S, et al. Surfactant replacement therapy in the experimental acute respiratory distress syndrome (ARDS). In: Cosmi EV, Scarpelli EM, eds. Pulmonary Surfactant System. Amsterdam: Elsevier, 1983; 2315
10 Häfner D, Beume R, Kilian U, Kraznai G, Lachmann B. Doseresponse comparisons of five lung surfactant factor (LSF) preparations in an animal model of adult respiratory distress syndrome (ARDS). Br J Pharmacolol 1995; 115: 4518[Abstract]
11 Gregory TJ, Steinberg KP, Spragg R, et al. Bovine surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 1997; 155: 130915[Abstract]
12 Lachmann B, Robertson B, Vogel J. In vivo lung lavage as an experimental model of the respiratory distress syndrome. Acta Anaesthesiol Scand 1980; 24: 2316[ISI][Medline]
13 Gommers D, Vilstrup C, Bos JAH, et al. Exogenous surfactant therapy increases static lung compliance, and cannot be assessed by measurements of dynamic compliance alone. Crit Care Med 1993; 21: 56774[ISI][Medline]
14 Veldhuizen RAW, Inchley K, Hearn SA, Lewis JF, Possmayer F. Degradation of surfactant associated protein B (SP-B) during in vitro conversion of large into small surfactant aggregates. Biochem J 1993; 295: 1417[ISI][Medline]
15 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of proteindye binding. Anal Biochem 1976; 72: 24854
16 Permutt S. Mechanical influences on water accumulation in the lungs. In: Fishman AP, Renkin EM, eds. Pulmonary Edema. Clinical Physiology Series. Bethesda: American Physiology Society, 1979; 17593
17 Veldhuizen RAW, Marcou J, Yao L-J, et al. Alveolar surfactant aggregate conversion in ventilated normal and injured lungs. Am J Physiol 1996; 270: L1528
18 Holm BA. Surfactant inactivation in adult respiratory distress syndrome. In: Robertson B, van Golde LMG, Batenburg JJ, eds. Pulmonary Surfactant. Amsterdam: Elsevier, 1992; 66584
19 Enhorning G. Surfactant replacement in adult respiratory distress syndrome. Am Rev Respir Dis 1989; 140: 2813[ISI][Medline]