Small dose of exogenous surfactant combined with partial liquid ventilation in experimental acute lung injury: effects on gas exchange, haemodynamics, lung mechanics, and lung pathology

S. Wolf1, H. Lohbrunner1, T. Busch1, A. Sterner-Kock4, M. Deja1, A. Sarrafzadeh2, U. Neumann3 and U. Kaisers1

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


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
A combination of exogenous surfactant and partial liquid ventilation (PLV) with perfluorocarbons should enhance gas exchange, improve respiratory mechanics and reduce tissue damage of the lung in acute lung injury (ALI). We used a small dose of exogenous surfactant with and without PLV in an experimental model of ALI and studied the effects on gas exchange, haemodynamics, lung mechanics, and lung pathology. ALI was induced by repeated lavages (PaO2/FIO2 less than 13 kPa) in 24 anaesthesized, tracheotomized and mechanically ventilated (FIO2 1.0) juvenile pigs. They were treated randomly with either a single intratracheal dose of surfactant (50 mg kg–1, Curosurf®, Serono AG, München, Germany) (SURF-group, n=8), a single intratracheal dose of surfactant (50 mg kg–1, Curosurf®) followed by PLV with 30 ml kg–1 of perfluorocarbon (PF 5080, 3M, Germany) (SURF-PLV-group, n=8) or no further intervention (controls, n=8). Pulmonary gas exchange, respiratory mechanics, and haemodynamics were measured hourly for a 6 h period. In the SURF-group, the intrapulmonary right-to-left shunt (Q·S/Q·T) decreased significantly from mean 51 (SEM 5)% after lavage to 12 (2)%, and PaO2 increased significantly from 8.1 (0.7) to 61.2 (4.7) kPa compared with controls and compared with the SURF-PLV-group (P<0.05). In the SURF-PLV-group, Q·S/Q·T decreased significantly from 54 (3)% after induction of ALI to 26 (3)% and PaO2 increased significantly from 7.2 (0.5) to 30.8 (5.0) kPa compared with controls (P<0.05). Static compliance of the respiratory system (CRS), significantly improved in the SURF-PLV-group compared with controls (P<0.05). Upon histological examination, the SURF-group revealed the lowest total injury score compared with controls and the SURF-PLV-group (P<0.05). We conclude that in this experimental model of ALI, treatment with a small dose of exogenous surfactant improves pulmonary gas exchange and reduces the lung injury more effectively than the combined treatment of a small dose of exogenous surfactant and PLV.

Br J Anaesth 2001; 87: 593–601

Keywords: lung, acute injury; ventilation, partial liquid; lung, surfactant; lung, gas exchange; blood, haemodynamics; model, animal


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Deficiency of alveolar surfactant, pulmonary hyperten sion, intrapulmonary right-to-left shunting, and poor arterial oxygenation are features of both experimental acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS).1 Loss of surfactant increases surface tension, end-expiratory alveolar collapse, and atelectasis.

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 kg–1, 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 kg–1 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 kg–1 of surfactant failed to give additional benefit compared with PLV alone.27 29

We compared a single dose of 50 mg kg–1 surfactant alone vs 50 mg kg–1 surfactant combined with PLV in a pig model of ALI, with measurements of gas exchange, haemodynamics, respiratory mechanics, and progression of lung injury.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
This study was approved by the Berlin Animal Protection Committee in accordance with German Animal Protection Law, and conforms with the Guide for the Care and Use of Laboratory Animals (DHHS, PHS, NIH Publication No. 85-23).

General experimental procedures
We studied 24 piglets (weight 23–27 kg), aged between 6 and 8 weeks. Anesthesia was induced with thiopental (10 mg kg–1 i.v.) and fentanyl (10 µg kg–1 i.v. followed by an infusion of 0.05–0.08 µg kg–1 min–1). Muscle relaxation was obtained with pancuronium bromide (0.15 mg kg–1 i.v. bolus, followed by a continuous infusion of 2.5 µg kg–1 min–1). 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 10–12 ml kg–1, respiratory rate 16 min–1, 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 1–5°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 10–12 ml kg–1, using volume steps of 10 ml each. CRS was calculated as mean of all generated pressure–volume 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 0–4-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 kg–1, Curosurf®) (SURF-group, n=8), or a single intratracheal dose of surfactant (50 mg kg–1), followed after 30 min by 30 ml kg–1 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 kg–1 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 ml–1, viscosity (at 25°C) 1.4 cp, vapour pressure (at 37°C) 6.8 kPa, solubility of oxygen (at 37°C) 49 ml 100 ml–1, solubility of carbon dioxide (at 37°C) 176 ml 100 ml–1, and surface tension (at 25°C) of 15 dyn s cm–1 (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 Kruskal–Wallis ANOVA followed by post hoc comparisons with Dunn’s 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, Dunn’s test also was applied. Statistical significance was assumed at P<0.05.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
All animals were comparable with regard to body weight and pre-study conditions. Pre-lavage data of pulmonary gas exchange, lung compliance, and haemodynamics did not differ significantly between groups (Tables 1 and 2).


View this table:
[in this window]
[in a new window]
 
Table 1 Time course of HR, MABP, MPAP, CO, SVR, and PVR during baseline (pre-lavage), after induction of ALI (post-lavage), and for 6 h thereafter, in controls (n=8 at ALI; four pigs died before 6 h after ALI), in pigs treated with a single intratracheal dose of 50 mg kg–1 of surfactant (Curosurf®) after induction of ALI (SURF-group) (n=8 pigs, none died), and in pigs treated with a single intratracheal dose of 50 mg kg–1 of surfactant (Curosurf®) followed by PLV with 30 ml kg–1 of perfluorocarbon (PF 5080) after induction of ALI (SURF-PLV-group) (n=8 pigs, none died). Data are mean (SEM). Intergroup comparison: controls vs SURF-PLV-group and controls vs SURF-group: *P<0.05, and SURF-PLV-group vs SURF-group: {dagger}P<0.05 (Kruskal–Wallis ANOVA and post hoc Dunn’s test). Intragroup comparison: data measured after induction of ALI vs data obtained at hourly intervals thereafter: {ddagger}P<0.05 (Friedman test and post hoc Dunn’s test)
 

View this table:
[in this window]
[in a new window]
 
Table 2 Time course of intrapulmonary shunting (Q·S/Q·T), arterial oxygen tension (PaO2), arterial carbon dioxide tension (PaCO2), arterial pH (pHa), oxygen delivery (DO2), oxygen consumption (V·O2), static compliance of the respiratory system (CRS), and survivors during baseline (pre-lavage), after induction of ALI (post-lavage), and for 6 h thereafter, in controls (n=8 at ALI; four pigs died before 6 h after ALI), in pigs treated with a single intratracheal dose of 50 mg kg–1 of surfactant (Curosurf®) after induction of ALI (SURF-group) (n=8 pigs, none died), and in pigs treated with a single intratracheal dose of 50 mg kg–1 of surfactant (Curosurf®) followed by PLV with 30 ml kg–1 of perfluorocarbon (PF 5080) after induction of ALI (SURF-PLV-group) (n=8 pigs, none died). Data are mean (SEM). Intergroup comparison: controls vs SURF-PLV-group and controls vs SURF-group: *P<0.05, and SURF-PLV-group vs SURF-group: {dagger}P<0.05 (Kruskal–Wallis ANOVA and post hoc Dunn’s test). Intragroup comparison: data measured after induction of ALI vs data obtained at hourly intervals thereafter: {ddagger}P<0.05 (Friedman test and post hoc Dunn’s test)
 
In all animals, induction of ALI increased Q·S/Q·T concomitant with a decrease in PaO2. Cardiac output (CO), mean pulmonary artery pressure (MPAP), and pulmonary vascular pressure (PVR) increased while mean arterial blood pressure (MABP), and systemic vascular resistance (SVR) decreased (Tables 1 and 2).

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).



View larger version (17K):
[in this window]
[in a new window]
 
Fig 1 Time course of arterial oxygen tension (PaO2) during baseline (pre-lavage), after induction of ALI (post-lavage), and for 6 h thereafter, in controls (n=8 at ALI; four pigs died before 6 h after ALI), in pigs treated with surfactant (Curosurf®) after induction of ALI (SURF-group) (n=8 pigs, none died), and in pigs treated with surfactant (Curosurf®) followed by PLV with 30 ml kg–1 of perfluorocarbon (PF 5080) after induction of ALI (SURF-PLV-group) (n=8 pigs, none died). Data are mean (SEM). Intergroup comparison: controls vs SURF-PLV-group and controls vs SURF-group: *P<0.05, and SURF-PLV-group vs SURF-group: {dagger}P<0.05 (Kruskal–Wallis ANOVA and post hoc Dunn’s test). Intragroup comparison: data measured after induction of ALI vs data obtained at hourly intervals thereafter: {ddagger}P<0.05 (Friedman test and post hoc Dunn’s test).

 
In the SURF group Q·S/Q·T decreased significantly compared with controls (51 (5)% at onset of ALI to 12 (2)% 6 h after treatment, P<0.05 vs controls; Fig. 2, Table 2). In the SURF-PLV-group Q·S/Q·T was significantly decreased compared with controls (54 (4)% at onset of ALI to 26 (3)% after 6 h of treatment, P<0.05 vs controls; Fig. 2, Table 2).



View larger version (17K):
[in this window]
[in a new window]
 
Fig 2 Time course of intrapulmonary shunting (Q·S/Q·T) during baseline (pre-lavage), after induction of ALI (post-lavage), and for 6 h thereafter, in controls (n=8 at ALI; four pigs died before 6 h after ALI), in pigs treated with surfactant (Curosurf®) after induction of ALI (SURF-group) (n=8 pigs, none died), and in pigs treated with a single surfactant (Curosurf®) followed by PLV with 30 ml kg–1 of perfluorocarbon (PF 5080) after induction of ALI (SURF-PLV-group) (n=8 pigs, none died). Data are mean (SEM). Intergroup comparison: controls vs SURF-PLV-group and controls vs SURF-group: *P<0.05, and SURF-PLV-group vs SURF-group: {dagger}P<0.05 (Kruskal–Wallis ANOVA and post hoc Dunn’s test). Intragroup comparison: data measured after induction of ALI vs data obtained at hourly intervals thereafter: {ddagger}P<0.05 (Friedman test and post hoc Dunn’s test).

 
Haemodynamics
There were no significant changes between groups in HR, MABP, and SVR. In the SURF-group the MPAP increased from 25 (1) mm Hg at onset of ALI to 30 (3) mm Hg after 6 h of treatment, and was significantly less than in controls and in the SURF-PLV-group (P<0.05 vs controls and vs SURF-PLV; Fig. 3, Table 1). In the SURF-group, PVR increased significantly from 266 (49) dyn s cm–5 at onset of ALI to 560 (83) dyn s cm–5 at 6 h of treatment (P<0.05 vs ALI-values; Table 1). In the SURF-PLV-group, PVR increased significantly from 268 (28) to 659 (82) dyn s cm–5 (P<0.05 vs ALI-values, Table 1). In the SURF-group and in the SURF-PLV-group, CO decreased significantly during the treatment period compared with ALI-values (P<0.05 vs ALI-values; Table 1). In controls there were no significant changes in PVR and CO.



View larger version (17K):
[in this window]
[in a new window]
 
Fig 3 Time course of MPAP during baseline (pre-lavage), after induction of ALI (post-lavage), and for 6 h thereafter, in controls (n=8 at ALI; four pigs died before 6 h after ALI), in pigs treated with surfactant (Curosurf®) after induction of ALI (SURF-group) (n=8 pigs, none died), and in pigs treated with surfactant (Curosurf®) followed by PLV with 30 ml kg–1 of perfluorocarbon (PF 5080) after induction of ALI (SURF-PLV-group) (n=8 pigs, none died). Data are mean (SEM). Intergroup comparison: controls vs SURF-PLV-group and controls vs SURF-group: *P<0.05, and SURF-PLV-group vs SURF-group: {dagger}P<0.05 (Kruskal–Wallis ANOVA and post hoc Dunn’s test). Intragroup comparison: data measured after induction of ALI vs data obtained at hourly intervals thereafter: {ddagger}P<0.05 (Friedman test and post hoc Dunn’s test).

 
Lung mechanics
After induction of ALI, static compliance of the respiratory system decreased from 22 (2) ml cm H2O–1 in all groups to 9 (1) ml cm H2O–1. No further changes of CRS occurred in the SURF-group. In the SURF-PLV-group, CRS improved significantly compared with controls from 9 (1) to 15 (0.4) ml cm H2O–1 at 6 h of treatment (P<0.05 vs controls; Fig. 4, Table 2).



View larger version (16K):
[in this window]
[in a new window]
 
Fig 4 Time course of static compliance of the respiratory system (CRS) during baseline (pre-lavage), after induction of ALI (post-lavage), and for 6 h thereafter, in controls (n=8 at ALI; four pigs died before 6 h after ALI), in pigs treated with surfactant (Curosurf®) after induction of ALI (SURF-group) (n=8 pigs, none died), and in pigs treated with surfactant (Curosurf®) followed by PLV with 30 ml kg–1 of perfluorocarbons (PF 5080) after induction of ALI (SURF-PLV-group) (n=8 pigs, none died). Data are mean (SEM). Intergroup comparison: controls vs SURF-PLV-group: *P<0.05 (Kruskal–Wallis ANOVA and post hoc Dunn’s test).

 
Lung injury
The non-dependent lobes in the SURF-group had a significantly smaller injury score for interstitial oedema and emphysema compared with controls and the SURF-PLV-group (P<0.05, Table 3). In the SURF-PLV-group, scores for interstitial oedema were significantly greater compared with controls in the non-dependent lobes (P<0.05, Table 3). Comparing tissue damage in dependent lobes, the SURF-group had significantly less atelectasis and emphysema than controls (P<0.05) and less interstitial oedema and emphysema than the SURF-PLV-group (P<0.05, Table 3). In the SURF-PLV-group, interstitial infiltration and atelectasis of the dependent lobes was less than in controls and the SURF-group (P<0.05 vs controls and vs SURF), while interstitial oedema and emphysema in the dependent lobes in the SURF-PLV-group was greater than in controls and the SURF-group (P<0.05, Table 3).


View this table:
[in this window]
[in a new window]
 
Table 3 Lung injury score of the non-dependent and the dependent lobes for atelectasis, interstitial infiltration, interstitial oedema, emphysema, and total lung injury score in controls (n=8 at ALI; four pigs died before 6 h after ALI), in pigs treated with a single intratracheal dose of 50 mg kg–1 of surfactant (Curosurf®) after induction of ALI (SURF-group) (n=8 pigs, none died), and in pigs treated with a single intratracheal dose of 50 mg kg–1 of surfactant (Curosurf®) followed by PLV with 30 ml kg–1 of perfluorocarbon (PF 5080) after induction of ALI (SURF-PLV-group) (n=8 pigs, none died). Data are mean (SEM). Intergroup comparison: controls vs SURF-PLV-group and controls vs SURF-group: *P<0.05, and SURF-PLV-group vs SURF-group: {dagger}P<0.05 (Kruskal–Wallis ANOVA and post hoc Dunn’s test). Intragroup comparison: non-dependent vs dependent lobes: §P<0.05 (Friedman test and post hoc Dunn’s test)
 
The overall lung injury score of the SURF-group was less in the non-dependent lobes, compared with the SURF-PLV-group and controls (P<0.05, Table 3).

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).


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In this study, we compared the effects of a single, small dose of surfactant alone and combined with a full dose of PLV on oxygenation, haemodynamics, respiratory mechanics, and lung injury in an animal model of ALI. A small dose of surfactant was better than a combined treatment with a small dose of surfactant and PLV to restore gas exchange. Respiratory mechanics were only improved in the group treated with the combination of surfactant and PLV. Atelectasis, interstitial oedema, and emphysema were significantly less in the surfactant group than in controls. Compared with the group receiving surfactant and PLV, the surfactant group had a significant smaller total lung injury score.

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 kg–1 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 kg–1), (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 kg–1) 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 kg–1 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 kg–1 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 kg–1 PFC with PLV using 18 ml kg–1 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 kg–1 PFC, nebulized PFC, 100 mg kg–1 artificial surfactant (ALEC), 100 mg kg–1 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 kg–1 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 kg–1 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.


    Acknowledgements
 
Supported by a grant from Deutsche Forschungsgemeinschaft (KA 1212/3–1). Curosurf® was generously provided by Serono AG, München, Germany.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Lewis JF, Jobe AH. Surfactant and the adult respiratory distress syndrome. Am Rev Respir Dis 1993; 147: 218–33[ISI][Medline]

2 Lee WL, Detsky AS, Stewart TE. Lung-protective mechanical ventilation strategies in ARDS. Intensive Care Med 2000; 26: 1151–5[ISI][Medline]

3 Greenfield LJ, Ebert PA, Benson DW. Effect of positive pressure ventilation on surface tension properties of lung extracts. Anesthesiology 1964; 25: 312–6[ISI]

4 McClenahan JB, Urtnowski A. Effect of ventilation on surfactant and its turn over rate. J Appl Physiol 1967; 23: 215–20[Free Full Text]

5 Hickling KG. Ventilatory management of ARDS: can it affect the outcome? Intensive Care Med 1990; 16: 219–26[ISI][Medline]

6 Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338: 347–54[Abstract/Free Full Text]

7 Goldsmith LS, Greenspan JS, Rubenstein DS, Wolson MR, Shaffer TH. Immediate improvement in lung volume after exogenous surfactant: alveolar recruitment versus increased distension. J Pediatr 1991; 119: 424–8[ISI][Medline]

8 Lewis JF, Goffin J, Yue P, McCaig LA, Bjarneson D, Veldhuizen RA. Evaluation of exogenous surfactant treatment strategies in an adult model of acute lung injury. J Appl Physiol 1996; 80: 1156–64[Abstract/Free Full Text]

9 Gregory TJ, Steinberg P, Spragg R, et al. Bovine surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 1997; 155: 1309–15[Abstract]

10 Walmrath D, Günther A, Ghofrani HA, et al. Bronchoscopic surfactant administration in patients with severe adult respiratory distress syndrome and sepsis. Am J Respir Crit Care Med 1996; 154: 57–62[Abstract]

11 Gladstone IM, Ray AO, Salafia CM, Perez-Fontan J, Mercurio MR, Jacobs HC. Effect of artificial surfactant on pulmonary function in preterm and full-term lambs. J Appl Physiol 1990; 69: 465–72[Abstract/Free Full Text]

12 Fuhrmann BP, Paczan PR, DeFrancisis M. Perfluorocarbon associated gas exchange. Crit Care Med 1991; 19: 712–22[ISI][Medline]

13 Tütüncü AS, Faithfull NS, Lachmann B. Comparison of ventilatory support with intratracheal perfluorocarbon administration and conventional mechanical ventilation in animals with acute respiratory failure. Am Rev Respir Dis 1993; 148: 785–92[ISI][Medline]

14 Papo MC, Paczan PR, Fuhrmann BP, et al. Perfluorocarbon-associated gas exchange improves oxygenation, lung mechanics, and survival in a model of adult respiratory distress syndrome. Crit Care Med 1996; 24: 466–74[ISI][Medline]

15 Zobel G, Rodl S, Urlesberger B, Dacar D, Trafojer U, Trantina A. The effect of positive end-expiratory pressure during partial liquid ventilation in acute lung injury in piglets. Crit Care Med 1999; 27: 1934–9[ISI][Medline]

16 Kirmse M, Fujino Y, Hess D, Kacmarek RM. Positive end-expiratory pressure improves gas exchange and pulmonary mechanics during partial liquid ventilation Am J Respir Crit Care Med 1998; 158: 1550–6[Abstract/Free Full Text]

17 Kaisers U, Kuhlen R, Keske U, et al. Superimposing positive end-expiratory pressure during partial liquid ventilation in experimental lung injury. Eur Respir J 1998; 11: 1035–42[Abstract/Free Full Text]

18 Lewandowski K, Rossaint R, Pappert D, et al. High survival rate in 122 ARDS patients managed according to a clinical algorithm including extracorporeal membrane oxygenation. Intensive Care Med 1997; 23: 819–35[ISI][Medline]

19 Göthberg S, Parker TA, Abman SH, Kinsella JP. High-frequency oscillatory ventilation and partial liquid ventilation after acute lung injury in premature lambs with respiratory distress syndrome. Crit Care Med 2000; 28: 2450–6[ISI][Medline]

20 Kelly KP, Stenson BJ, Drummond GB. Randomised comparison of partial liquid ventilation, nebulised perfluorocarbon, porcine surfactant, and combined treatments on oxygenation, lung mechanics, and survival in rabbits after saline lung lavage. Intensive Care Med 2000; 26: 1523–30[ISI][Medline]

21 Merz U, Kellinghaus M, Häusler M, Pakrawan N, Klosterhalfen B, Hörnchen H. Partial liquid ventilation with surfactant: effects on gas exchange and lung pathology in surfactant-depleted piglets. Intensive Care Med 2000; 26: 109–16[ISI][Medline]

22 Hartog A, Vazquez de Anda GF, Gommers D, et al. Comparison of exogenous surfactant therapy, mechanical ventilation, with high end-expiratory pressure and partial liquid ventilation in a model of acute lung injury. Br J Anaesth 1999; 82: 81–6[Abstract/Free Full Text]

23 Tarczy-Hornoch P, Hildebrandt J, Standaert TA, Jackon JC. Surfactant replacement increases compliance in premature lamb lungs during partial liquid ventilation in situ. J Appl Physiol 1998; 84: 1316–22[Abstract/Free Full Text]

24 Wolfson MR, Kechner NE, Roache RF, et al. Perfluorochemical rescue after surfactant treatment: effect of perflubron dose and ventilatory frequency. J Appl Physiol 1998; 84: 624–40[Abstract/Free Full Text]

25 Mrozek JD, Bing DR., Meyers PA, Connett JE, Mammel MC. High-frequency oscillation versus conventional ventilation following surfactant administration and partial liquid ventilation. Pediatr Pulmonol 1998; 26: 21–9[ISI][Medline]

26 Davidson A, Heckmann JL, Donner RM, Miller TF, Shaffer TH, Wolfson MR. Cardiopulmonary interaction during partial liquid ventilation in surfactant-treated preterm lambs. Eur J Pediatr 1998; 157: 138–45[ISI][Medline]

27 Mrozek JD, Smith KM, Bing DR, et al. Exogenous surfactant and partial liquid ventilation: physiologic and pathologic effects. Am J Respir Crit Care Med 1997; 156: 1058–65[Abstract/Free Full Text]

28 Tarczy-Hornoch P, Hildebrandt J, Mates EA, et al. Effects of exogenous surfactant on lung pressure-volume characteristics during liquid ventilation. J Appl Physiol 1996; 80: 1764–71[Abstract/Free Full Text]

29 Leach CL, Holm B, Morin FC, et al. Partial liquid ventilation in premature lambs with respiratory distress syndrome: efficacy and compatibility with exogenous surfactant. J Pediatr 1995; 126: 412–20

30 Sydow M, Burchardi H, Zinserling J, Ische H, Crozier TA, Weyland W. Improved determination of static compliance by automated single volume steps in ventilated patients. Intensive Care Med 1991; 17: 108–14[ISI][Medline]

31 Kaisers U, Max M, Walter J, et al. Partial liquid ventilation with small volumes of FC 3280 increases survival time in experimental ARDS. Eur Respir J 1997; 10: 1955–61[Abstract/Free Full Text]

32 Lachmann B, Robertson B, Vogel J. In-vivo lavage as an experimental model of the respiratory distress syndrome. Acta Anaesthesiol Scand 1980; 24: 231–6[ISI][Medline]

33 Kaisers U, Max M, Schnabel R, et al. Partial liquid ventilation with FC 3280 in experimental lung injury: dose-dependent improvement of gas exchange and lung mechanics. Appl Cardiopulm Pathophysiol 1996; 6: 163–70

34 Cotton RB, Olsson T, Law AB, et al. The physiologic effects of surfactant treatment on gas exchange in newborn premature infants with hyaline membrane disease. Pediatr Res 1993; 34: 495–501[Abstract]

35 Goldsmith LS, Greenspan JS, Rubenstein SD, Wolfson MR, Shaffer TH. Immediate improvement in lung volume after exogenous surfactant: alveolar recruitment versus increased distention. J Pediatr 1991; 119: 424–8[ISI][Medline]

36 Moen A, Yu XQ, Almaas R, Curstedt T, Saugstad OD. Acute effects on systemic circulation after intratracheal instillation of Curosurf or Survanta in surfactant-depleted newborn piglets. Acta Paediatr 1998; 87: 297–303[ISI][Medline]

37 Morris KP, Cox PN, Mazer CD, Frndova H, McKerlie C, Wolfe R. Distribution of pulmonary blood flow in the perfluorocarbon-filled lung. Intensive Care Med 2000; 26: 756–63[ISI][Medline]

38 Dantzker DR, Lynch JP, Weg JG. Depression of cardiac output is a mechanism of shunt reduction in the therapy of acute respiratory failure. Chest 1980; 77: 636–42[Abstract]





This Article
Abstract
Full Text (PDF)
E-Letters: Submit a response to the article
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Wolf, S.
Articles by Kaisers, U.
PubMed
PubMed Citation
Articles by Wolf, S.
Articles by Kaisers, U.