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CRITICAL CARE AND TRAUMA

The Effects of Airway Pressure and Inspiratory Time on Bacterial Translocation

Perihan Ergin Ozcan, MD^*, Nahit Cakar, MD^*, Simru Tugrul, MD^*, Ozkan Akinci, MD^*, Atahan Cagatay, MD, Dilek Yilmazbayhan, MD, Figen Esen, MD^*, Lutfi Telci, MD^*, and Kutay Akpir, MD^*

From the *Departments of Anesthesiology and Intensive Care; Infectious Disease and Clinical Microbiology; and Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Address correspondence and reprint requests to Perihan Ergin Ozcan, MD, Department of Anesthesiology and Intensive Care, Istanbul Medical Faculty, Istanbul University, Capa Klinikleri 34093, Capa, Istanbul, Turkey. Address e-mail to pergin{at}istanbul.edu.tr.

	Abstract

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BACKGROUND: Mechanical ventilation with high peak inspiratory pressure (PIP) induces lung injury and bacterial translocation from the lung into the systemic circulation. We investigated the effects of increased inspiratory time on translocation of intratracheally inoculated bacteria during mechanical ventilation with and without extrinsic positive end-expiratory pressure (PEEP).

METHODS: Rats were ventilated in pressure-controlled mode with 14 cm H₂O PIP, 0 cm H₂O PEEP, I:E ratio 1/2, and Fio₂ 1.0. Subsequently, 0.5 mL of 10⁵ cfu/mL Pseudomonas aeruginosa was inoculated through tracheostomy and rats were randomly assigned to six groups; two low-pressure groups (LP)1/2, 14 cm H₂O PIP, 0 cm H₂O PEEP, I:E = 1/2, and LP2/1 14 cm H₂O PIP, 0 cm H₂O PEEP, I:E = 2/1; two high-pressure groups (HP)1/2, 30 cm H₂O PIP, 0 cm H₂O PEEP, I:E = 1/2, and HP2/1, 30 cm H₂O PIP, 0 cm H₂O PEEP, I:E = 2/1; two HP PEEP groups (HPP)1/2, 30 cm H₂O PIP, 10 cm H₂O PEEP, I:E = 1/2, and HPP2/1, 30 cm H₂O PIP, 10 cm H₂O PEEP, I:E = 2/1. Blood cultures were obtained every 30 min. The rats were killed and their lungs were processed.

RESULTS: When compared with baseline values, Pao₂ decreased in the LP1/2, LP2/1, HP1/2, and HP2/1 groups at the last time point, but the decline in Pao₂ reached statistical significance in only the HP1/2 group. The bacterial translocation rate was greater in group HPP2/1 than group HPP1/2 (P = 0.01).

CONCLUSIONS: We found that high PIP, with or without prolonged inspiratory time, increased the rate of bacterial dissemination. PEEP prevented bacterial translocation in the high PIP group. However, the protective effect of PEEP was lost when inspiratory time was prolonged.

	Introduction

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Mechanical ventilation is widely used as a supportive treatment for respiratory failure in intensive care units. Although it is a life-saving procedure, the use of mechanical ventilation might cause several life-threatening complications. A number of experimental and clinical studies have demonstrated that mechanical ventilation can induce or exacerbate lung injury (1–3), which has been called "ventilator-induced lung injury" (VILI).

Inverse ratio ventilation (IRV) is a ventilatory concept that can be used in patients with acute lung injury and acute respiratory distress syndrome to improve gas exchange (4,5). IRV is defined by an inspiratory-to-expiratory time ratio (I:E) of more than one. The mechanisms by which IRV improves gas exchange have not been completely elucidated. The observed increment in mean airway pressure (MawP) and intrinsic positive end-expiratory pressure (i-PEEP) as a result of prolonged inspiratory time during IRV may be responsible for the improved gas exchange. The same changes caused by IRV on airway pressure, however, may also contribute to VILI. Casetti et al. (6) found that increasing the inspiratory time during high pressure/high volume mechanical ventilation was associated with increases in various measures of lung injury.

Lung pathology, lung wet weight to dry weight ratio, oxygenation, and respiratory mechanics have all been used as a marker of VILI. Similarly, translocation of intratracheally inoculated bacteria has also been used as a marker of lung injury (7). The effects of different mechanical ventilation variables, such as positive end-expiratory pressure (PEEP), tidal volume (V_T), peak airway pressure, and recruitment maneuvers, have been studied on the translocation of intratracheally inoculated bacteria in several experimental studies (7–9). The effect of inspiratory time on translocation of intratracheally instilled bacteria is unclear. In the present study, we investigated the effects of increased airway pressure and inspiratory time, with or without PEEP, on bacterial translocation during mechanical ventilation.

We hypothesized that increasing the duration of applied inspiratory pressure by inverse ratio ventilation would increase the rate of bacterial translocation

	METHODS

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The Institutional Animal Investigation Committee approved the study protocol. Care and handling of the animals were in accordance with the European community guidelines. In this study we used 36 Sprague Dawley rats weighing 250–300 g.

Animal Preparation
Rats were anesthetized with 1%–2% enflurane (Ethrane; Abbott Laboratories, North Chicago, IL) in 33% nitrous oxide and 65% oxygen together with intraperitoneal injection of ketamine (50 mg/kg). After induction of anesthesia, tracheostomy was performed using a 16-gauge cannula. The rats were ventilated in pressure-controlled ventilation mode with a Servo 300 ventilator (Siemens Servo 300; Siemens-Solna, Sweden) with a peak inspiratory pressure (PIP) of 14 cm H₂O, a PEEP of 0 cm H₂O, an inspired fraction of oxygen (Fio₂) of 1.0, respiratory rate of 30 breaths/min, and an I:E of 1/2. Vecuronium bromide (Norcuron, Organon Technica B.V., Boxtel, The Netherlands), (0.5 mg/kg) was used for muscle relaxation and intraperitoneal ketamine was used for maintenance of anesthesia when necessary. Using an aseptic surgical technique, the right or left carotid artery was cannulated with a 24-gauge catheter (Becton Dickinson, UT) to monitor arterial blood gases and arterial blood pressure (Mercury, Mennen Medical, NY) using disposable transducers (Deltran ABL System Medical Products, UT). Body temperatures were also monitored continuously using a rectal probe and normothermia was maintained with a heating lamp.

Preparation and Instillation of Bacteria
The bacterial solution was prepared as follows: One tube containing an inoculum of 1 x 10⁵ cfu/mL of Pseudomonas aeruginosa (ATCC 27853) was prepared for each rat separately. This solution was stored on ice until it was instilled into the rat's trachea.

First blood samples were obtained from each rat at baseline before instillation of the bacterial solution. Then 500 µL of saline containing 10⁵ cfu/mL P. aeruginosa was injected into the trachea by the same method we used for previous experiments (9). To maximize the distribution of bacteria through the lungs, 5 mL of air was injected after the bacterial instillation.

After instillation of bacteria, we obtained the blood samples at 30, 60, 90, and 120 min. We then inoculated a sterile tube containing brain–heart solution with the blood and performed four serial dilutions using four additional tubes. All tubes were incubated at 35°C overnight and the turbidity in each tube was assessed over 7 days. We measured the time to turbidity and obtained subcultures on blood agar and MacConkey agar. Bacteremia was defined as the presence of one or more colonies of P. aeruginosa in the blood. Isolated bacteria were identified by using standard microbiological methods (10).

Experimental Protocol
After a 15-min stabilization period, the baseline values for ventilatory variables (V_T, PIP, MawP, PEEP, i- PEEP) and mean arterial blood pressure (MAP) were recorded. At each stage, we removed 1.5 mL of blood through the arterial cannula under sterile condition and used 1 mL of this blood for baseline blood culture and 0.5 mL for a blood gas analysis (ABL 700; Radiometer, Copenhagen, Denmark). During the experimental protocol, all rats received a total of 7 mL colloid solution (hydroxyethyl starch 450/0.7, 6%, Eczacbas/Baxter), intraarterially to replace the blood loss caused by blood sampling. Isotonic NaCl was also infused when MAP decreased more than 20% from baseline.

After inoculation, rats were randomly divided into six groups:

1. Low-pressure (LP)1/2 group: 14 cm H₂O PIP, 0 cm H₂O PEEP, I:E = 1/2.
   
2. LP2/1 group: 14 cm H₂O PIP, 0 cm H₂O PEEP, I:E = 2/1.
   
3. High-pressure (HP)1/2 group: 30 cm H₂O PIP, 0 cm H₂O PEEP, I:E = 1/2.
   
4. HP2/1 group: 30 cm H₂O PIP, 0 cm H₂O PEEP, I:E = 2/1.
   
5. High-pressure PEEP (HPP)1/2 group: 30 cm H₂O PIP, 10 cm H₂O PEEP, I:E = 1/2.
   
6. HPP2/1 group: 30 cm H₂O PIP, 10 cm H₂O PEEP, I:E = 2/1. All other ventilatory variables were kept the same as at baseline.
   

Blood cultures were obtained under sterile conditions every 30 min during the 2-h study period, and ventilatory variables, MAP, and rectal temperature were recorded at the same time. Immediately after the 2-h study period, the rats were killed by an intraperitoneal injection of sodium thiopental (120 mg/kg). The thorax was opened using an aseptic surgical technique under 5 cm H₂O continuous positive airway pressure (CPAP) and the lungs were removed together with the heart.

Morphologic Evaluation
At the end of the study, the lungs were removed and fixed by intratracheal instillation of 10% formalin for 24 h and then embedded in paraffin for histological evaluation. Two longitudinal sections (5 µm thick) from each lobe of the lungs were obtained and stained with hemotoxylin-eosin. A total of 10 high-power fields (five from the periphery and five from the central portion of each lobe) were evaluated randomly. The sections were examined with a grading scale (0–3) for four different pathologic criteria (perivascular interstitial edema, intraalveolar hemorrhage, intraalveolar edema, and intraalveolar polymorphonuclear leukocytes infiltration). The histological scores for each of the four different pathologic descriptions from the two sections from each lobe were then averaged to obtain an average histology score for each animal. A pathologist who was blinded to the study groups performed the histological analyses.

Statistical Analysis
Data are expressed as mean ± sd. Inter-group comparisons were analyzed by Kruskal–Wallis ANOVA; Dunn's multiple comparisons test was used for post hoc analyses if the ANOVA revealed a P < 0.05. A Wilcoxon's test was used for intra-group analysis and a nonparametric Gaussian approximation test was used for correlation analyses. Kaplan–Meier curves and the log rank test were used to analyze for bacterial translocation, and a P < 0.05 was also considered statistically significant in these analyses.

	RESULTS

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Oxygenation and Gas Exchange Results
There were no differences in baseline pH, Pao₂, and Paco₂ values among the groups (Table 1). V_t increased in the HP1/2 group (14.5 ± 0.6 mL to 21.3 ± 3.7 mL) and the HP2/1 (13.5 ± 1.6 mL to 20 ± 3.3 mL) groups when compared with LP and HPP groups. V_t remained unchanged in the LP and HPP groups. When compared with baseline values, Pao₂ decreased in the LP1/2, LP2/1, HP1/2, and HP2/1 groups at the last time point, but the decline in Pao₂ reached statistical significance in only the HP1/2 group (370 ± 167 mm Hg to 94 ± 36 mm Hg) (P < 0.05). Oxygenation remained stable throughout the experiment in the HPP1/2 and HPP2/1 groups. Paco₂ decreased in the HP1/2 group (36.3 ± 11.3 mm Hg to 29 ± 10.8 mm Hg) and HP2/1 group (31.8 ± 5.6 mm Hg to 23.6 ± 8.2 mm Hg) and increased in the HPP1/2 group (36 ± 10.5 mm Hg to 54.6 ± 8.1 mm Hg) relative to baseline values. These differences were statistically significant only in the HPP1/2 group (P = 0.02). Arterial pH decreased in the HPP1/2 group because of the increase in Paco₂ (P = 0.02). We did not observe any differences in arterial pH in any other group.

We recorded MAP continuously during the experimental protocol, but performed statistical analyses for values measured at 30, 60, 90, and 120 min. Relative to baseline values MAP decreased in all groups at the end of the experiment. MAP significantly decreased only in the HP2/1 group at the end of the experiment and stayed relatively similar throughout the experiment. We did not observe significant changes in any groups before the 120th min time point. Higher amounts of fluids were administered in IRV groups; however, these differences did not reach statistical significance (LP1/2 15.6 ± 0.5 mL, LP2/1 18.6 ± 1.5 mL, HP1/2 19 ± 1.4 mL, HP2/1 22 ± 5 mL, HPP1/2 18.8 ± 1.7 mL, HPP2/1 21.1 ± 1.4 mL).

When compared with baseline, MawP values increased in LP2/1, HP1/2, HP2/1, HPP1/2, and HPP2/1 groups at 30 min (P < 0.05). As a result of high PEEP and/prolonged inspiratory time, MawP was higher in the HPP2/1 group when compared with the other groups (P < 0.05). Table 1 shows Pao₂, Paco₂, pH, airway pressures, MAP, and V_t at baseline and at the end of the experiment.

Blood Culture Results
We obtained 178 blood cultures from the six experimental groups (Table 2). We did not observe any positive blood culture at baseline. In the HP1/2 and HPP1/2 group, two rats died 90 min after they developed shock which did not respond to fluid resuscitation. The last available measurements were used for statistical analysis in these groups. At the time of death, blood cultures from these rats were all negative. We did not observe any positive blood cultures at the end of the experiment in the LP1/2 and LP2/1 groups. The earliest positive blood culture was determined at 60 min in the HPP2/1 group (Fig. 1). At the end of the experiment, positive blood cultures were observed in all rats in the HPP2/1 group.

View larger version (14K): [in this window] [in a new window]   Figure 1. Kaplan–Meier curves displaying the percentage of positive blood cultures in terms of time in each group. LP = Low-pressure group, HP = high-pressure group, HPP = high-pressure positive end-expiratory pressure (PEEP) group.

As mentioned earlier, MawP was higher in the HPP2/1 group relative to other groups. We found a correlation between MawP and translocation rate (P = 0.037) (Fig. 2).

View larger version (14K): [in this window] [in a new window]   Figure 2. The correlation between mean airway pressure and number of positive blood cultures. LP = Low-pressure group, HP = high-pressure group, HPP = high-pressure positive end-expiratory pressure (PEEP) group.

The comparison between translocation rates for groups HPP1/2 and HPP2/1 was significant (P = 0.01) at the 90 and 120 min time points. In the HP2/1 group the first positive blood culture was found at 90 min. At the end of experiment, four rats exhibited positive blood cultures in this group.

In the HP1/2 and HPP1/2 groups, positive blood cultures were observed only at the end of the experiment, 120 min. Although a few rats had positive blood cultures in the HP1/2 and HP2/1 groups, these findings were not statistically significant when compared with the HPP2/1 group. Table 2 summarizes the blood culture results from each group as a function of time.

Histology Results
Quantitative pathology scores of lung injury are given in Table 3. Perivascular interstitial edema appeared to be more widely distributed in the HP and HPP groups, but these differences were not statistically significant. On the other hand, substantial perivascular interstitial edema was found in the HP1/2 group, and the difference between groups HP1/2 and HP2/1 was statistically significant (P < 0.05). HP1/2 rats had a higher degree of intraalveolar hemorrhage than the LP and HPP groups, but the difference did not reach statistical significance. However, the difference between the HP1/2 and HP2/1 groups was significant (P < 0.05). Intraalveolar edema and polymorphonuclear leukocyte infiltration were similar among all groups and also between normal and prolonged inspiratory time groups.

	DISCUSSION

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The present study reports the following major findings: 1) intratracheal instillation of P. aeruginosa significantly worsened oxygenation only in the HP and normal inspiratory time group (HP1/2); 2) the rate of dissemination of intratracheally instilled bacteria from the alveoli to the bloodstream increased with increasing PIP and I:E ratio, 3) 10 cm H₂O of PEEP did not prevent translocation of bacteria in the prolonged inspiratory time group, 4) there was a correlation between MawP and bacterial translocation rate.

In spite of the bacterial challenge, increasing I:E ratio protected oxygenation. Although the exact mechanism of IRV on oxygenation has not been clearly delineated, increasing MawP and iPEEP values were most likely responsible for improving gas exchange (11). We did not find any iPEEP in the prolonged inspiratory time groups. However, we used only I:E of 2/1. If we had used ratios of I:E 3/1 or 4/1, we might then have observed an increase in iPEEP. Based on our available data, we cannot fully predict the effect of higher I:E ratios on the rate of bacterial translocation.

Increasing the inspiratory time fraction with IRV may cause a significant increase in MawP and impede venous return (12). We observed a decrease in MAP; however this change was not statistically significant in the HPP 2/1 group, which had the highest MawP. Our results are consistent with previous studies (13,14), which demonstrated no significant alteration in cardiac output when the inspiratory period was no more than two times that allowed for expiration.

Several investigators have studied bacterial translocation through the lungs (7–9). Verbrugge et al. (8) demonstrated that mechanical ventilation with a combination of PIP of 30 cm H₂O without PEEP induced Klebsiella pneumonia bacteremia after 3 h. They obtained blood cultures after only 3 h of mechanical ventilation. Therefore, the onset of dissemination in their experimental model could not be determined. In our study, the number of positive blood cultures in the HP1/2 group was 3/5 at the end of the experiment. In this group, we did not observe any positive blood cultures before 120 min. Conceviably, if we had prolonged our experimental protocol longer than 120 min, we might have found more positive cultures at the end of the experiment.

Cakar et al. (9) also demonstrated that high inflation pressures (45 cm H₂O PIP) without PEEP caused dissemination of intratracheally inoculated bacteria into the systemic circulation in rats. However, in that study, repetitive recruitment maneuvers (45 cm H₂O CPAP for 30 s every 15 min for 2 h) did not cause translocation of bacteria.

Nahum et al. (7) showed that over-distention of the lungs caused bacterial translocation and increased lung injury in dogs. In that study, the high transpulmonary pressure with low-PEEP group (35 cm H₂O PIP and 3 cm H₂O PEEP) had the earliest positive blood culture at 30 min. Furthermore, the number of animals that developed positive blood cultures in this group was more than that in other groups (ventilated with 13 cm H₂O PIP and 3 cm H₂O PEEP and 30 cm H₂O PIP and 10 cm H₂O PEEP). In the same study, PEEP had a protective effect on bacteremia despite lung over-distention. Our study differs from previous studies, as we explored the effect of PIP, PEEP, and inspiratory time on bacterial translocation. Our findings suggest that over-distention is the main determinant of bacterial translocation. The correlation of the translocation rate with MawP supports this hypothesis. Repetitive opening and closing may also promote bacterial translocation. PEEP, by stabilizing unstable alveoli, may prevent repetitive opening and closing and translocation of bacteria. However, prolonging inspiratory time may accentuate over-distention and override the protective effect of PEEP.

Van Kaam et al. (15) induced pneumonia by intratracheal injection of Group B streptococci. They noted that animals that had preexisting lavage-induced lung injury developed bacteremia sooner and more readily than those with normal lungs. In lavaged animals, treatment with exogenous surfactant and an "open lung" ventilation strategy (accomplished by using a recruitment procedure and setting PEEP 2 cm H₂O above closing pressure) protected against development of bacteremia. The best results were obtained when both an "open lung" ventilatory strategy and exogenous surfactant were used (15). These results suggest that both the presence of underlying lung injury and forces acting on the lungs by the ventilator influence translocation of bacteria from the lungs into the systemic circulation.

Savel et al. (16) studied bacterial translocation in a rabbit model. They instilled P. aeruginosa into the lung then ventilated with either high V_t (15 mL/kg⁾ or low V_t (6 mL/kg) and a PEEP level of 3–5 cm H₂O for both groups. Even though their results did not reach statistical significance, they observed early bacteremia in animals which were ventilated with the "high stretch" mode of mechanical ventilation.

A number of investigators have demonstrated a relationship between airway pressure and VILI. However, very few studies explored the effect of inspiratory time on VILI. Casetti et al. (6) demonstrated that inspiratory time can affect the degree of lung injury associated with high pressure mechanical ventilation. In contrast to their findings at a PIP of 30 cm H₂O, we found better histological variables in the prolonged inspiratory time group when compared with the normal inspiratory time group. Casetti et al. (6) used higher peak airway pressure (45 cm H₂O) in their study, and the effect of inspiratory time may have been masked by the extent of lung injury caused by airway pressure.

Our study has certain limitations. First, the ventilation period was limited to 2 h. Prolonging this period might have changed our results. Second, we did not make homogenate cultures of the lungs at the end of the experiment, so we do not know the rate of bacterial growth in each group. Third, we only measured MAP, which does not fully reflect the hemodynamic changes caused by IRV. It is possible that cardiac output changed throughout the experiment.

In summary, in our experimental protocol in rats increasing PIP and I:E ratio promoted bacterial translocation. The possible protective effect of PEEP was lost at higher I:E ratios.

	CONCLUSION

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We demonstrated that prolonged inspiratory time increases the rate of dissemination of intratracheally inoculated bacteria. This effect was correlated with MawP. Moreover, the potential protective effect of PEEP was lost when it was added to IRV. Our data suggest that for development of VILI, the duration of high pressure exposure may be as important as high inspiratory pressures. Determination of the exact role of inspiratory time in promoting lung injury will require a series of experiments that explore the combined effects of I:E ratio on MawP, total PEEP, and hemodynamics.

	ACKNOWLEDGMENTS

 
The authors acknowledge Dr. Avi Nahum for his advice and comments during the preparation of this article. This study was performed in the experimental laboratory founded by Prof. Dr. Kutay Akpir in Istanbul University in Department of Anesthesiology and Intensive Care.

	Footnotes

 
Accepted for publication November 6, 2006.

Supported by Istanbul University Grant 1561-16012001.

	REFERENCES

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Ozcan, P. E. Articles by Akpir, K. Search for Related Content PubMed PubMed Citation Articles by Ozcan, P. E. Articles by Akpir, K. Related Collections Critical Care Ventilation