1Klinik für Anaesthesiologie und Operative Intensivmedizin, Charité, Campus Virchow Klinikum, Medizinische Fakultaet der Humboldt-Universitaet, Augustenburger Platz 1, D-13353 Berlin, Germany, 2Abteilung für Neurochirurgie, Charité, Campus Virchow Klinikum, Medizinische Fakultaet der Humboldt-Universitaet, Augustenburger Platz 1, D-13353 Berlin, Germany, 3Chirurgische Klinik und Poliklinik, Charité, Campus Virchow Klinikum, Medizinische Fakultaet der Humboldt-Universitaet, Augustenburger Platz 1, D-13353 Berlin, Germany and 4Molekulare Haematologie, Klinikum der Johann Wolfgang von Goethe Universitaet, Theodor-Stern-Kai 7, D-60590 Frankfurt Main, Germany
Accepted for publication: May 10, 2001
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Abstract |
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Br J Anaesth 2001; 87: 593601
Keywords: lung, acute injury; ventilation, partial liquid; lung, surfactant; lung, gas exchange; blood, haemodynamics; model, animal
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Introduction |
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Mechanical ventilation can further damage the alveolocapillary unit by overdistension, and cyclic collapse and re-opening of terminal airways.25 Mechanical ventilation with tidal volumes of 6 ml kg1, a positive end-expiratory pressure (PEEP) level above the lower inflection point, and a peak inspiratory pressure below the upper inflection point may protect against this effect.2 6 Other treatments to reduce the mechanical shear stress of the lung include surfactant replacement,711 partial liquid ventilation (PLV),1217 and extracorporal membrane oxygenation (ECMO).18 Giving surfactant may reduce surface tension, improve gas exchange and lung mechanics.711 In PLV the lung is partially filled with a perfluorocarbon and conventional mechanical ventilation is resumed. PLV can improve gas exchange and lung mechanics without significantly affecting systemic circulation.1217
Exogenous surfactant and PLV have been investigated using different doses and different experimental models of ALI.1929 The effects on gas exchange, haemodynamics, lung mechanics, and lung damage were variable.
A combination of 100 mg kg1 of surfactant with PLV, restored pulmonary gas exchange more efficiently in an experimental model of neonatal ALI than surfactant therapy alone. However, a combination of PLV with only 5 mg kg1 of surfactant failed to give additional benefit compared with PLV alone.27 29
We compared a single dose of 50 mg kg1 surfactant alone vs 50 mg kg1 surfactant combined with PLV in a pig model of ALI, with measurements of gas exchange, haemodynamics, respiratory mechanics, and progression of lung injury.
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Methods |
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General experimental procedures
We studied 24 piglets (weight 2327 kg), aged between 6 and 8 weeks. Anesthesia was induced with thiopental (10 mg kg1 i.v.) and fentanyl (10 µg kg1 i.v. followed by an infusion of 0.050.08 µg kg1 min1). Muscle relaxation was obtained with pancuronium bromide (0.15 mg kg1 i.v. bolus, followed by a continuous infusion of 2.5 µg kg1 min1). Immediately after induction, the pigs were tracheotomized and intubated with a 9.0 mm outer diameter tracheal tube, fitted with a heat and moisture exchanger.
The animals were placed supine and ventilated in a volume controlled mode (tidal volume 1012 ml kg1, respiratory rate 16 min1, FIO2 1.0, I:E ratio 1:1, PEEP 5 cm H2O) with an EVITA 2 model 76 ventilator (Dräger, Lübeck, Germany). Core temperature was maintained within ±0.5°C of the pre-study value using a heating pad. No drugs were used to support the circulation.
We placed a pulmonary artery catheter (model 93A-431-7.5 Fr, Baxter Healthcare Corporation, Irvine, CA, USA) percutaneously via the femoral vein, and an arterial cannula (18 G; Vygon, Ecouen, France) into the femoral artery, for blood sampling and haemodynamic measurements. Heart rate (HR), central venous pressure (CVP), mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), and pulmonary artery wedge pressure (PCWP) were recorded using a Hewlett-Packard monitoring system (Model 66 S, Böblingen, Germany). Measurements were taken with pigs in the supine position with zero at the level of the midaxilla. Vascular pressures were the average taken at end-expiration of three successive respiratory cycles. Cardiac output (CO) was determined by thermodilution using the mean of four measurements (10 ml saline at 15°C) arbitrarily performed during different phases of the respiratory cycle. Intrapulmonary shunt (Q·S/Q·T), systemic vascular resistance (SVR), and pulmonary vascular resistance (PVR) were calculated using standard formulae.
All blood samples (arterial and mixed venous) were collected anaerobically, and analysed within 5 min (ABL 520, Radiometer, Copenhagen, Denmark). Arterial oxygen saturation (SaO2) and mixed venous oxygen saturation (SvO2) were measured by spectrophotometry with the analyser calibrated with pig blood (OSM 3 Hemoximeter, Radiometer). Static compliance of the respiratory system (CRS) was determined using automated inspiratory, repetitive occlusions (1 s) at single volume steps (SCASS).30 Measurements started with 10 ml Vt up to a maximum Vt of 1012 ml kg1, using volume steps of 10 ml each. CRS was calculated as mean of all generated pressurevolume curves from the inspiratory limb.
Lung tissue from all animals was examined histologically. After killing the animals, the tracheal tube was clamped at end-expiration (PEEP 5 cm H2O) and the lungs were removed. Perfluorocarbon was left in situ in animals treated with PLV. Tissues were fixed in 5% formalin. Specimens from the cranial ventral (non-dependent) and caudal dorsal (dependent) lobes were stained with haematoxylin and eosin and then scored using a semiquantitative scoring system by an experienced veterinary pathologist (A. S-K.), blinded to treatment, for interstitial infiltration, interstitial oedema, emphysema, and atelectasis. Each variable was scored using a 04-point scale, with no injury scored 0, injury in 25% of the field scored 1, injury in 50% of the field scored 2, injury in 75% of the field scored 3, and injury throughout the field scored 4. The total score maximum was 16.
Induction of ALI
Repeated lavage with warmed isotonic saline (37°C) was done to produce lung surfactant depletion as reported by Lachmann and co-workers, and described in detail elsewhere.31 32 Induction of ALI was assumed when the PaO2/FIO2 ratio was persistently less than 13 kPa for 1 h.
Experimental procedure
After induction of ALI, the animals were randomly assigned to receive a single intratracheal dose of surfactant alone (50 mg kg1, Curosurf®) (SURF-group, n=8), or a single intratracheal dose of surfactant (50 mg kg1), followed after 30 min by 30 ml kg1 of perfluorocarbon (PF 5080, 3M, Germany) (SURF-PLV-group, n=8), or no further intervention (controls, n=8). Evaporative losses of PF 5080 were replaced at a dose of 4 (3) ml kg1 every hour as previously found by our group.33
PF 5080 (C8F18) is a non-ozone-depleting PFC with boiling point 102°C, density (at 25°C) 1.76 g ml1, viscosity (at 25°C) 1.4 cp, vapour pressure (at 37°C) 6.8 kPa, solubility of oxygen (at 37°C) 49 ml 100 ml1, solubility of carbon dioxide (at 37°C) 176 ml 100 ml1, and surface tension (at 25°C) of 15 dyn s cm1 (information taken from 3M data sheet). Curosurf® is isolated from minced pig lungs and contains 99% lipids, mainly phospholipids, and 1% low molecular weight hydrophobic apoproteins SP-B and SP-C.16
Statistical analysis
Results are expressed as mean (SEM). The data were obtained at baseline (pre-lavage), immediately after the induction of ALI (post-lavage) and at hourly intervals for 6 h thereafter. Statistical analysis was performed using SPSS for Windows 8.0 and Sigmastat (SPSS Inc., Chicago, IL, USA). Differences between groups were evaluated using KruskalWallis ANOVA followed by post hoc comparisons with Dunns test (intergroup comparison). The Friedman test was used to compare the data after induction of ALI with the data measured during the subsequent 6 h (intragroup comparison). For post hoc testing, Dunns test also was applied. Statistical significance was assumed at P<0.05.
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Results |
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Gas exchange
Surfactant alone improved PaO2 from 8.1 (0.7) kPa after onset of ALI to 61.2 (4.7) kPa after 6 h of treatment (P<0.05 vs controls; Fig. 1, Table 2). The increase of PaO2 in the SURF-group was greater than the increase in the SURF-PLV-group after 6 h of treatment (P<0.05 vs SURF-PLV; Fig. 1, Table 2). In the PLV-SURF-group the increase of PaO2 from 7.2 (0.5) kPa after onset of ALI to 30.8 (5.0) kPa after 6 h of treatment was greater than in controls (P<0.05 vs controls; Fig. 1, Table 2).
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Survival
All animals in both treatment groups survived to the end of the study. In the control-group, four animals died of irreversible hypoxaemia during the study, one after 3 h, two after 4 h, and one 5 h after induction of ALI (Table 2).
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Discussion |
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Surfactant therapy combined with PLV has been studied in different types of ALI.19 29 Studies have been done in surfactant deficient pre-term animals,19 24 26 29 isolated lungs of pre-term animals,23 27 newborn animals with ALI induced by surfactant wash-out,21 25 27 and experimental ALI in adult animals.20 22 Criteria for onset of ALI after surfactant wash-out was a PaO2/FIO2 ratio below 8 kPa (60 mm Hg), with the exception of the studies by Hartog and co-workers and Kelly and co-workers, who used a value below 13 kPa (100 mm Hg) to indicate ALI.20 22 The duration of PaO2/FIO2 less than 8 kPa of 30 min to indicate the induction of ALI was specified only in one study.21 Our lavage procedure caused a stable PaO2/FIO2 ratio of 7.6 (0.6) kPa (57 (5) mm Hg) for at least 1 h after the last lavage. The severity of the lung injury in our animals resembles surfactant deficient pre-term animals, shown by the high shunt fraction, which was 54 (4)% after lung injury.
Mrozek and co-workers compared four different treatments in newborn piglets, after induction of ALI. One group received 100 mg kg1 surfactant, one group received PFC in a dose equivalent to the functional residual capacity, one group received PFC 30 min after surfactant replacement, and one group received surfactant 30 min after instillation of PFC.27 In contrast to our finding that a single dose of surfactant caused the greatest improvement in PaO2, Mrozek and colleagues found that a combination of surfactant and PLV was better than the effect of surfactant alone on gas exchange, lung mechanics, and lung pathology. They make no comment on the decrease in PaO2 after instillation of PFC in the group treated with PLV after surfactant replacement.
These differences could be attributed to the following: (1) different timepoints of measurement, (2) the use of a bovine surfactant (Survanta), (3) a higher dose of surfactant (100 mg kg1), (4) newborn piglets as study subjects, and (5) the use of pre-oxygenated perflubron (LiquiVent). Another difference was positioning the animals while filling the lungs with PFC, which might have allowed greater perfluorocarbon dose and a more homogenous distribution of PFC throughout the lungs, although this technique appears to be impractical under clinical circumstances. In a study of ALI induced in premature lambs, Leach and co-workers compared either surfactant replacement, a combination of surfactant replacement and PLV, or PLV alone.29 In this study, a very small dose (5 mg kg1) of an artificial surfactant (Exosurf) did not improve oxygenation and respiratory mechanics when compared with conventional ventilation. The combination of surfactant and PLV was not better than PLV alone. Leach and co-workers attributed the lack of surfactant efficacy to the small dose used and to the modest physiologic activity of synthetic surfactant, which gives a greater surface tension than natural surfactant.29
In our study, improvements in oxygenation and intrapulmonary right-to-left shunt were delayed in the SURF-PLV-group. This could have been because: (1) PLV was started 30 min after surfactant was instilled, to avoid wash-out of exogenous surfactant; (2) inhomogeneous surfactant distribution could have caused PFC to only enter some regions and, thereby, limit alveolar recruitment. Leach and co-workers describe a transient increase in the expiratory resistance of their surfactant-PLV group and suggested that the distal movement of perfluorocarbons could have been delayed, as surfactant will remain in small airways and alveolar ducts.27
In a study from Göthberg and co-workers using a model of premature ALI, the treatment of PLV combined with conventional ventilation or combined with high-frequency oscillatory ventilation (HFOV) 2 h after giving 100 mg kg1 of surfactant (Infasurf) improved oxygenation compared with treatment with surfactant and conventional ventilation alone.17 HFOV after surfactant replacement improved PaO2 to a similar extent than HFOV combined with PLV and was significantly more effective than PLV and conventional ventilation. The different results of a treatment with PLV and conventional ventilation after surfactant replacement, compared with our data, might be because of different models, a different PFC, a later application of PFC, and different doses of surfactant. Improvement in oxygenation with HFOV, with and without PLV, could be explained by changes in airway pressures and the development of a high intrinsic PEEP from the ventilatory pattern. Previous studies showed that combining PFC and high levels of PEEP enhances the effects of PLV on pulmonary gas exchange. 1517
The improvement in CRS in our piglets treated with the combination of surfactant and PLV supports the findings of other investigators, and appears to be dose dependent.9 13 20 We measured the static compliance of the respiratory system, with an inspiratory shutter technique, to exclude effects of PFC vapour-pressure on expiratory volumes. We used 30 ml kg1 of perfluorocarbon, approximately the functional residual capacity of healthy lungs and added further liquid according to our past observations.33 Tütüncü and co-workers compared the effects of PLV with 18 ml kg1 PFC with PLV using 18 ml kg1 saline, in a similar model of ALI in rabbits, and found that compliance of the respiratory system increased in the PFC group.13 Studying adult rabbits with induced ALI, Kelly and colleagues compared the effects of different treatments.20 The treatments were PLV with 20 ml kg1 PFC, nebulized PFC, 100 mg kg1 artificial surfactant (ALEC), 100 mg kg1 porcine surfactant (Curosurf®), the combination of PLV and ALEC, the combination of PLV and Curosurf®, and a control group. Our observations support their findings for arterial oxygenation. Regarding lung mechanics, 100 mg kg1 of Curosurf® improved compliance as effectively as the combination of PLV and Curosurf®. In our study, the smaller dose of exogenous surfactant, was not sufficient to improve lung mechanics. Kelly and co-workers point out that surfactant from animals contains surfactant apoproteins, which prevent inhibition of surfactant by protein-rich fluid in lungs after induction of ALI, and that this effect is dose-dependent.20 In studies in humans, lung compliance decreases after surfactant treatment, despite increases in functional residual capacity and improvements in oxygenation. This could be because of slow recruitment of atelectatic lung areas, with stabilization of the initially opened lung units.34 35 Lack of improvement in lung compliance after surfactant administration in experimental ALI was also found by Mrozek and co-workers.27 We consider that the small dose of surfactant used in our study did not entirely overcome surfactant inhibition, and that the amount of lung tissue opened up in the SURF-group, although sufficient to improve gas exchange, was not sufficient to produce effects on CRS.
Treatment with surfactant alone caused less histological injury, for interstitial oedema, atelectasis, and emphysema compared with controls and compared with the SURF-PLV-group. Comparing the overall lung injury scores between groups, treatment with surfactant alone caused less damage in non-dependent lobes compared with controls and the SURF-PLV-group. A small dose of surfactant reduces the inflammatory response in ALI, prevents further atelectasis, and improves gas exchange. The effects on inflammation could be attributed to the apoproteins of natural surfactant, which might prevent inflammation. The greater lung injury scores in the SURF-PLV-group contrasts with previous results of Mrozek and co-workers, who found least injury with the combined treatment.27 They suggest that the lower inspiratory pressures needed for effective alveolar ventilation could be the reason for less lung injury in this group. The different PFC used for PLV and a higher dose of surfactant could account for these differences. In rats with lavage-induced ALI, Hartog and colleagues compared lung injury after treatment with surfactant, PLV, and high values of PEEP vs healthy controls and injured controls.22 Surfactant prevented progression of lung injury, when compared with healthy controls, and PLV increased lung tissue injury compared with healthy controls.
In our study, we found that cardiac output decreased significantly during the study in both treatment groups, which has not been reported previously in short term studies of lavage-induced lung injury.26 36 37 However, DO2 and V·O2 remained unchanged in both groups, indicating maintenance of a sufficient oxygen delivery. A possible explanation for the lower values of CO might be reduced sympathic activity in both treatment groups because of better oxygenation. This view is supported by poorer survival in control animals. As suggested by Dantzker and co-workers, a reduction in CO could reduce the intrapulmonary right-to-left shunt.38 The magnitude of this mechanism of shunt reduction with a CO reduction of 40% in the SURF-group and 30% in the SURF-PLV-group, suggests that this would only partly account for the reduction found, and indicate other mechanisms, such as alveolar recruitment, could be involved.
The increase in MPAP in animals treated with the combination of surfactant and PLV could be caused by the PFC. In a study from Morris and co-workers healthy pigs had their lungs filled with 40 ml kg1 of perfluorocarbons and were conventionally ventilated.35 Pulmonary blood flow was diverted from the dependent regions of the lung, associated with an increase in MPAP. The authors suggested that a greater hydrostatic pressure gradient in PFC-filled alveoli, compared with the gradient in the blood vessels, could cause this effect.37
In conclusion, using an experimental model of ALI in piglets, we found that treatment with a single small dose of surfactant improved oxygenation, decreased intrapulmonary right-to-left shunt, and reduced lung tissue damage more effectively than a combination of surfactant with PLV. However, only the combined treatment of exogenous surfactant and PLV improved lung mechanics. Taken with other evidence, these findings show that further research is needed to find the least dose of surfactant that is effective.
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Acknowledgements |
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References |
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