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Published ahead of print on May 25, 2006, doi:10.1164/rccm.200506-907OC
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American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 408-414, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200506-907OC

Original Article

Intervention at the Level of the Neuroendocrine–Immune Axis and Postoperative Pneumonia Rate in Long-term Alcoholics

Claudia Spies, Verena Eggers, Gyongyi Szabo, Alexandra Lau, Vera von Dossow, Helge Schoenfeld, Hilke Althoff, Katrin Hegenscheid, Birgit Bohm, Torsten Schroeder, Sebastian Pfeiffer, Sabine Ziemer, Christian Paschen, Martin Klein, Christian Marks, Peter Miller, Michael Sander, Klaus-D. Wernecke, Evelin Achterberg, Udo Kaisers and Hans-Dieter Volk

Department of Anesthesiology and Intensive Care Medicine, Institute of Laboratory Medicine and Pathobiochemistry, and Institute of Medical Biometry, Campus Charité Mitte and Campus Virchow Klinikum; Institute of Medical Immunology, Campus Charité Mitte; Department of Otorhinolaryngology and Head and Neck Surgery, Campus Charité Mitte, Campus Virchow Klinikum, and Campus Benjamin Franklin; Clinic and Polyclinic for Oral and Maxillofacial Surgery and Plastic Surgery, Campus Virchow Klinikum; and Department of Maxillofacial and Plastic Surgery, Campus Benjamin Franklin, Charité–University Medicine Berlin, Berlin, Germany; Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts; and Center for Drug and Alcohol Programs, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina

Correspondence and requests for reprints should be addressed to Claudia Spies, M.D., Department of Anesthesiology and Intensive Care Medicine, and Emergency Medicine and Pain Therapy, Charité–University Medicine Berlin, Campus Charité Virchow Klinikum and Campus Charité Mitte, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: claudia.spies{at}charite.de


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Postoperative pneumonia is three to four times more frequent in patients with alcohol use disorders followed by prolonged intensive care unit (ICU) stay. Long-term alcohol use leads to an altered perioperative hypothalamus–pituitary–adrenal (HPA) axis and immunity.

Objectives: The aim of this study was to evaluate HPA intervention with low-dose ethanol, morphine, or ketoconazole on the neuroendocrine–immune axis and development of postoperative pneumonia in long-term alcoholic patients.

Methods: In this randomized, double-blind controlled study, 122 consecutive patients undergoing elective surgery for aerodigestive tract cancer were included. Long-term alcohol use was defined as consuming at least 60 g of ethanol daily and fulfilling the Diagnostic and Statistical Manual of Mental Disorders IV criteria for either alcohol abuse or dependence. Nonalcoholic patients were included but only as a descriptive control. Perioperative intervention with low-dose ethanol (0.5 g/kg body weight per day), morphine (15 µg/kg body weight per hour), ketoconazole (200 mg four times daily), and placebo was started on the morning before surgery and continued for 3 d after surgery. Blood samples to analyze the neuroendocrine–immune axis were obtained on the morning before intervention and on Days 1, 3, and 7 after surgery.

Measurements and Main Results: In long-term alcoholic patients, all interventions decreased postoperative hypercortisolism and prevented impairment of the cytotoxic T-lymphocyte type 1:type 2 ratio. All interventions decreased the pneumonia rate from 39% to a median of 5.7% and shortened intensive care unit stay by 9 d (median) compared with the placebo-treated long-term alcoholic patients.

Conclusions: Intervention at the level of the HPA axis altered the immune response to surgical stress. This resulted in decreased postoperative pneumonia rates and shortened intensive care unit stay in long-term alcoholic patients.

Key Words: aerodigestive tract cancer • alcohol use disorder • cortisol • pneumonia • T-cell–mediated immunity

Every fifth patient admitted to a general hospital has an alcohol use disorder (1). In patients undergoing surgery of the aerodigestive tract, the rate of alcohol abuse exceeds 50% (2–4). Infections are reported to be more frequent among alcoholic patients compared with control patients in either medical or surgical settings (3, 5). Long-term alcoholic patients have a three- to fourfold increased risk of infection after surgery (6). Because of this increased postoperative morbidity, intensive care unit (ICU) treatment and overall hospital stay are prolonged (2, 6–8). Among all infections, pneumonia is the most relevant and it is associated with a worse outcome for the patient and increased hospital costs (2, 6, 8). The pneumonia rate reported from previous studies is about 35% (8), which is strikingly high compared with 12.8% in ventilated medical–surgical ICU patients (9).

Surgical trauma (10–12), alcohol-related injury (13), and cancer (14) result in an initial proinflammatory response, after which a compensatory antiinflammatory response ensues. Imbalances between pro- and antiinflammatory cytokines are reported under the influence of alcohol in experimental and clinical situations (8, 15–17). Disturbances of the stress axis are reported to have a major impact on infections (15, 18). Hypercortisolism is reported in long-term alcoholic patients after surgical stress (6, 19). In long-term alcoholic patients, serum cortisol levels are increased after surgical stress (6, 19). Long-term alcoholic patients are also characterized by a lowered preoperative helper T-cell (Th1:Th2) ratio before surgery, an immediate postoperative suppression of the cytotoxic T-cell (Tc1:Tc2) ratio, as well as a decreased IFN-{gamma}:interleukin (IL)-10 ratio in LPS-stimulated whole blood cells (8). These immune abnormalities were associated with an increased postoperative pneumonia rate (8).

Therefore, interventions at the level of the hypothalamus–pituitary–adrenal (HPA) axis might ameliorate the detrimental effects of the altered neuroendocrine–immune axis on this immunity. Ethanol at a low concentration (0.5 g/kg/d) has immune-stimulating effects in an experimental model, and also increases viral elimination from liver tissue (20). In addition, ethanol at this low dose was reported to inhibit corticotropin-releasing hormone–mediated adrenocorticotropic hormone (ACTH) secretion (21). Morphine acts as a powerful inhibitor of the HPA axis by reducing ACTH and cortisol response to corticotropin-releasing hormone in the activated stress axis (22, 23). Ketoconazole (400–800 mg/d) inhibits the HPA axis by inhibiting adrenal cortisol synthesis, and is clinically used to treat Cushing syndrome (24).

At present, no study has investigated the effect of intervention at the level of the HPA axis on postoperative stress responses that may favorably modulate altered immunity effects in long-term alcoholic patients. Morphine and ethanol may act on the HPA axis by central and peripheral means, whereas ketoconazole is considered a peripheral renal adrenal blocker.

Therefore, the primary aims of this study were as follows:

  1. To evaluate the neuroendocrine–immune axis under intervention with morphine, ethanol, ketoconazole, and placebo, respectively, in long-term alcoholic patients perioperatively (laboratory outcome measure: postoperative hypercortisolism)
  2. To determine whether these interventions result in a decreased postoperative infection—in particular, pneumonia rate—in long-term alcoholic patients (clinical outcome measure: postoperative pneumonia rate)

Some of the results of this study have been previously reported in the form of an abstract (25).


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
After approval from the institutional ethics committee and written, informed consent had been obtained, 141 patients scheduled for aerodigestive cancer surgery were evaluated for this double-blind, randomized controlled clinical trial with a retrospective post hoc analysis. Patients were not included in the study if they had an unclear alcohol history, evidence of drug abuse, a body mass index less than 20 kg/m2, any diagnosed infection in the last 14 d before surgery, or liver cirrhosis (Child-Pugh class B or C), or who were human immunodeficiency virus positive (8, 26), taking corticosteroids, mentally ill, or not admitted to an ICU after surgery. Because of these criteria, 13 patients had to be excluded; 128 patients were included and gave their written, informed consent. The study design is shown in Figure 1.


Figure 1
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  		Figure 1. Study design. ICU = intensive care unit.

 
Patients were randomly assigned to the following four groups (n = 32 per group), the day before surgery:
Placebo: Intravenous and per os or enteral per gastric tube placebo medication
Ethanol: Continuous intravenous ethanol infusion (0.5 g/kg/d) and per os or enteral per gastric tube placebo medication
Morphine: Continuous intravenous morphine infusion (15 µg/kg/h) and per os or enteral per gastric tube placebo medication
Ketoconazole: Ketoconazole (4 x 200 mg; Nizoral) and prednisone (1 x 5 mg at 6:00 A.M.; Decortin) per os or enteral per gastric tube, and continuous intravenous placebo infusion. According to the standard protocol for treatment of ectopic Cushing syndrome, prednisone is required if patients are treated with ketoconazole to avoid oversuppression of the HPA axis (24)

The nonalcoholic patients were included only as a descriptive control, and were not included in the statistical analysis. The reason for this is that it was intended to have the cortisol levels of the interventional group in the range of the nonalcoholic patients. However, this has never been explored in this setting, as far as we know, and either oversuppression or inadequate suppression could have occurred. Therefore, we randomized these nonalcoholic patients during the study period. Because the prevalence of long-term alcoholic patients scheduled for surgery in our setting is described to be approximately 50% (2, 8), it was assumed that this would result in approximately n = 16 long-term alcoholic patients per treatment group.

After inclusion, six patients had to be excluded because they were not admitted to the ICU (n = 5) or refused postoperative blood drawing (n = 1).

Long-term alcoholic patients had a daily intake of at least 60 g of ethanol per day for at least 1 yr preoperatively and fulfilled the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) (27) criteria for either alcohol dependence or alcohol abuse. We used the same cutoff (more than 60 g of ethanol per day) regardless of sex (3, 6, 8). Patients drinking less than 60 g/d and not fulfilling the DSM-IV criteria were included in the nonalcoholic group (2). Data regarding the nonalcoholic patients and additional detail on the methods used to make these measurements are provided in the online supplement.

The infusion rate for all patients was 37 ml/h. According to the study protocol, study medication in all groups was started on the morning before surgery and continued until the third postoperative day. In the case of hypocortisolemia (less than 100 nmol/L) after starting treatment with any intervention, 100 mg of hydrocortisone was given intravenously over 30 min, followed by continuous intravenous infusion at a rate of 0.18 mg/kg/h. All patients received standardized anesthesia with isoflurane, fentanyl, and cisatracurium. All alcohol-dependent patients received prophylactic treatment with midazolam (7).

Blood samples were drawn on the morning before surgery and on Days 1, 3, and 7 between 7:00 A.M. and 10.00 A.M. after surgery. In addition, cortisol was also assessed on the day of surgery and on Day 2 after surgery to determine whether patients required prednisone replacement. The methods for determination of Th1:Th2 and Tc1:Tc2 ratios, IFN-{gamma} and IL-10 from LPS-stimulated whole blood cells, as well as cortisol are described in a previous publication (8). Additional details on the methods used to make these measurements are provided in the online supplement. Alcohol-related laboratory data, including mean corpuscular volume and {gamma}-glutamyltransferase and carbohydrate-deficient transferrin levels, were obtained on admission to the hospital (7).

Postoperatively in the ICU, the Acute Physiology and Chronic Health Evaluation III (APACHE III) score (28), Multiple Organ Dysfunction score (29), as well as ventilatory needs and length of stay were documented. All infections were diagnosed according to the criteria recommended by the Centers for Disease Control and Prevention (Atlanta, GA) (30) and the frequency of patients who had any infection was documented. In the case of pneumonia, the diagnosis was made if systemic signs of infection were present, new or worsening infiltrates were seen on the chest X-ray, and new onset of purulent sputum or a change of sputum with bacteriologic evidence were found (31). Additional detail is provided in the online supplement. The differential diagnosis of alcohol withdrawal syndrome (AWS) was made according to the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) scale (32). Treatment of AWS was guided to achieve a CIWA-Ar less than 20 (33).

Statistical Analyses
All data are expressed as medians and interquartiles. Nonparametric multivariate analysis of variance for repeated measurements in a two-factorial design (first factor [group]: interventions vs. placebo, second factor [time]) (34), the Mann-Whitney U test, and Fisher exact test were used. Diagnostic test performance was evaluated by receiver operating characteristics analysis (35). p < 0.05 was considered significant. Analyses were performed with SAS for Windows, release 8.02 (SAS Institute, Inc., Cary, NC).

We calculated the sample size on the basis of postoperative infection rates for long-term alcoholic patients and nonalcoholic patients (17). Assuming comparable infection rates for nonalcoholic patients and treated long-term alcoholic patients versus placebo-treated long-term alcoholic patients, we calculated 16 patients per group (altogether 48 treated alcoholic patients and 16 with placebo) with {alpha} = 5% and a power of 80% (two-sided {chi}2 test). Having the final results from this study with respect to the cortisol levels, overall infections, and pneumonia, we performed a power analysis of the group of long-term alcoholic patients. The nonparametric Mann-Whitney U test and the {chi}2 test, respectively, with a (two-sided) {alpha} of 5% and sample sizes of 18 (placebo) versus 18 + 16 + 19 = 53 (treatment), showed a power of 91% regarding the laboratory outcome variable cortisol (Day 1 after surgery: 1,182.2 ± 999.1 vs. 337.8 ± 180.4), 95% regarding the clinical outcome variable overall infections (50 vs. 7.5%), and 87% regarding pneumonia (38.9 vs. 5.7%) in long-term alcoholic patients. All calculations were conducted with the help of nQuery Advisor release 6.0 (Statistical Solutions Ltd., Crosse's Green, Cork, Ireland).


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The basic characteristics of patients did not differ between interventional and placebo-treated long-term alcoholic patient groups. Alcohol-related diagnosis and alcohol-related laboratory data are provided in Table 1. No patient had any signs of infection on the day of surgery.


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  		TABLE 1. BASIC PATIENT CHARACTERISTICS AND ALCOHOL-RELATED PARAMETERS IN LONG-TERM ALCOHOLIC PATIENTS

 
The preoperative cortisol level for alcoholic patients was 411 (309–504) nmol/L. Perioperative intervention with ethanol, morphine, or ketoconazole prevented the postoperative cortisol increase in long-term alcoholic patients compared with their placebo-treated control patients (Figure 2).


Figure 2
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  		Figure 2. Pre- and postoperative cortisol values (nmol/L) in long-term alcoholic patients. Groups: placebo (solid circles), ethanol (open diamonds), morphine (open triangles), and ketoconazole (open squares). Data are given as median and interquartile range (25th and 75th percentiles).

 
The preoperative Th1:Th2 ratio was 12.4 (7.2–21.9) and the Tc1:Tc2 ratio was 28.3 (15.5–82.4) in long-term alcoholic patients. Postoperatively, Th1:Th2 ratios and Tc1:Tc2 ratios were suppressed in placebo-treated long-term alcoholic patients. Any intervention ameliorated the postoperative suppression of the Th1:Th2 ratio in long-term alcoholic patients. However, the difference was not significant (Figure 3). The postoperative suppression of the Tc1:Tc2 ratio in long-term alcoholic patients was prevented by any intervention (Figure 3). The IFN-{gamma}:IL-10 ratio did not differ between long-term alcoholic groups and did not change at all during the study period (Table 2).


Figure 3
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  		Figure 3. Relative changes in type 1:type 2 helper T-cell (Th1:Th2) ratio (A) and type 1:type 2 cytotoxic T-cell (Tc1:Tc2) ratio (B) in long-term alcoholic patients. Groups: placebo (solid circles), ethanol (open diamonds), morphine (open triangles), and ketoconazole (open squares). Data are given as median and interquartile range (25th and 75th percentiles).

 

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  		TABLE 2. RATIO OF IFN-{gamma} TO IL-10 (%)

 
Receiver operating characteristics analysis revealed that cortisol as well as Th1:Th2 and Tc1:Tc2 ratios were predictive of the later onset of pneumonia in long-term alcoholic patients (Table 3).


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  		TABLE 3. RECEIVER OPERATING CHARACTERISTICS ANALYSES BETWEEN NEUROENDOCRINE IMMUNE PARAMETERS AND NOSOCOMIAL PNEUMONIA

 
APACHE III scoring on admission to the ICU did not differ between long-term alcoholic patient groups (Table 4). Placebo-treated long-term alcoholic patients had an increased postoperative overall infection rate, in particular pneumonia rate (7 of 18, 39%), the median of which occurred on Day 4 (3–5) after surgery. All interventions decreased the pneumonia rate in long-term alcoholic patients (Table 4). Only one placebo-treated patient and one ketoconazole-treated long-term alcoholic patient developed urinary tract infection postoperatively. Placebo-treated long-term alcoholic patients had a tendency to develop more wound infections (4 of 18, 22%) compared with any of the intervention groups (ethanol, 1 of 18 [6%]; morphine, 1 of 16 [6%]; ketoconazole, 1 of 19 [5%]). Moreover, three patients in the placebo-treated group and three patients in the ketoconazole-treated group developed AWS. ICU stay was significantly prolonged among the placebo-treated long-term alcoholic patients compared with any of the intervention groups (Table 4).


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  		TABLE 4. APACHE III SCORES, LENGTH OF INTENSIVE CARE UNIT STAY, AND POSTOPERATIVE COMPLICATIONS

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The most important result of this study was that interventions that targeted the HPA axis to prevent hypercortisolism in long-term alcoholic patients and altered postoperative T-cell–mediated immunity resulted in a decreased postoperative pneumonia rate and a reduced ICU stay. Our results support the hypothesis that therapeutic interventions at the neuroendocrine level provide therapeutic benefit in long-term alcoholic patients undergoing major surgery by affecting neuroendocrine–immune regulatory pathways.

To the best of our knowledge, this is the first study to demonstrate that a perioperative intervention with ethanol, morphine, or ketoconazole significantly prevented hypercortisolism in long-term alcoholic patients after aerodigestive tract surgery. Ethanol, morphine, and ketoconazole might have influenced the HPA axis at different levels. Low-dose ethanol inhibits signal transduction between the hypothalamus and pituitary (21). In a clinical study, ethanol infusion significantly decreased cortisol levels in early withdrawal (36). Morphine is considered to act on the activated HPA axis via negative feedback, proopiomelanocortin synthesis, and liberation of derived peptides such as ACTH from the pituitary (37). In a clinical investigation, Rittmaster and coworkers (23) showed that morphine (0.14–10 mg/kg) diminished the ACTH and cortisol response to corticotropin-releasing hormone. Ketoconazole inhibits cortisol synthesis in the adrenal glands (24). At a dose of 400 to 800 mg, ketoconazole significantly reduced plasma and urine concentrations of cortisol in patients with Cushing syndrome of different etiology (24). Our observation of blunted cortisol levels in ethanol-, morphine-, or ketoconazole-treated long-term alcoholic patients suggests that similar mechanisms were likely involved.

The preferential induction of a Th2 versus Th1 immune response, suggested in long-term alcoholic patients before surgery, is associated with a reduced delayed-type hypersensitivity reaction shown previously (6, 8). Surgery can amplify the ethanol-induced altered immune response as both alter Th1:Th2 and Tc1:Tc2 ratios in the same manner (10, 11, 38, 39). In vitro studies suggested that doses of 0.5 g/kg/d of ethanol may be immunoprotective (20) and may stop the induction and increase in Th2 cells. Higher ethanol doses may be immunodepressant (7, 20). Morphine treatment usually promotes Th2 differentiation (39), but patients with alcohol use disorders probably have a lack of endogenous opioids under stress (40), which might influence T-cell ratios independent of stress response (41), but increase stress and decrease Th1:Th2 ratios further on (42). Ketoconazole might suppress helper T-cell type 2 function by reducing IL-4 and IL-5 secretion in anti-CD3/CD28–stimulated T cells from both patients with atopic dermatitis and normal donors (43). Interestingly, the effect of ketoconazole on lymphocyte function is not only a direct one in the presence of monocytes (44). The perioperative prevention of hypercortisolism in long-term alcoholic patients seemed to shift the immune response toward Th1 and Tc1 cells. Similar findings were reported by a previous study, in which it was suggested that low cortisol levels of healthy humans during early nocturnal sleep enhanced Th1 cytokine activity (45).

In long-term alcoholic patients the IFN-{gamma}:IL-10 ratio was low during the whole study period. IFN-{gamma} promotes the differentiation of precursors into Th1 or Tc1 cells, whereas IL-10 induces the generation of Th2 or Tc2 cells. Furthermore, IL-10 plays a key role in mediating immunosuppression in surgical trauma (46) and is enhanced immediately after surgery in long-term alcoholic patients (17). The production of IFN-{gamma} is thought to be deactivated by major surgical trauma (47). It is well known that the influence of ethanol on cellular immunity is dose dependent (20). IFN-{gamma}, as a T-cell product and monocyte activator, is able to inhibit IL-10 production in alcohol treatment (48). Decreased production of IL-10 stimulated by LPS after morphine administration was shown in vivo in mice (49). Low doses of morphine may have a direct bearing on the resolution and complete elimination of infection, whereas high doses result in suppression of macrophages (50). It has been reported that ketoconazole does not influence IFN-{gamma} secretion (51) or reduce synthesis (44). In our study none of the interventions led to significant changes of the IFN-{gamma}:IL-10 ratio in long-term alcoholic patients.

In the present study we demonstrated, to the best of our knowledge for the first time, that with ethanol, morphine, and ketoconazole interventions, postoperative intercurrent infections were significantly reduced compared with placebo-treated long-term alcoholic patients, followed by significantly reduced ICU stays in these patients. Ethanol- and morphine-treated long-term alcoholic patients showed a statistically significant lower pneumonia rate, whereas ketoconazole-treated patients showed a nonsignificant trend toward a lower rate. In this study, 6 of 71 alcohol-dependent patients (three patients in the placebo group and three patients in the ketoconazole group) developed AWS despite prophylactic treatment. Possibly because ketoconazole is not centrally mediated, it might not have influenced the development of AWS.

Postoperatively, cortisol as well as T-cell–mediated immune reactivity were predictive of later onset of pneumonia in this limited sample of long-term alcoholic patients. It is known that elevated cortisol levels result in immune suppression and are associated with an increased incidence of infection rates (52). In all the intervention groups, long-term alcoholic patients showed preserved T-cell–mediated immunity. This might be considered an adaptation to maintain effective immunity and progression of infection (12, 53) and might be another hint that "helpless" cytotoxic T cells might be one important fact in the development of postoperative infections (54).

The limitations of this study are as follows:

  1. Smoking might have affected the immune response and is reported to have an impact on infectious outcome (55). However, in our patients we did not observe any differences between smoking and nonsmoking long-term alcoholic patients regarding the investigated neuroendocrine–immune responses or outcome.
  2. Other stress axis interventions such as sympatholysis were not considered for this study, and might have given similar results. This is of particular interest because only with the centrally acting HPA axis was a significant effect seen on the pneumonia rate. Peripheral HPA blocking with ketoconazole showed only a trend, that is, centrally interfering systems besides the HPA axis might be involved (19).
  3. Most of our patients were male and had a median age of 55 (50–60) yr. The immune system might differ between sexes. However, with the limitation of a small number of females in our study, we did not observe any differences between female and male long-term alcoholic patients.
  4. The immune system might have already been influenced by the cancer diagnosis. However, patients were not malnourished, and T4 stages are not scheduled for surgery in our hospital (only palliative care).
  5. Only a few neuroendocrine–immune parameters (e.g., of the more than 140 known chemokines) were measured. Therefore, we are not able to conclude whether any other marker might have been more valuable in predicting the later onset of infections.

In conclusion, this is the first study, to the best of our knowledge, showing that perioperative intervention with low-dose ethanol, morphine, or ketoconazole prevented hypercortisolism in long-term alcoholic patients after aerodigestive tract tumor resection. The hypercortisolism was associated with altered T-cell–mediated immune reactivity and an increased postoperative infection rate. Our study suggests that perioperative intervention at the level of the neuroendocrine–immune axis in long-term alcoholic patients might prevent postoperative pneumonia and should, therefore, be considered in patients with alcohol use disorders before the onset of major surgery.


   Acknowledgments
 
The authors thank Greg Bagby (Department of Physiology, LSU Health Sciences Center, New Orleans, LA) and Steve Nelson (Department of Pulmonary and Critical Care, LSU Health Sciences Center) and colleagues Markus Rudeck, M.D., Peter Rosenberger, M.D., and Tim Neumann, M.D., for help with the study and the manuscript. In addition, the authors thank Petra Muschinski, M.D., Eugen Eliasch, M.D., Tanja Freund, M.D., and Michaela Hartmann, Cand. Med., for invaluable help during data collection. All the latter colleagues worked in the Department of Anesthesiology and Intensive Care Medicine, Campus Charité Mitte, Charité - University Medicine Berlin, Berlin, Germany, during the study period.


   FOOTNOTES
 
Supported by the German Research Society (DFG SP 432/1-1, 432/1-2, and 432/2-1). Morphine and prednisone were provided by Merck.

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.200506-907OC on May 25, 2006

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form June 13, 2005; accepted in final form May 23, 2006


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 ABSTRACT
 METHODS
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 DISCUSSION
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