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Loss of Alveolar Macrophages During Anesthesia and Operation in Humans

Kotani, Naoki MD, PhD; Lin, Chung-Yuan MD; Wang, Jian-Sheng MD; Gurley, Judith M. MD; Tolin, Fredrik P. MD; Michelassi, Fabrizio MD; Lin, Hsiu-San MD, PhD; Sandberg, Warren S. MD, PhD; Roizen, Michael F. MD

General Article

Pulmonary macrophages play an important role in the host defense against infection, and the importance of this role is probably enhanced when the upper airway defenses are circumvented by endotracheal intubation.Studies in animals suggest that exposure to volatile anesthetics compromises the viability and function of alveolar macrophages. We studied the effect of surgery and anesthesia on the alveolar macrophages of 41 human subjects undergoing lower abdominal procedures of varying lengths during nitrous oxide-isoflurane anesthesia. Alveolar macrophages were harvested from bronchoalveolar lavage fluid obtained before incision and compared to those recovered just before emergence from anesthesia. Macrophages were analyzed for aggregation and viability, assessed by the ability of viable cells to exclude trypan blue dye. Operations lasting 2 h or less led to little aggregation and had little effect on viability. However, there was a strong correlation between loss of macrophages and the duration of surgery and anesthesia. Aggregation increased and viability decreased as a function of procedure length. Studies are needed to determine whether prolonged surgery contributes to the incidence of postoperative pulmonary complications by disturbing the function and survival of alveolar macrophages in humans.

(Anesth Analg 1995;81:1255-62)

Departments of Anesthesia and Critical Care (Kotani, Lin, Wang, Sandberg, Roizen), Surgery (Gurley, Tolin, Michelassi), and Medicine, University of Chicago, Chicago, Illinois (Sandberg, Roizen), and the Department of Radiology, Washington University School of Medicine, St. Louis, Missouri (Lin).

Supported in part by the Chicago Anesthesia and Critical Care Research Foundation. WSS was supported by the Medical Scientist Training Program.

Accepted for publication July 14, 1995.

Address correspondence and reprint requests to Michael F. Roizen, MD, Professor and Chair, Department of Anesthesia and Critical Care, MC4028, University of Chicago, Chicago, IL 60637.

Pulmonary complications, frequently including pulmonary infection, are a major cause of postoperative morbidity and mortality [1-3]. Endotracheal intubation and mechanical ventilation bypass the nose and pharynx, which normally function as the first physiologic barriers to bacteria. Alveolar immune cells constitute the second line of pulmonary defense. Roughly 85% of the alveolar immune cells are macrophages [4]. By phagocytosing inhaled foreign bodies and by secreting various cytokines, alveolar macrophages play an important role in preventing postoperative infection [5,6].

General anesthesia impairs immunologic defense mechanisms [7-9], but studies of this problem focus on immunologic changes in the blood. For example, 70% nitrous oxide or equipotent (1 minimum alveolar anesthetic concentration) concentrations of halothane or enflurane inhibit in vitro chemotaxis of blood monocytes, whereas isoflurane has no effect [10]. Such changes suggest that anesthetics affect immune function. With respect to immunologic competence in the lung, several studies (conducted in vitro with animal cells) suggest that volatile anesthetics can suppress the cytotoxic or phagocytic response of alveolar macrophages [8,11-14].

Prolonged anesthesia increases the risk of postoperative pulmonary complications [2,3], but the mechanism by which risk is increased is not understood. We designed a study to test the hypothesis that prolonged operation and anesthesia lead to reduced alveolar macrophage function and viability in humans. To do this, we measured the level of alveolar macrophage aggregation, reflecting response to inflammation [15], in bronchoalveolar lavage samples obtained from anesthetized patients before and after operation. We also assessed macrophage viability, reflected by the ability of viable cells to exclude trypan blue dye [4], in the same samples. Aggregation and loss of viability were analyzed with respect to procedure length.

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The Institutional Review Board of the University of Chicago Hospitals and the Division of the Biological Sciences approved the protocol for this study. Of 62 patients who gave written informed consent to participate in the study, 41 ultimately participated. Participants were of ASA physical status I or II, 18-70 yr of age, and were undergoing elective surgery of the lower alimentary tract. Exclusion criteria were history of lung disease (chronic obstructive or restrictive, chronic pulmonary infection, collagen vascular disease or lung neoplasia), history of smoking, physical findings suggestive of lung disease, and chest roentgenographic or spirometric abnormalities (forced vital capacity and forced expiratory volume in 1 sec below 60% of control values). Of the original 62 patients, 21 were excluded on the basis of the above criteria. Postoperatively, each patient was evaluated daily for symptoms and signs of pulmonary complications (including infection) until discharge. When available, chest roentgenograms were also evaluated. No follow-up was undertaken after discharge. Preoperative screening and postoperative follow-up were conducted by one physician (N.K.) to ensure consistent application of criteria.

Many of the patients were undergoing operation for management of inflammatory bowel disease and may have been receiving steroid therapy. However, patients were not excluded on the basis of steroid use or medical management of their underlying disease or on the basis of previous operations or anesthetic exposure.

Anesthesia was induced with intravenous thiamylal and fentanyl, followed by vecuronium or pancuronium to facilitate tracheal intubation. Anesthesia was maintained with 0.5%-2.0% isoflurane and 50% nitrous oxide, supplemented with intermittent administration of fentanyl. Ventilation at 10 mL centered dot kg-1 centered dot min-1 was provided mechanically to maintain an end-expiratory CO2 of 4.5%-5%. Care was not standardized with respect to gas flow rates or humidification; 18 of the 41 patients were anesthetized using low flow technique to maintain humidity. Pancuronium or vecuronium provided abdominal muscle relaxation.

Alveolar cells were harvested by bronchoalveolar lavage (BAL) performed on all patients by the same investigator (C.-Y.L.) with a flexible fiberoptic bronchoscope (Olympus BF-B3; Olympus Corp., Lake Success, NY). The tip of the bronchoscope was wedged into a subsegment of the left or right lower lobe of the lung, and irrigation was with 20 mL of sterile 0.9% saline solution. Lavage fluid was recovered by gentle suctioning. Lavage was repeated five times, for a total of 100 mL of saline. BAL was performed before ("Pre") and after ("Post") operation on anesthetized patients, i.e., just after induction of anesthesia and again at the end of surgery when the patient was still anesthetized and skin was being approximated. Pre and Post BAL was performed on opposite lower lobes, and the samples were placed on ice immediately after collection.

To separate recovered alveolar cells and determine cell type and viability, we applied standard techniques to the recovered lavage fluid [4]. Manipulations of the cell suspensions were performed at 4 degrees C. First, we removed mucus by straining the fluid through a single layer of loose cotton gauze. We then pooled the resulting fluid in a sterile siliconized container and, using a hemocytometer, counted the alveolar cells in a portion of the fluid. Cell viability was determined by adding 0.4% trypan blue dye to the fluid (making a 0.2% solution). Viability estimates were based on microscopic counting of 1000 cells, noting their ability to exclude the dye. We then centrifuged the lavage fluid at 500g for 10 min and decanted the supernatant. The cells were washed with phosphate-buffered saline and resuspended in fresh buffer at a concentration of 0.5 times 106 cells/mL. The resuspended cells were stained with Diff-Quick stain (American Hospital Supply Corp., McGaw Park, IL), and slides were made for determination of cell type and aggregation by light microscopy.

The entire procedure was performed at 4 degrees C in the buffers described above, without addition of Mg2+ or other cations. Because the cell suspensions were chilled immediately after removal, we assumed that viability and aggregation reflected the state of the cells immediately before chilling.

Cell aggregation was expressed as the percentage of aggregated nuclei in cells per 1000 nuclei counted in two or three slide preparations. Changes in cell aggregation were calculated by subtracting the percentage of aggregated cells in the Pre samples from the percentage in the Post samples. Changes in cell viability were calculated in the same way. We did not count multinucleated giant cells, which made up 2%-5% of the harvested alveolar cells.

We used linear regression to compare the percentage change in both aggregation and viability with duration of anesthesia. We also attempted to assess the effect of isoflurane exposure on alveolar macrophage viability and aggregation. Isoflurane dose was estimated from vaporizer settings and expressed as percent-hours of isoflurane for each patient. We then normalized the data for macrophage viability and aggregation to 1% isoflurane by dividing percent change (in aggregation or viability) by percent-hours of isoflurane. Linear regression was again used to compare the normalized percentage change in aggregation and viability to the duration of anesthesia.

Analysis of the relationship between the duration of operation and the size of macrophage aggregates was also performed. We divided cell aggregates into two groups: aggregates of 2-9 cells and aggregates of 10 or more cells. Changes in cell aggregation were again calculated by subtracting the percentage of aggregated cells in the Pre samples from the percentage in the Post samples.

We used paired t-tests to analyze differences within groups, and analysis of variance with Tukey's procedure for multiple comparisons of means to analyze differences between groups. A difference was considered statistically significant if P < 0.05.

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All 41 patients had surgical procedures involving the ileum, colon, or rectum. The same surgeon (F.M.) performed all of the procedures. For all patients, the course of anesthesia was uneventful, and emergence from anesthesia, assessed by presence of spontaneous movement and the ability to follow commands, occurred within 10 min of the conclusion of the operation. No serious postoperative pulmonary complications had occurred by the time of patient discharge from the hospital. The ages, sex, diagnoses, procedures, and anesthesia times for the patients are given in Table 1.

Table 1

Table 1

(Table 2) shows the characteristics of BAL fluid recovered before and after operation. The amount of fluid recovered, the cell count in the BAL fluid, and the percentages of each cell type are given for the Pre and Post operation lavage samples. Ciliated cells and erythrocytes, which constituted less than 5% of the harvested cells, were not included in our analysis. No significant differences between Pre and Post values were found for any of these variables.

Table 2

Table 2

Aggregation and loss of viability are compared with duration of operation and anesthesia in Figure 1 and Figure 2. Cell clumps ranged in size from as few as two to as many 100. Increases in aggregation were strongly correlated with duration of surgery (R = 0.82, R2 = 0.67) Figure 1. When the isoflurane concentration was normalized to 1%, assuming a linear dose response between aggregation and isoflurane concentration, increase in correlation was not significant (R = 0.89, R2 = 0.79; data not shown).

Figure 1

Figure 1

Figure 2

Figure 2

The size of the macrophage aggregates also increased with longer operations. To demonstrate this observation, we have divided the data into three categories of duration: short (<2 h; n = 13), intermediate (2-6 h; n = 17), and long (>6 h; n = 11). Average percentages of alveolar macrophages in aggregates found before and after operation (Pre and Post) are shown for each category in Table 3. On average, 8%-10% of the cells in the Pre samples in all categories are found in 2-9 cell aggregates. The Pre samples contained virtually no 10-cell or larger aggregates. For short procedures, aggregation was unchanged at the end of operation. For intermediate procedures lasting 2-6 h, the percentage of macrophages in 2-9 cell aggregates increased in the Post BAL fluid, while the number of aggregates having 10 or more cells was essentially unchanged. When procedures exceeded 6 h, the percentage of macrophages in aggregates of 10 or more cells increased significantly, as did the number of smaller aggregates Table 3. The larger aggregates ranged in size from 10 to approximately 100 macrophages, representing a significant fraction of the macrophages present. Although more than 95% of aggregates consisted of only macrophages, several aggregations contained lymphocytes with other lymphocytes or with macrophages.

Table 3

Table 3

(Figure 2) shows that cell viability decreased as the duration of operation and anesthesia increased. The increase in nonviable cells found in Post samples is strongly correlated with procedure length (R = 0.82, R2 = 0.67) and approaches 25% for the longest procedures. Most of the nonviable cells were aggregated macrophages. Nonviable lymphocytes were rare. Normalization of the results to 1% isoflurane had no effect on the correlation between procedure duration and loss of viability (data not shown).

Of the 41 patients, 19 had received steroid therapy before surgery and were given perioperative stress doses of hydrocortisone. These patients were distributed randomly throughout the parent sample with respect to duration of surgery. Analysis of aggregation and loss of viability as a function of the duration of surgery was repeated independently for each group and showed no significant differences between groups, indicating that steroid exposure was not a major independent influence on alveolar macrophage survival (data not shown).

Inspired gas was humidified by a low flow anesthetic technique in 18 patients, who were distributed throughout the groups. The remaining 23 patients received higher gas flows. No differences between the two subgroups could be found with respect to aggregation or viability of alveolar macrophages (data not shown).

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We have demonstrated that aggregation of alveolar macrophages increases and viability decreases with prolonged anesthesia and surgery. These changes may be due to the disruptive effects of anesthesia or surgery, or both, on the normal milieu of pulmonary macrophages, or they may reflect toxic effects on the macrophages. Anesthesia-related effects can be divided into those caused by manipulation of the airway and pulmonary tissues (i.e., intubation and positive pressure mechanical ventilation) and those caused by exposure to anesthetic gases and increased oxygen tension. Effects related to surgery include fluid shifts due to inflammation and insensible losses from exposed gut, release of inflammatory mediators or gut bacteria (or both) into the bloodstream with prolonged handling of the gut, as well as changes in immune response related to the stress response to surgery. Because all of these factors varied independently in our study, it was impossible to identify which, if any, was the primary cause of the reduced macrophage viability we observed.

During anesthesia, the lung is exposed to multiple potential insults. Intubation and mechanical ventilation bypass anatomic barriers to infection. Inflation of the endotracheal cuff can inhibit the outward flow of mucus around the cuff. Constant tidal volumes provided by mechanical ventilation may not provide optimal protection from infection. Alveolar macrophages are uniquely dependent on oxidative metabolism for phagocytosis and oxygen radical formation [5], suggesting that they may be less effective in atelectatic areas. In anesthetized rats, mechanical ventilation with constant tidal volumes reduced the clearance of exogenously introduced Staphylococcus aureus from the lung as compared to unanesthetized controls or anesthetized animals given periodic sighs (large breaths exceeding tidal volume) [16]. The salutary effect of sighing was attributed to the reexpansion of small atelectatic regions, which maintained the normal air-liquid-surfactant interface and reduced areas of hypoxia [16]. Although it is possible that bacterial clearance, and by extension, pulmonary macrophage function, is depressed by the development of atelectasis during prolonged mechanical ventilation, it is unlikely that this mechanism is solely responsible for the decrease in viability we observed.

In dogs, the state of anesthesia itself impaired mucociliary clearance in a dose-dependent fashion [17]. Both halothane and thiopental caused this effect in intubated, mechanically ventilated animals [18]. A similar result was obtained in humans undergoing abdominal vascular surgery or lower extremity orthopedic procedures. After the relatively short orthopedic cases, radiopaque particles insufflated into the lung at the end of operation were cleared within 48 h. In the abdominal cases, which lasted approximately three times longer, a large fraction of the particles was retained even after 100 h. Because the two groups of patients differed in anesthetic regimen, the site and duration of operation, and underlying health, the exact cause of the observed differences could not be determined [19]. Thus, although it is difficult to separate their effects, it appears that general anesthesia and endotracheal intubation undermine a major anatomic defense against pulmonary infection.

During mechanical ventilation, alveolar macrophages in our patients were exposed to volatile anesthetics, N2 O, supernormal oxygen tensions, and dry inspired gases, all of which are potentially toxic. Exposure to supernormal oxygen tension, 60% O2 for up to 24 h, was well tolerated by alveolar macrophages from guinea pigs [14], suggesting that oxygen toxicity was not the cause of alveolar macrophage death and aggregation in our patients.

Although the humidity of inspired gas was not measured in this study, approximately half of our patients received low flow anesthesia to provide humidification. Humidification did not appear to have a major influence on alveolar macrophage viability or aggregation, but the small number of patients in our study precludes detection of differences in aggregation and viability between the two groups.

The toxic effects of inhaled and intravenous anesthetics on alveolar macrophages are incompletely understood [7-9]. Volatile and barbiturate anesthetics appear to suppress phagocytosis by circulating and tissue macrophages in vivo [8]. Halothane (4% in air) caused dose-dependent inhibition of protein synthesis in alveolar macrophages in vitro. Halothane did not appear to kill the cells directly, as assessed by release of cellular lactate dehydrogenase, nor did it deplete cellular adenosine triphosphate (ATP) over 30 min [11]. At clinically relevant concentrations, halothane, isoflurane, and enflurane reversibly inhibited the microbicidal oxidative activity of alveolar macrophages [12,13]. Administration of 5% halothane or 5% enflurane in 60% O2 over 24 h decreased the concentration of ATP in alveolar macrophages exposed to the gas phase [14]. At clinically relevant concentrations in 50:50 N2 O: O2 these drugs reduced cellular ATP after 6 h. The contribution of the halogenated drugs could not be separated from the effect of the carrier gas because 50:50 N2 O: O2 depleted cellular ATP and 60% O2 alone did not deplete intracellular ATP after 24 h [14]. These studies (conducted in vitro with animal cells) suggest that volatile anesthetics can suppress the cytotoxic or phagocytic response of alveolar macrophages.

Thus, high isoflurane concentration during the course of anesthesia may have decreased alveolar macrophage viability and increased aggregation in our study. The studies cited above suggest that the effect of anesthetics on alveolar macrophages is reversible. In our study, duration of anesthesia and percent-hours of isoflurane were highly correlated (i.e., patients received relatively constant doses of isoflurane for the duration of their procedures), so an independent effect of the concentration of isoflurane could not be assessed. Isoflurane concentration was measured qualitatively so that the normalization of the data to isoflurane dose was not precise. A group of similar patients not exposed to isoflurane would have been required to detect an independent effect of isoflurane on alveolar macrophage aggregation and viability.

Steroid exposure is another possible contributor to the loss of alveolar macrophages we observed. Almost half of the patients in the study had received steroids in the immediate preoperative period, most for management of inflammatory bowel disease. No significant differences were found when aggregation and loss of viability as a function of the duration of surgery were compared for patients who had received steroids and those who had not. The analyses were limited in their power to detect small differences in macrophage survival owing to steroid exposure, but they were sufficient to exclude steroids as the sole cause of our observations.

The effects of surgery on alveolar macrophage function are also poorly understood. In mice, simple midline laparotomy during ether anesthesia reduced antigen presentation and interleukin-1 synthesis by peritoneal macrophages, while ether alone had no effect [20]. Alveolar macrophages were recovered between 6 and 24 h after cecal ligation and puncture in mice (inducing sepsis); macrophages did not increase in number or decrease in viability. Over time, the macrophages showed signs of activation, including increased spreading and oxygen radical production as the mice developed sepsis [21].

Prolonged handling of the gut during operation in our patients may have led to the release of gut bacteria, bacterial endotoxin, inflammatory mediators such as interleukin-1 or tumor necrosis factor, or any combination of these, into the bloodstream. These agents, if deposited in the lung, may have activated alveolar macrophages [22], although it is unclear how activation by contaminants from the gut would then lead directly to the death of alveolar macrophages. If what we observed was the result of exposure to substances released from the gut during operation, then it is possible that the complexity of the procedure (i.e., the amount of manipulation sustained by the gut) is the factor most closely associated with the loss of alveolar macrophages, and the correlation arises between procedure duration and loss of macrophages because more complex procedures tend to be longer.

The loss of alveolar macrophage viability we observed during anesthesia and operation may have been entirely due to a single factor, but it is also possible that multiple factors contributed. For example, in a rabbit model of inflammatory lung injury, intravenous administration of rabbit C5a, a complement-derived chemotactic factor, induced neutrophil migration to the pulmonary microvasculature but not translocation into the alveolar spaces. However, when this maneuver was accompanied by anesthesia with intubation, mechanical ventilation, and operation (femoral artery cutdown), neutrophils increased significantly in the alveolar air-spaces [23]. The aforementioned study illustrates the cumulative effects of multiple insults in the development of lung injury.

The fact that no postoperative pulmonary complications occurred during our study might at first suggest that the loss of alveolar macrophages has little impact on clinical outcome. However, prolonged operation and anesthesia are associated with increased incidence of such complications [1-3]. The overall incidence of postoperative pulmonary complications related to anesthesia, mostly atelectasis and pneumonia, varies from 3% to 76%. These figures depend on the criteria used to define pulmonary complications and on the diligence of those searching for the problem [1]. Thus, it is likely that our patient group (especially those undergoing long procedures with the highest likelihood of pulmonary complication) was too small to permit detection of differences in the incidence of postoperative pulmonary complications.

The clinical importance of a 25% reduction in the numbers of viable alveolar macrophages or a 40% increase in aggregation with the longest cases is not clear. Some speculations are possible. Reductions of 25% in viable macrophages may not have disastrous consequences because most patients do not develop pulmonary infections postoperatively. Like most organ systems, the lung possesses considerable reserve capacity, and it is reasonable to assume that this reserve applies to the pulmonary phagocytic system as well. Reserve capacity may explain why reductions in viable macrophages are tolerated without pulmonary complications. Alternatively, the aggregated and nonviable macrophages noted in our study may represent only the most severely injured cells. Many alveolar macrophages may be injured without being killed outright by anesthesia and surgery, and the function of the injured cells may have been compromised to the point that true phagocytic reserve capacity was quite small. Such injury need not be clinically evident, since the loss of reserve capacity in most physiologic processes is usually clinically silent. One may then speculate that pulmonary complications occur when additional insults are delivered to lungs that have suffered serious but clinically undetected reductions in phagocytic capacity. A larger study with strict criteria to define pulmonary complications is needed to determine whether loss of alveolar macrophages correlates with the development of pulmonary complications.

Although our study cannot detect the cause of alveolar macrophage aggregation and death, there is a clear correlation between the duration (or perhaps the complexity) of the procedure and macrophage death. This result may help to explain why longer cases tend to have higher pulmonary morbidity and may serve as a reminder to clinicians to be especially vigilant for pulmonary complications after long cases. Because procedure length is a relatively inflexible quantity, efforts to minimize decreased viability of alveolar macrophages may be directed toward minimizing those insults that damage them in vitro. However, it is unclear what steps will prove efficacious because the mechanism underlying the loss of macrophage viability in vivo is still unknown. Hopefully, a series of interventional studies in animals will elucidate the mechanism of alveolar macrophage death during surgery and anesthesia as well as the clinical significance of this phenomenon.

We are grateful to Elisabeth Lanzl and Pauline Snider for editorial review of the manuscript.

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