Sulla

Study objectives: To evaluate the effect of pentoxifylline treatment on gas exchange and mortality immediately after bilateral instillation of hydrochloric acid.

Design: Randomized, prospective, placebo-controlled trial.

Setting: Animal laboratory of a university hospital.

Subjects: Twenty-four, adult, male Sprague-Dawley rats.

Methods: Sevoflurane-anesthetized rats (n = 12 in each group) underwent tracheostomy and insertion of a cannula into a hind paw vein and the left carotid artery. All animals received volume-controlled mechanical ventilation (zero positive end-expiratory pressure; fraction of inspired oxygen, 0.21). Acute lung injury was induced by instillation of 0.4 mL/kg 0.1 mol/L hydrochloric acid. The animals were randomized into two groups. The pentoxifylline group (n = 12) received a bolus of 20 mg/kg IV pentoxifylline after aspiration, followed by a continuous infusion of 6 mg/kg/h. The placebo group (n = 12) received an equivalent volume of saline solution. Arterial blood samples were collected for blood gas analysis 15 min and 0 min prior to aspiration and 30, 90, 180, 270, and 360 min after aspiration. Hemodynamic parameters, temperature, and ECG were recorded simultaneously. The primary end point was 6 h after aspiration. All surviving rats were killed by IV administration of pentobarbital. To assess morphologic changes due to lung injury, all animals underwent CT in inspiratory hold at the end of the experiment.

Measurements and results: No difference in baseline measurements was observed. In pentoxifylline-treated rats, Pa[O.sub.2] was significantly increased (p < 0.05) at 30, 90, 180, 270, and 360 min. Mortality at 6 h was 17% in the pentoxifylline group vs 67% in the placebo group. Placebo-treated rats showed significant abnormalities in CT lung scans compared with the pentoxifylline group. Conclusions: Acid aspiration impairs gas exchange and induces hypotension. Pentoxifylline administration shortly after acid instillation results in significant alleviation of impaired oxygenation, stabilization of BP with higher heart rates, and improved survival after 6 h. (CHEST 2005; 127:613-621)

Key words: acute lung injury; aspiration; aspiration pneumonitis; CT; pentoxifylline; phosphodiesterase inhibitor; pulmonary edema; rats

Abbreviations: ALI = acute lung injury; HR = heart rate; MABP = mean arterial BP; PEEP = positive end-expiratory pressure; TNF = tumor necrosis factor; VT = tidal volume.

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Aspiration pneumonitis is one of the major causes of ARDS. It frequently occurs in patients with disturbance of consciousness due to drug overdose or cerebrovascular disease, and sometimes after aspiration of regurgitated gastric contents in patients with impaired upper airway reflexes during induction of anesthesia or recovery from it. This syndrome was first described by Mendelson (1) in 1946, who revealed the importance of acid in its pathogenesis. The severity of the pathophysiologic changes resulting in lung inflammation depends on several factors such as pH, volume of the aspirate, and presence of particulate gastric matter. (2,3) The development of acute lung injury (ALI) typically follows a biphasic pattern as was shown in a rat model. (4) Although there has been substantial progress in the understanding of complex inflammatory mechanisms that mediate ALI, therapeutic strategies are still limited and the aspiration of gastric contents is still a serious event. Approximately one third of patients will acquire more severe symptoms, and approximately 22% are at risk for ARDS with high mortality. (5,6) Numerous investigations (7,8) have identified several inflammatory factors associated with lung injury, such as neutrophil-mediated reactive oxygen species and proinflammatory cytokines such as tumor necrosis factor (TNF)-[alpha], interleukin-1, and interleukin-8. TNF-[alpha] seems to play an important role in the pathogenesis of acid-induced aspiration pneumonitis not only in experimental models but also in humans. (9,10)

Preliminary experimental studies support the hypothesis that pentoxifylline can attenuate ALI by reducing release of TNF-[alpha]. Kudoh et al (11,12) showed that oxygenation impairment was reduced alter pentoxifylline pretreatment in acid-injured lungs of rabbits. In spite of promising results of pentoxifylline therapy in several animal models of ARDS, (13-16) its therapeutic value in attenuating lung injury of patients is still uncertain. The phosphodiesterase inhibitor lisofylline is a metabolite of pentoxifylline that shows multiple antiinflammatory properties and has recently been investigated by the ARDS Clinical Trials Network in a large, prospective, placebo-controlled multicenter study. (17) Lisofylline treatment was administered in patients with clinically diagnosed ARDS within a 36-h window. No significant differences were seen in terms of 28-day mortality, ventilator-free days, or resolution of organ failures. The authors (17) concluded from their results that lisofylline has no role in the treatment of patients with ALI or ARDS.

In order to assess the effects of pentoxifylline treatment immediately after acid aspiration, we measured gas exchange, hemodynamic parameters, mortality, and pulmonary edema in a placebo-controlled, prospective, experimental study on male Sprague-Dawley rats. Oxygenation is one of the first variables to be impaired after direct lung injury. Factors that can impair gas exchange in ALI include pulmonary edema, pneumothorax, pleural effusion, and atelectasis. CT is an important tool in detecting abnormalities and describing morphologic changes in lung tissue after lung injury. (18,19) We therefore analyzed the correlation between clinical parameters and the time course of lung pathology after acid instillation using CT. To do this, we developed an algorithm that color-coded the grayscale values of a typical CT lung window to improve the visualization of the lung tissue CT changes for the nonradiologist.

MATERIALS AND METHODS

Anesthesia, Fluid Balance, Monitoring

The local Bioethics Committee approved the experimental protocol for this study. Twenty-four, adult, male Sprague-Dawley rats weighing 280 to 320 g (Charles River; Sulzfeld, Germany) were cared for and handled according to the guidelines of the German National Institute of Health. On arrival at our facility, all rats received food and water ad libitum. Anesthesia was induced in a 2-L container and maintained by inhalation of an inspired concentration of 2.5% sevoflurane, tracheostomy was performed, and a 14-gauge IV cannula was advanced to a position approximately 1 cm above the carina. A hind paw vein and a carotid artery were exposed and cannulated using 26-gauge and 24-gauge needles, respectively. In order to maintain fluid balance, we administered 5 mL/kg/h saline solution. Normothermia (37 [+ or -] 0.7[degrees]C [mean [+ or -] SD]) was maintained by positioning animals supine on an electric hotplate. Each rat was then continuously monitored for ECG, invasive mean arterial BP (MAPB), oxygen saturation, and rectal temperature (Siemens 9000C; Siemens Medical Systems; Erlangen, Germany). All animals received volume-controlled mechanical ventilation (Animal Ventilator: REMA Labortechnik; Heidelberg, Germany). We chose a tidal volume (VT) of 10 mL/kg and applied no positive end-expiratory pressure (PEEP) in order to stress lung tissue mad increase lung injury. The respiratory rate was adjusted to maintain arterial PC[O.sub.2]] between 35 mm Hg and 45 mm Hg. Sevoflurane was administered using an anesthesia circuit system (Sulla 303V; Draeger; Lubeck, Germany). All rats received a fraction of inspired oxygen of 0.21 during the entire experiment. After completion of the invasive procedures, a period of 30 min of hemodynamic stabilization was allowed for two baseline measurements of MABP, heart rate (HR), and blood gas samples (ABL-30 blood gas analyzer; Radiometer; Copenhagen, Denmark). Subsequently, ALI wits induced by instillation of 0.4 mL/kg 0.1 mol/L HCl (pH approximately 1.25) into both lungs. The animals were randomly assigned to one of two groups: a bolus of 20 mg/kg IV pentoxifylline 10 min after aspiration followed by 6 mg/kg/h, and placebo consisting of normal saline solution. Blood gas samples (each 0.3 mL) were obtained 30, 90, 180, 270, and 360 min after aspiration mad replaced by 0.6 mL of saline solution. The end point of the experiment was survival after 6 h.

Determination of Pentoxifylline Blood Levels

At the end of each experiment, 1 mL of blood was sampled and centrifuged at 3,000g for 15 min. The supernatant was transferred to a polypropylene tube and stored at -70[degrees]C until analysis. Pentoxifylline and lisofylline concentrations were measured using the method of Grasela and Rocci. (20)

CT

To assess changes in lung morphology and detect lung pathologies such as pneumothorax, pleural effusion, atelectasis, and edema, a spiral GT scan (Somatom Plus 4; Siemens Medical Systems) of the thorax was performed in all 24 animals. This was done either after 6 h or immediately after death during inspiratory hold with a VT of 10 mL/kg. Using a collimation of 1 mm and a pitch of 1, spiral CT scans were reconstructed with 1-mm slice thickness (140 kilovolts, 58 mA) applying an edge-enhancing filter algorithm. Two radiologists who were blinded to the procedures and therapies reviewed the CT scans in consensus reading. The entire lung was assessed using a score from 0 to 3. The assessment was performed separately in the bronchial/peribronchial structures and the alveolar space of the entire lung, respectively. A normal lung without any disease was assessed as 0, while a consolidation of > 70% of the lung was scored as 3. A slightly increased attenuation was scored as 1, while increased attenuation in combination with consolidation < 70% was assessed as 2.

To allow better visualization of grayscale findings using a typical CT lung window setting, we color-coded the grayscale values. (21) By assessing colors from blue to red within the typical Hounsfield unit range of the lung (-1,000 to -200), we achieved a better discrimination of fine grayscale changes.

Statistical Analysis

The P[O.sub.2], PC[O.sub.2], and pH values were analyzed by general linear models for unbalanced and dependent data, using statistical software (SAS 8.2; SAS Institute; Gary, NC). Compound symmetry was assumed for the structure of the covariance matrix. The variables were modeled dependent on treatment, time, and their interaction. An autoregressive covariance structure with time as a continuous variable was used for the statistical evaluation of the cardiocirculatory parameters. Additionally, a second model with time as a discontinuous variable (only selected time points) was determined as above for group comparisons at specific times. For comparison of the treatment groups at corresponding time points, the differences of the predicted means were calculated with 95% confidence intervals. The confidence intervals were adjusted for multiple comparisons (Tukey-Kramer adjustment). Survival was analyzed by Kaplan-Meier curves, and comparison of the survival fractions was calculated using the log-rank test. Values of CT assessment of both groups were analyzed for statistical differences using the Mann-Whitney U test.

RESULTS

Blood Gas Analysis

The Pa[O.sub.2] values and arterial gas analyses are summarized in Figure 1. There were no differences between the groups in the baseline measurements 15 min and immediately prior to tracheal acid instillation. As expected, the Pa[O.sub.2] showed an initial decline in both groups 30 min after acid instillation. At this time point, the Pa[O.sub.2] did not differ significantly between groups, although the placebo group had a mean Pa[O.sub.2] 15 mm Hg lower than the pentoxifylline-treated animals. While Pa[O.sub.2] almost returned to baseline values 90 min after acid instillation in the pentoxifylline group, Pa[O.sub.2] values of placebo-treated animals decreased continuously and were hypoxic at the end of the experiment in surviving animals. The Pa[O.sub.2] decreased from 81.4 [+ or -] 5.7 mm Hg before aspiration to 74.2 [+ or -] 11.4 mm Hg at 6 h after aspiration (p < 0.05 vs baseline) in the pentoxifylline group, but the decrease was not significant. In the placebo group, Pa[O.sub.2] decreased markedly from 79.3 [+ or -] 5.4 mm Hg at baseline to 46.9 [+ or -] 5.4 mm Hg at the end of the experiment (Fig 1). We observed significant group- and time-dependent effects for the entire course of the experiment. This is in accordance with the statistically significant group- and time-dependent effects seen in the linear model-based evaluation (fixed effects: time, p < 0.0001; group, p < 0.0001). Comparing the treatment group with the placebo group at corresponding time points, we also observed significant differences of the means from 90 min after acid instillation until the end of observation (Fig 1).

[FIGURE 1 OMITTED]

The pH values differed between the treatment and placebo groups. There was no difference in baseline between the two groups. In the placebo group, pH values decreased at 180 min after acid instillation from normal range to 7.3 [+ or -] 0.1, whereas in the pentoxifylline group pH remained in the normal range (Fig 2). Base excess values tended to be more negative in the placebo group, indicating metabolic acidosis (Table 1). While we found significant effects of treatment and time (linear model fixed effects: time, p < 0.0001; group, p < 0.0054), in the comparison of corresponding time points, only the pH at the time point 270 min after acid instillation was significantly different between pentoxifylline-treated and placebo-treated groups (p < 0.05).

[FIGURE 2 OMITTED]

In the pentoxifylline group, PaC[O.sub.2] values were between 37.3 [+ or -] 3.8 mm Hg at baseline and 37.6 [+ or -] 2.3 mm Hg at the end of the experiment, while in the placebo group PaC[O.sub.2] increased more noticeably from 37.7 [+ or -] 3.8 before aspiration to 42.9 [+ or -] 5.2 mm Hg after 6 h. We observed that PaC[O.sub.2] values in the placebo group tended to be in the upper part of the physiologic range compared with values in the pentoxifylline group despite adjustment of respiratory rate. Significant differences were not observed between the groups at corresponding time points (Fig 3).

[FIGURE 3 OMITTED]

MABP and HR

Basal measurements of MABP of both groups were not different. MABP decreased only slightly from 76 [+ or -] 5.8 to 67.5 [+ or -] 6.0 mm Hg until the end of experiment in the pentoxifylline-treated animals, but the MABP in the placebo group showed a marked decrease from 74 [+ or -] 6.4 to 62.6 [+ or -] 4.2 mm Hg. MABP values of both groups were significantly different from 180 min after acid instillation to the end of the experiment (Fig 4, top). BP values showed a significant dependency on time and treatment in both groups.

In the first 60 min after acid instillation, HR increased in both groups. Thereafter, HR in the pentoxifylline group remained slightly elevated, whereas HR in the placebo group decreased markedly from 135 min to 360 min after instillation (Fig 4, bottom). The HR was time dependent in the placebo group, but not in the pentoxifylline group.

[FIGURE 4 OMITTED]

Survival

The two groups showed different mortality rates. After 210 min, a steep increase in mortality was observed in the placebo-treated animals. After 6 h, 8 of 12 animals were dead, representing a mortality rate of 67%, while mortality in the pentoxifylline group was only 17%. Kaplan-Meier survival analysis (Fig 5) showed that pentoxifylline treatment resulted in a significantly higher survival fraction (p < 0.05, log-rank test).

[FIGURE 5 OMITTED]

Pentoxifylline Blood Levels

High-performance liquid chromatography examinations showed a serum pentoxifylline concentration of 8.4 [+ or -] 5.8 [micro]g/mL (mean [+ or -] SD) in the pentoxifylline group, while the serum concentration of lisofylline was 1.8 [+ or -] 0.9 [micro]g/mL at the end of experiment in surviving rats after 360 min.

CT

Pulmonary CT scans of animals dying 3 h or 4 h after aspiration showed little or no change. CT scans of surviving animals showed significant differences after 6 h. The lungs of the 4 surviving placebo-treated animals were compared with that of the 10 surviving pentoxifylline-treated animals. While bronchial/peribronchial attenuation was comparable in both groups (median: pentoxifylline, 1.0; placebo, 1.5), increased attenuation of the alveolar space was significantly lower in the pentoxifylline group (median: pentoxifylline, 0; placebo, 2; one-sided Mann-Whitney U test, p < 0.05).

Figure 6, top, demonstrates some typical CT findings of a pentoxifylline-treated animal assessed as 1, showing just slightly increased lung attenuation. Additionally, a typical lung of a surviving placebo-treated animal assessed as 2 is shown in Figure 7, top, revealing increased attenuation with some minor consolidation. None of the lungs showed pneumo thorax, relevant pleural effusion, or total atelectasis of a lobe or the entire lung.

[FIGURES 6-7 OMITTED]

DISCUSSION

Although several experimental studies (14,15) have demonstrated that pentoxifylline has beneficial effects on lung inflammation and may result in decreased lung injury, the effect of early treatment on pulmonary function and hemodynamic parameters after an aspiration event has not been previously reported. Aspiration of gastric components leads to activation of macrophages and release of proinflammatory cytokines such as TNF-[alpha], which is followed by neutrophil infiltration into the interstitial and alveolar space. The injury of the alveolocapillary membrane results in severe lung endothelial injury with the development of edema in the lung and a decrease in pulmonary gas exchange efficiency. (7)

The overall objective of this study was to determine if pentoxifylline treatment after an aspiration event is able to stabilize oxygenation and reduce mortality in animals receiving ventilation. We observed the time course of blood gas levels, HR, and BP over a 6-h period because this allowed us to compare our data with those of previous studies. CT is a noninvasive procedure and an important diagnostic tool that can be used to assess lung damage in experimental animals and in man. (22,23) To cheek for possible effects on lung pathology, we decided to study CT scans and correlated the findings with the oxygenation data.

We found that a decrease in Pa[O.sub.2] 30 rain after acid instillation was one of the first findings after acid aspiration; this is often caused by bronchospasm and aspirated fluid in the alveolar space. (1,5) The initial lowering in Pa[O.sub.2] values--although not significant--was more marked in the placebo group than in the pentoxifylline group 30 min after aspiration. Because hemodynamic patterns in both groups were very similar after 30 rain, they cannot explain the clear difference in Pa[O.sub.2] values. Pentoxifylline has been shown to cause relaxation of smooth bronchial muscles and pulmonary vessels, which might explain the improvement in oxygenation shortly after the harmful event. (24) However, in the later part of the ongoing experiment, we found significantly better oxygenation in pentoxifylline-treated rats than in placebo-treated rats, which cannot be explained by the latter effect alone.

Arterial oxygenation can be influenced by many factors, including pulmonary blood flow distribution and lung volume. Because we wanted to minimize the number of variables tested, we performed no recruitment maneuvers during anesthesia, allowing the development of atelectasis in dependent lung regions. When we compared CT scans of surviving animals after 6 h, we found a typical ground-glass opacification as a radiologic marker reflecting an active inflammatory process of the lung. The involvement of both the lung interstitium with abnormal thickening of the alveolar wall, and incomplete filling of the alveolar space has previously been described. (25) As expected, we also found additionally major dependent opacity in the placebo group showing consolidation. These consolidated lung regions were almost completely airless. The consolidated lung regions may have been due to either a complete filling of the alveolar spaces with liquid or to total collapse of alveolar space (atelectasis), or to a combination of both. (25-27) Because of the small size of the lungs, it was difficult to assess changes in the lung tissue. We therefore used a CT color-coding technique that has previously been used for better visualization of other organs. (28) The assessment of radiologic changes in CT scans of the lungs alter color-coding turned out to be easier than in grayscale CT scans, and is a tool that was already described with a more simplified approach by Rouby et al. (23)

Because atelectasis cannot be influenced by pharmacologic action and the ventilation strategy of both groups was identical, the significant improvement in oxygenation in pentoxifylline-treated animals can be explained by attenuation of pulmonary edema as seen in CT scans. We found that PaC[O.sub.2] values tended to be higher in the placebo group, although the difference between groups was not significant. This could be a result of decreased ventilation, consistent with the lungs becoming stiffer due to atelectasis and pulmonary edema. This might have contributed to the acidosis in the placebo group. Recent work on an experimental rat model showed that atelectasis has a negative effect on right ventricular function, residual capacity, and microvascular endothelial structure. (29) Based on echocardiographic and ultrastructural tissue findings, the authors (29) presented data that animals receiving ventilation with zero PEEP and not intermittently recruited died as a consequence of high pulmonary vascular resistance and resulting right ventricular failure. Although the experiment was performed in uninjured rat lungs, the mortality was up to 59% in nonrecruited animals, which developed atelectasis and an impaired right ventricular function with metabolic acidosis. In our experiments, we observed a higher mortality rate of 67% in the placebo-treated animals, since we used a model that added injurious ventilation to the primary insult. However, there was a significant decrease in mortality in animals treated with pentoxifylline.

Pentoxifylline is a potent phosphodiesterase inhibitor that typically affects cardiac function and has been previously investigated in other models of shock, cardiac impairment, and ARDS. (17,30-32) Pentoxifylline modulates production of the proinflammatory cytokine TNF-[alpha], which modifies cardiovascular parameters. [33,34] The observation that mean HR increased by 8 to 10% in pentoxifylline-treated rats while MABP remained stable is probably due to positive inotropic and chronotropic effects of the drug, and has been reported in previous studies [13,33,34] of patients and animals.

Our findings provide further evidence on the beneficial effects of pentoxifylline. Of these, the most striking is the effect of pentoxifylline treatment in improving survival under experimental conditions. Our results stand in contrast to the recently published ARDS Network study (17) with lisofylline in ARDS patients, in which the authors found no reduction in ventilator-free days, organ failures, or 28-day mortality. There are several possible explanations for this discrepancy.

First, one of the major differences between our experiment and the ARDS study was the timing. While we treated animals immediately after the acid instillation, patients in the lisofylline study (35) were treated within a 36-h window after the ARDS definition was met. Numerous studies (36-39) show the importance of early treatment with a TNF-[alpha] suppressor. Secondly, the effective dosage of pentoxifylline and means of administration could play a more important role than realized so far. We chose a pentoxifylline concentration that has been used in several animal models by other research groups. This dose of pentoxifylline has been shown to be effective in experimental models of lung injury. (11,40) It may be advantageous to infuse pentoxifylline continuously as we did for pharmacokinetic reasons, because the drug has a relatively short plasma half-life of 0.8 h, while its metabolites are measurable for 1.6 h. To ensure a constant plasma concentration of pentoxifylline and achieve constant TNF-[alpha] suppression in the "cytokine storm" during ALI, it may be necessary to infuse the drug continuously instead of administering it every 6 h as done in the lisofylline study, (35) However, there are no data concerning plasma levels of pentoxifylline in ALI. Our data on plasma levels of pentoxifylline and lisofylline in the experimental model should provide a useful basis for estimating appropriate dosages for the clinical setting.

However, some caution is required in extrapolating to the clinical context. Unlike other studies of acid aspiration-induced lung injury, the ventilator strategies in this study were intended to increase the lung injury by using a VT of 10 mL/kg and zero PEEP. A significant increase in epithelial and endothelial damage with consequent increased pulmonary edema has been shown in a rat model (41) when animals received ventilation with high VTs. Although most clinicians would not provide ventilation with VTs as high as 10 mL/kg and no PEEP to patients after an aspiration event, there are settings in which careful ventilation cannot be ensured (eg, emergencies outside the clinical setting). Early treatment after an aspiration-induced lung injury is only possible if the harmful event is witnessed, and this may only be possible in the minority of cases. It would be useful to determine the cut-off point, after which pentoxifylline administration no longer has beneficial effects on pathophysiology.

In summary, the results of this experimental study in rats have significant implications for the clinician because acid aspiration still has a high mortality, and an effective pharmacologic therapy is not yet established for patients after acid aspiration. (1,3,42-44) We report that pentoxifylline administration soon after an aspiration event improves oxygenation and may prevent the need for higher, harmful oxygen concentrations for adequate oxygenation. (45) We suggest that in the first 6 h after lung injury induced by acid aspiration, treatment with pentoxifylline leads to improvement of right ventricular function due to its inotropic effect and thus stabilizes hemodynamic parameters, resulting in a significant better survival. Further investigations of other phosphodiesterase inhibitors and their effects on cardiopulmonary parameters and right ventricular function are warranted.

CONCLUSIONS

Acid aspiration impairs gas exchange and induces hypotension. These data suggest that early treatment with pentoxifylline effectively improves oxygenation, markedly stabilizes systemic hemodynamics, and results in better survival after 6 h in a model of acid aspiration-induced lung injury.

ACKNOWLEDGMENT: The authors thank David Tracey, PhD, Department of Anatomy, University of New South Wales, Sydney, Australia for helpful comments regarding this manuscript.

* From the Departments of Anesthesiology (Drs. Pawlik, Gruber, and Taeger), Radinlogy (Drs. Schrever and Feuerbach), and Pharmacology (Dr. Ittner), University of Regensburg, Regensburg, Germany; and Department of Anesthesiology (Dr. Selig), University Hospital Ulm, Ulm, Germany.

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Manuscript received July 17, 2003; revision accepted September 9, 2004.

Correspondence to: Michael Pawlik, MD, Department of Anesthesiology, University of Regensburg, Franz-Josef-Strauss-Allee 6, D-93042 Regensburg, Germany; e-mail: michael.pawlik@klinik. uni-regensburg.de

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