Published ahead of print on July 13, 2006, doi:10.1164/rccm.200512-1942OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200512-1942OC
Lung Volume Recruitment after Surfactant Administration Modifies Spatial Distribution of Ventilation Department of Anesthesiological Research, Center for Anesthesiology, Emergency and Intensive Care Medicine, University of Göttingen, Göttingen; Department of Anesthesiology and Intensive Care Medicine, University of Kiel, Kiel, Germany; Department of Neonatology, Royal Children's Hospital, Melbourne, Australia; Department of Physics and Medical Technology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands; Anesthesiological Investigation Unit, University Hospital of Geneva; and Pediatric and Neonatal Intensive Care Unit, Children's Hospital, University of Geneva, Geneva, Switzerland Correspondence and requests for reprints should be addressed to Prof. Dr. Inéz Frerichs, Department of Anesthesiology and Intensive Care Medicine, University of Schleswig-Holstein, Schwanenweg 21, D-24105 Kiel, Germany. E-mail: frerichs{at}anaesthesie.uni-kiel.de
Rationale: Although surfactant replacement therapy is an established treatment in infant respiratory distress syndrome, the optimum strategy for ventilatory management before, during, and after surfactant instillation remains to be elucidated. Objectives: To determine the effects of surfactant and lung volume recruitment on the distribution of regional lung ventilation. Methods: Acute lung injury was induced in 16 newborn piglets by endotracheal lavage. Optimum positive end-expiratory pressure was identified after lung recruitment and surfactant was administered either at this pressure in the "open" lung or after disconnection of the endotracheal tube in the "closed" lung. An additional recruitment maneuver with subsequent optimum end-expiratory pressure finding was executed in eight animals; in the remaining eight animals, end-expiratory pressure was set at the same level as before surfactant without further recruitment. ("Open" and "closed" lung surfactant administration was evenly distributed in the groups.) Regional ventilation was assessed by electrical impedance tomography. Measurements and Main Results: Impedance tomography data, airway pressure, flow, and arterial blood gases were acquired during baseline conditions, after induction of lung injury, after the first lung recruitment, and before as well as 10 and 60 min after surfactant administration. Significant shift in ventilation toward the dependent lung regions and less asymmetry in the right-to-left lung ventilation distribution occurred in the postsurfactant period when an additional recruitment maneuver was performed. Surfactant instillation in an "open" versus "closed" lung did not influence ventilation distribution in a major way. Conclusions: The spatial distribution of ventilation in the lavaged lung is modified by a recruitment maneuver performed after surfactant administration.
Key Words: acute lung injury • electrical impedance tomography • lung lavage Since the introduction of exogeneous surfactant treatment in infants suffering from respiratory distress syndrome, mortality and risk of air leak have been significantly reduced (1–3). However, the incidence of chronic lung disease related to ventilator-induced injury and alveolarization arrest has not been altered (2–5). With the recent development of lung-protective ventilation strategies, more care has been taken for using lower tidal volumes at somewhat higher positive end-expiratory pressure (PEEP) levels than previously. In addition, lung volume recruitment maneuvers have been advocated to improve intrathoracic gas volume and gas exchange (6). Several studies have shown no improvement or even a decrease in dynamic lung compliance after surfactant therapy (7–9), indicating that the immediate positive effects of surfactant on oxygenation may primarily be attributable to the stabilization of already open lung units and not only to recruitment of collapsed ones. It has also been observed that a recruitment maneuver at the time of surfactant administration enhanced the clinical effect and led to an immediate improvement in dynamic compliance, suggesting recruitment of previously unventilated lung units (10). Poor clinical response to surfactant treatment may be a consequence of nonuniform distribution of surfactant within the lungs (11, 12), which, as experimentally shown by lung staining and histologic techniques, may become more homogeneous if recruitment is performed (12, 13). The difficulty in defining the most appropriate method of surfactant administration and the most favorable mechanical ventilation strategy is partly associated with the fact that the functional effects of surfactant instillation on regional lung ventilation could not be assessed previously. Only global indices of ventilatory and respiratory function (e.g., functional residual capacity, compliance of the respiratory system, arterial partial pressures of O2 [PaO2] and CO2 [PaCO2]) have been available under in vivo conditions. The radiation-free imaging technique of electrical impedance tomography (EIT) affords a new opportunity to assess the regional effects of both surfactant administration and mechanical ventilation strategies. EIT has been shown to detect regional pulmonary gas volume changes in a variety of experimental and clinical conditions (14–18). Preliminary observations in critically ill preterm infants requiring exogenous surfactant indicate that EIT might become a useful bedside tool for monitoring regional lung ventilation in this patient group (19). In our current study, we applied EIT to study the effects of surfactant instillation on regional lung ventilation in an animal model of acute lung injury while applying two different ventilation strategies in the postsurfactant period. We expect our study to provide novel information regarding the regional ventilatory response of the lung tissue to surfactant administration and mechanical ventilation.
Animal Preparation and Instrumentation The experimental methods used in this study were approved by the university and state's committee for animal care, and adhered to the guidelines on animal experimentation. Newborn piglets were premedicated with midazolam (0.5 mg/kg) and atropine (0.5 mg). Anesthesia was induced with intramuscular ketamine (35 mg/kg) and maintained with fentanyl (20 µg/kg/h) and midazolam (0.3 mg/kg/h). The animals were tracheotomized and then mechanically ventilated (Galileo Gold; Hamilton Medical, Bonaduz, Switzerland) with an initial tidal volume of 10 ml/kg and PEEP of 5 cm H2O at 30–40 breaths/min. Intravenous and intraarterial catheters were inserted for monitoring blood pressures, blood sampling, and infusions. Airway opening pressure and airflow were monitored continuously (Florian respiratory monitor; Acutronic Medical Systems, Zug, Switzerland), and PaO2 and PaCO2 were recorded with an indwelling arterial blood gas electrode (Paratrend 7; Diametrics Medical, High Wycombe, UK). Sixteen self-adhesive electrodes (Blue Sensor BR-50-K; Ambu, Friedberg, Germany) were attached on the chest circumference at the level of the sixth parasternal intercostal space and connected to the Goe-MF II EIT system (Viasys Healthcare, Höchberg, Germany) (20). EIT measurements were performed with the following settings: electrical currents of 5 mArms and 70 kHz; scan rate, 13 scans/s; scanning intervals, 30 s to 15 min.
Protocol After the induction of acute lung injury and a stabilization period of 1 h, a recruitment maneuver was performed by repeated increments of 2 cm H2O PEEP in the pressure control mode up to a maximum peak inspiratory pressure of 30 cm H2O. Afterwards, PEEP was slowly reduced and the critical closing pressure determined as the PEEP level at which the continuously monitored PaO2 started to substantially fall. Optimum PEEP was then defined as the pressure 2 cm H2O above this critical closing pressure (21). After re-recruitment, PEEP was rapidly decreased to this optimum PEEP level. All animals then received 100 mg/kg porcine surfactant (Curosurf; Nycomed, Munich, Germany) over less than 1 min either in the "closed" lung (i.e., after endotracheal tube disconnection without ongoing ventilation) or in the "open" lung (i.e., without endotracheal tube disconnection at unchanged ventilator settings), and were randomly allocated to one of two postsurfactant management groups. In the No Recruitment group, after surfactant therapy no additional recruitment maneuver was performed and the animals were ventilated at PEEP values corresponding to the previously defined optimum PEEP. Stepwise reduction of PEEP was permitted with increasing oxygenation. In the Recruitment group, recruitment was performed again as described above and a new optimum PEEP was defined. Ventilation continued in all animals for 60 min after surfactant administration.
Off-line Data Analysis A short EIT data sequence for the duration of 30 to 60 s was selected and analyzed in each of the six measurement periods in each animal studied. Depending on their duration, these data sequences rendered 390 to 780 simple EIT scans of the instantaneous distribution of electrical impedance within the chest cross-section. These scans showed the relative changes in local electrical impedance with respect to the local reference impedance. The local reference impedance values corresponded to the average impedance values determined from the individual sets of EIT data in each pixel. The sequences of simple EIT scans were then used to generate functional EIT scans of regional lung ventilation according to a procedure described previously (14). These functional scans (see Figures 1A and 2) show the pixel values of the ventilation-related (i.e., end-inspiratory to end-expiratory) amplitude of relative impedance change averaged over a number of consecutive breaths. In each of the six measurement periods, one functional EIT scan of regional lung ventilation was generated (see Figure 2) presenting in light tones the distribution of local tidal volumes during the period analyzed. The functional EIT scans of regional lung ventilation were the starting points for the subsequent novel data evaluation, leading to the quantification of (1) fractional ventilation in a total of 64 regions of interest, as well as in the right and left lung regions; (2) generation of ventilation profiles in the right and left lung regions; and (3) determination of anterior-to-posterior shifts in ventilation. These procedures are presented in detail in Figure 1.
Statistical Methods Statistical analysis was performed using GraphPad Prism, version 4.0 (GraphPad Software, San Diego, CA). Data are presented as mean and standard deviation unless otherwise stated. Two-way analysis of variance (ANOVA) was used to test the effects of the type of surfactant instillation and recruitment maneuver after surfactant. One-way ANOVA with Bonferroni's post test was applied for comparisons within each group. p values less than 0.05 were considered significant.
Sixteen newborn piglets were studied, equally assigned to the Recruitment and No Recruitment groups. In each group, half of the animals received surfactant into an "open" lung, whereas in the other half, surfactant was instilled into a "closed" lung. Because the type of surfactant instillation ("open" vs. "closed" lung instillation) did not significantly affect the findings, only the results pertaining to the Recruitment and No Recruitment groups are presented for the rest of this section. (Nevertheless, the data for all individual animals studied can be found in Figures 3 and 4.)
The Recruitment and No Recruitment groups were comparable regarding body weight (2.4 ± 0.2 vs. 2.1 ± 0.3 kg), number of lavages performed (8.6 ± 1.7 vs. 8.6 ± 2.1), and optimum PEEP (8.3 ± 2.1 vs. 9.0 ± 1.8 cm H2O). Further reference data are given in Tables 1 and 2. In the No Recruitment group, slightly higher respiratory system compliance was found after lung lavage before surfactant instillation. In the postsurfactant period, PEEP was slightly lower in the No Recruitment group because the experimental protocol did not allow PEEP to exceed the previously defined optimum values.
The distribution of regional lung ventilation in the chest cross-section differed among the measurement periods. Figure 2 shows the functional EIT scans of regional lung ventilation with the corresponding profiles of fractional lung ventilation obtained in two representative piglets without (top) and with (bottom) a recruitment maneuver in the postsurfactant period. In both animals, substantial redistribution of lung ventilation occurred after the induction of acute lung injury. Both the EIT scans and the ventilation profiles revealed a predominant ventilation of the anterior, nondependent lung regions. The application of a recruitment maneuver after the lavage sequence changed the ventilation distribution pattern and recruited the posterior lung regions, which became ventilated again. A distinct heterogeneity of ventilation distribution with reduced ventilation in the left lung region was observed in the animal without recruitment 10 min after surfactant administration, which persisted even after 60 min. The distribution of regional ventilation in the animal with recruitment after surfactant was more homogeneous and stable, with almost equal distribution of the ventilated gas between the right and left lung regions. The ventilation distribution in the six different phases of the experiment quantified in terms of the anterior-to-posterior shifts in ventilation in the right and left lung regions is shown in Figure 3. In all animals studied, the induction of acute lung injury resulted in a shift in regional lung ventilation toward the anterior lung regions, which was reversed after the recruitment maneuver. When compared with the ventilation distribution pattern preceding the surfactant instillation, a shift in regional ventilation toward the nondependent lung regions occurred in the No Recruitment group in the last two measurement phases. This loss in ventilation of the dependent lung regions was not observed in the Recruitment group. As a result, there was a significant difference in the ventilation distribution pattern between the Recruitment and No Recruitment groups at both 10 and 60 min after surfactant administration. The effects of acute lung injury, surfactant instillation, and subsequent ventilation strategy on the distribution of lung ventilation between the right and left lung regions are presented in Figure 4. In all but two animals, the fractional ventilation of the right lung increased after the lavage sequence when compared with the baseline data. This process was reversed after the recruitment maneuver was performed. After surfactant instillation, significantly higher variance in the fractional ventilation of the right lung was detected in the No Recruitment group compared with the Recruitment group. The contribution of the right lung region to the overall ventilation in the chest cross-section was in the range of 46 to 68% in the piglets without recruitment and 48 to 56% in those with recruitment after surfactant. PaO2 and PaCO2 values, parameters of respiratory system mechanics, as well as other reference data obtained during different phases of the measurements are shown in Tables 1 and 2. Both groups of animals experienced an increase in arterial oxygenation after the first lung recruitment maneuver was performed subsequent to lavage. This improvement in oxygenation persisted in the animals treated with surfactant and subjected to the second recruitment maneuver. In the No Recruitment group, PaO2 was significantly lower during the last two measurement phases when compared with the Recruitment group. Respiratory system compliance was significantly lower in the No Recruitment group after surfactant administration compared with baseline, and by the end of the experiment was below the corresponding value in the Recruitment group. The post-treatment values of respiratory system resistance in the No Recruitment group were significantly above those at baseline during the entire postsurfactant period.
Our study revealed that endotracheal instillation of surfactant followed by a recruitment maneuver resulted in a different spatial distribution of regional lung ventilation than surfactant administration without subsequent recruitment. This effect was discernible both in the early and late phases of the follow-up period and pertained to the anterior-to-posterior ventilation distribution along the direction of the gravity vector. The gross distribution between the right and left lung regions was not significantly affected; however, the No Recruitment group exhibited a markedly higher variance of this parameter. Our data did not show any statistical difference of ventilation distribution between the two modes of surfactant administration (instillation in the "open" or "closed" lung, respectively). A control group of animals with acute lung injury not receiving surfactant was not included in our series of experiments. Our study was not designed to study the isolated effect of surfactant instillation; therefore, our findings only allow conclusions to be drawn regarding the effect of the postsurfactant management on regional lung ventilation. However, several studies have already confirmed the significant effects of surfactant on lung function using the same experimental lavage model of acute surfactant depletion as in our study (22–25). These investigations used a number of different surfactant preparations, including the preparation and dosage used in our experiments. Significant differences in PaO2 and PaCO2, oxygenation index, static and dynamic respiratory system compliance, lung volume, and ventilation efficiency index were noted between surfactant-treated and control animals in the postsurfactant period, which was of similar or identical duration to ours. Moreover, our previous experimental observations indicated that lung volume recruitment maneuvers alone, without associated surfactant administration, did not produce any lasting alteration of global lung mechanics or distribution of ventilation in the saline-lavaged piglet (26). Substantial change in ventilation distribution only occurred after instillation of surfactant 3 h after the induction of acute lung injury. Our observations are in harmony with the results of the few studies performed so far addressing the question of whether lung recruitment might be beneficial after surfactant therapy. These studies found improved indices of global lung mechanics if volume recruitment was performed after surfactant administration (10, 13). In our study, compliance of the respiratory system and oxygenation were lower in the animals without volume recruitment after surfactant. In these animals, EIT identified a preferential distribution of inspired air into the nondependent lung regions indicative of the existence of nonventilated lung areas in dorsal regions and explaining the persistence of poor respiratory system mechanics. Even though the gas exchange parameters improved in both groups during the postsurfactant follow-up period, such heterogeneous ventilation would be expected to make the animals without recruitment after surfactant more prone to the development of ventilator-induced lung injury, due to the increased regional stress on collapsed and probably overinflated lung areas. The use of EIT enabled us to visualize the effects of acute lung injury, lung volume recruitment, surfactant administration, and subsequent mechanical ventilation strategy on regional lung ventilation. The functional EIT scans of regional lung ventilation generated from individual measurement phases offered the maximum resolution with which the distribution of regional tidal volumes in the chest cross-section could be assessed: the scans showed the ventilation-related impedance changes in a total of 912 pixels. (The resolution of EIT scans is 32 x 32 pixels; however, only a circular area of this size within the two-dimensional scans contains the EIT data.) In the present study, we have additionally introduced another method of visualizing the information pertaining to regional lung ventilation. We have calculated the sum of ventilation-related impedance changes in 64 regions of interest equally divided between the right and left halves of the functional scans. This procedure allowed the generation of two ventilation profiles, characterizing the ventilation distribution in the right and left lungs. Such profiles have been created previously, but using only 32 pixel values (i.e., one row of data) instead of all 912 pixel values available, and the depicted data did not show the ventilation-related impedance changes in terms of the end-inspiratory to end-expiratory (i.e., tidal) differences of relative impedance change (27). The ventilation profiles generated in the way described in this study make an easy assessment of the redistribution of ventilation occurring along the anterior-to-posterior axis possible by simple visual examination. The changes in regional lung ventilation in the anterior-to-posterior direction have the highest degree of relevance for the differentiation of shifts in ventilation between the dependent and nondependent lung regions in supine (or prone) subjects because they may significantly influence the overall pulmonary gas exchange by modifying the ventilation–perfusion matching. To better characterize the shifts in distribution of inspired air occurring in this direction, we have used an additional EIT variable, the "center of ventilation." The validity and reproducibility of this variable were checked in a separate study (see the online supplement). The "center of ventilation" quantifies the shifts in ventilation by referring them to the chest dimension and allows the determination of their changes with time (or measurement period). Our experiments revealed significantly more anteriorly located "centers of ventilation" in the No Recruitment group in the postsurfactant period. This is indicative of less ventilation in the posterior, dependent regions and is in harmony with the findings of worse oxygenation and respiratory system mechanics in this group. Because the data from the whole cross-section studied were used to determine the sums of ventilation-related impedance changes in 64 regions of interest, the calculation of the fractional ventilation in individual regions or in the right and left lung regions was feasible. Although the average right-to-left lung ventilation distribution was not different among the groups, the variance of this rather gross variable was much higher in the No Recruitment group, indicative of extreme differences in the distribution of air between the right and left lung regions in some instances. The application of EIT and evaluation of EIT data using different evaluation tools may be of benefit in defining the optimum strategy in the therapy of respiratory distress syndrome. It is an accepted fact that this therapy should be aimed at achieving two major goals: (1) maximization of the beneficial effects of surfactant and (2) minimization of the adverse effects of mechanical ventilation with decreased incidence of ventilator-induced lung injury. The high incidence of chronic lung disease (2–5, 28, 29) and the results of several clinical and experimental studies (7–13) suggest that the current strategies to administer surfactant and the ventilatory management before, during, and after surfactant therapy are still not optimal. Previous experimental and clinical observations using EIT (19, 26) indicate that this diagnostic modality is able to assess the functional effects of both surfactant instillation and the mode of mechanical ventilation selected on regional lung ventilation. The current results show that EIT identified the changes in regional lung ventilation distribution elicited by the development of acute lung injury, lung recruitment, and different ventilator strategy in the postsurfactant period. In conclusion, the results of our study indicate that early lung volume recruitment after surfactant therapy may have an influence on the spatial distribution of regional lung ventilation and, as a result, improve the efficiency of pulmonary gas exchange. The current EIT findings did not identify any differences in ventilation distribution between the animals with surfactant instillation into the "open" and "closed" lung. With the published experimental data on improved lung mechanics and oxygenation with lung recruitment during surfactant administration of other groups, these combined and interactive effects of surfactant and lung recruitment will need further exploration in a clinical setting.
Supported by a restricted research grant by Viasys Healthcare. Surfactant (Curosurf) was generously provided by Nycomed.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200512-1942OC on July 13, 2006 Conflict of Interest Statement: I.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.A.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.v.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.R.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.C.R. has received a study grant of $6000 for this specific study by Viasys Healthcare, and 16 free vials of Curosurf from Nycomed for this study. Received in original form December 21, 2005; accepted in final form July 11, 2006
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TOP
ABSTRACT
METHODS
Z) were calculated in all pixels lying within the individual ROIs. The 64 values calculated are presented as two anterior-to-posterior profiles of local ventilation in the right and left halves of the chest, respectively (dark and light gray bars, C). The fractional ventilation in each ROI relative to the total ventilation in the whole chest cross-section was then determined, and expressed as a percentage (D). The numbers in the left and right upper corners of these diagrams specify the fractional ventilation in the right and left halves of the thoracic cross-section. In this example, 69% of total ventilation occurred in the right and 31% in the left part of the chest after lung injury. The ventilation asymmetry was reduced after surfactant administration (60% right, 40% left). In the final evaluation step, the geometric center of ventilation was calculated and projected on the anterior-to-posterior axis of the chest (E). The dark and light gray circles represent the centers of ventilation in the right and left halves of the chest after lung injury. The dark and light gray squares show the same data after surfactant therapy. A plot of the centers of ventilation over time allows visualization of the shifts in regional lung ventilation in the anterior-to-posterior direction during the different experimental phases (F). In this example, the results from the IL and S10 phases indicate that anterior regions were preferentially ventilated after lung injury. After surfactant administration, a shift in ventilation distribution toward posterior regions took place.
symbols indicate significantly greater ventilation of the dorsal lung regions in the Recruitment group in the postsurfactant period (
This manuscript is dedicated to the memory of our friend and colleague Huibert van Genderingen, who tragically passed away on November 4, 2005. 
