Of adults from Western countries, 4.6% (18–59 yr) admitted to medical and surgical wards of hospitals have an alcohol use disorder (AUD).1,2
Long-term alcoholic patients have a three to fivefold increased postoperative infection rate compared to nonalcoholic patients. Nosocomial pneumonia is the most frequent infection in these patients.3–5 Thirty-eight percent of long-term alcoholic patients, 10% of “social drinkers” and 7% of nonalcoholic patients will develop pneumonia after surgery.3
Alcohol withdrawal syndrome (AWS) occurs in 50% of patients in whom the diagnosis has been missed by preoperative assessment. Conversely, when AUD is detected and appropriate perioperative measures are taken, AWS occurs in only 25% of patients with AUD.3,6 The severity of AWS is increased fourfold in surgical compared to psychiatric patients.6–8
Additionally, long-term abusers of alcohol have a two times greater risk of postoperative bleeding complications and are twice as likely to need secondary surgeries.7
As might be expected, the duration of intensive care unit (ICU) treatment and mechanical ventilation is significantly longer in these patients.4,5,9,10
Furthermore, the mortality rate associated with surgery is increased several folds in AUD patients.3,11
Increased postoperative infection rates in AUD patients are a result of an altered immune response.3,5,9,10,12 Alcohol has been reported to have adverse effects on cellular and humoral immunity. It affects the number of immune-competent cells as well as the function of remaining cells.
Due to altered immunity in patients with AUD causing a greater number of postoperative complications, especially infections, perioperative interventions are needed which buffer these immune perturbations.
Alcohol per se leads to alterations in the immune system. Exposure to alcohol inhibits proliferation of CD3+ T cells and blunts the number of CD4+ and CD8+ T cells.13 Long-term alcoholic patients have a decreased skin response to delayed-type hypersensitivity (DTH) before surgery,5,9 reflecting disturbance of the T1/T2 balance. In previous investigations, we found that the preoperative ratio of T helper cells 1 to T helper cells 2 (Th1/Th2 ratio) is significantly reduced in long-term alcoholic patients undergoing upper-aerodigestive tract surgery compared to nonalcoholic patients.9 Multivariate logistic regression revealed that the preoperatively low Th1/Th2 ratio was predictive of infections at a later point. This low ratio was also associated with a higher risk of prolonged treatment time, and prolonged ICU treatment in particular. This correlated with a higher incidence of postoperative complications, particularly postoperative infections, and included a risk of additional complications. Th1 cytokines, such as interferon γ (IFN-γ), are decreased due to chronic alcohol consumption, whereas Th2 cytokines, such as interleukin (IL)-4 and IL-10, are increased.14 Moreover, the cytotoxic lymphocyte ratio (Tc1/Tc2 ratio) is not different between long-term alcoholic patients and nonalcoholic patients before surgery.9
Alcohol-associated changes in the balance between proinflammatory and antiinflammatory cytokines have also been reported.9,15,16 The level of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α) and IL-6, as well as the antiinflammatory cytokine IL-10, did not differ between long-term alcoholic patients and nonalcoholic patients without liver disease,9,10,15,17–19 whereas increased concentrations of plasma cytokines were found in long-term alcoholic patients with liver disease.16,17,20
There are conflicting reports regarding the effect of alcohol on the IFN-γ/IL-10 ratio in lipopolysaccharide (LPS)-stimulated blood. In some studies, the ratio did not differ between long-term alcoholic patients and nonalcoholic patients.9,10 However, Szabo demonstrated that acute alcohol intake leads to an increase in the levels of LPS-stimulated proinflammatory cytokines IL-12 and IFN-γ and a decrease in the antiinflammatory cytokine IL-10.21
From a clinical standpoint, all this serves to illustrate that preoperative identification of alcohol-associated immune dysregulation may be a reliable means of identifying a subset of patients at high risk of postoperative complications. These laboratory observations may also serve as an important starting point in the search for interventions designed to decrease the perioperative risk in these patients. It would seem likely that interventions capable of buffering or abolishing these alcohol-induced changes in the immune system might prove to be of clinical benefit. Another important issue to resolve in future studies is when interventions should begin.
Intraoperative Phase Until Day 1 After Surgery
Surgical stress already begins to have measurable effects on the immune system during the very early stages of a procedure.9,10,15,22 The immune system responds to surgical stress with a primarily proinflammatory reaction, which is then followed by an antiinflammatory response.23 Major surgical trauma leads to a postoperative decrease of Th1 cells without a significant alteration in Th2 dynamics, the net result of which is a decrease in the Th1/Th2 ratio after surgery.24,25 Conversely, procedures causing less surgical stress, such as laparoscopies, do not significantly alter T cell IFN-γ, IL-4, and IL-10 production in CD4+ and CD8+ cells within the first 24 h.26
A previous study demonstrated that the level of the proinflammatory cytokine TNF-α is decreased and the antiinflammatory cytokine IL-10 is increased within the first 2 h after incision.27 In addition, expression of the monocytic human lymphocyte antigen (HLA)-DR decreases significantly within 2 h after the start of an operation.27 The level of the pro- and antiinflammatory cytokine IL-6 increases during the first 20 min after incision.28 Using a multifactorial analysis in patients undergoing major noncardiac surgery, we found that surgical trauma was associated with an increased IL-6 response. In a subset of patients who developed severe infections or sepsis after a median of 3 days (range: 1–8 days) after surgery, the intraoperative levels of IL-6 and IL-10 were significantly increased. These findings suggest that immediate cytokine responses during surgery might be relevant to the later onset of severe infections and sepsis.22
Surgical stress by itself provokes a decrease in the level of LPS-stimulated proinflammatory cytokines in whole blood cells, but this phenomenon disappears within 24 h of surgery.29
There are few data regarding T cell-mediated immunity and plasma cytokines during surgery in long-term alcoholic patients. A number of changes have been observed in the immediate postoperative period.
We have previously shown that the preoperatively decreased Th1/Th2 ratio remains depressed in long-term alcoholic patients after upper-digestive tract surgery.9 DTH is significantly impaired postoperatively in long-term alcoholic patients.9,12 On day 1 after surgery, a depressed Th1/Th2 ratio is predictive of postoperative pneumonia.10 In the same study, we observed a decrease in the Tc1/Tc2 ratio on the first postoperative day. The decrease in the Tc1/Tc2 ratio on the first postoperative day was predictive of postoperative infections, especially nosocomial pneumonia.9
The levels of proinflammatory cytokines TNF-α and IL-6 do not differ between long-term alcoholic patients and nonalcoholics.30,31 IL-10 in long-term alcoholic patients is significantly increased on ICU admission compared to in nonalcoholic patients.30,31 Immediately after surgery, the ratio between IL-6 and IL-10 is decreased in long-term alcoholic patients and is predictive of an increased postoperative infection rate.15,30
We have previously reported that a preoperatively decreased Th1/Th2 ratio tends to remain depressed for up to 5 days in long-term alcoholic patients undergoing upper-digestive tract surgery.9 In the same study, we found that the postoperative Tc1/Tc2 ratio remained suppressed for 5 days in long-term alcoholic patients, whereas it increased in nonalcoholic patients.9,10
IL-10 depresses the antigen-presenting capacity of monocytes/macrophages by inducing down-regulation of expression of major histocompatibility complex class II. The intraoperative reduction in monocyte HLA-DR expression in surgery is reported to remain depressed during the first postoperative week.27 In long-term alcoholic patients undergoing upper-aerodigestive tract surgery, the plasma IL-10 level remains significantly increased for 5 days after surgery compared to nonalcoholic patients.9
The LPS-stimulated IFN-γ/IL-10 ratio in whole blood cells is decreased on day 1 after surgery in long-term alcoholic patients, but is increased in nonalcoholic patients.9 In long-term alcoholic patients, the ratio remains low until day 5 after surgery. In addition, the low ratio on the first postoperative day is predictive of the later onset of postoperative infections.
von Dossow et al.32 demonstrated that long-term alcoholic patients have an altered plasma cytokine response at the onset of infection and early septic shock. In their study, long-term alcoholic patients who developed infections and were observed to be in the early phase of septic shock had lower plasma levels of IL-1ß, IL-6, and IL-8 lower than normal. The antiinflammatory cytokine IL-10 did not differ in comparison with nonalcoholic patients. Sander et al.15 demonstrated that a postoperatively reduced IL-6/IL-10 ratio immediately after admission to the ICU is associated with increased postoperative infection rates in long-term alcoholic patients. Prolonged ventilation time and ICU stay were observed to be consequences of this phenomenon.3,4,9,10
The most frequent infectious complication in patients with AUD in the ICU is pneumonia.3,9,10 The gram-negative bacterium Klebsiella pneumoniae (K. pneumoniae) frequently causes nosocomial infections in immune-compromised hosts.33,34 In such infections, both the frequency and severity are increased.35,36 T cell-mediated immune response is critical for the clearance of K. pneumoniae.36,37 The proinflammatory cytokines IFN-γ and TNF-α have both been shown to be crucial for the clearance of K. pneumoniae from the lung.38–43
In a murine K. pneumoniae infection model, previous alcohol treatment resulted in greater lung damage. While the percentages of IFN-γ-producing CD4+ and CD8+ cells in the spleen were significantly decreased, the percentages of TNF-α-producing CD4+ and CD8+ cells were significantly increased after infection in ethanol-treated animals.44
Interventions and Clinical Relevance
There is considerable scope for perioperative interventions designed to change immune disturbances associated with long-term alcohol use. However, before any interventions can be considered, the patient's level of alcohol consumption must be determined. The detection of patients with a history of alcohol misuse is not straightforward; there is no simple diagnostic test with a high level of sensitivity and specificity for AUD. Nevertheless, the importance of recognizing an AUD in patients cannot be over-stressed: identification is the prime way to prevent postoperative complications in these patients.45,46 There is not just one variable to use to detect patients with AUD. The best available diagnostic tools are the CAGE (alcohol-related) questionnaire and laboratory markers, such as carbohydrate-deficient transferring and γ-glutamyltransferase.46
Tonnesen et al.12 have reported that an abstinence period of 2 mo resulted in improved DTH in patients with AUD. Furthermore, 1-mo abstinence before surgeries was found to reduce postoperative morbidity from 71% to 31%.5 There is no consensus regarding whether advocating preoperative abstinence for periods of 1 mo or more is a practicable approach to the problem. Furthermore, this approach is not possible in patients with emergent indications for surgery.
Spies et al.10 designed a perioperative approach to prevent altered T-cell-mediated immunity, leading to a decreased postoperative pneumonia rate and reduced ICU stay. This study supported the hypothesis that therapeutic interventions with low-dose ethanol (0.5 g · kg−1 · d−1), morphine (15 μg · kg−1 · h−1), and ketoconazole (200 mg 4 times daily) at the hypothalamus-pituitary-adrenal (HPA) axis provide therapeutic benefit by affecting neuroendocrine-immune regulatory pathways. Morphine and ethanol may act centrally on the HPA axis, and ketoconazole is an isolated peripheral renal adrenal blocker. Prolonged hypercortisolism is often seen after major surgery in long-term alcoholic patients. Hypercortisolism is associated with alterations in T cell-mediated immune response. The perioperative HPA axis inhibition with these interventions described in our study prevented the postoperative hypercortisolism and altered postoperative T-cell-mediated immunity in long-term alcoholic patients after aerodigestive tract surgery.10 In all the intervention groups, long-term alcoholic patients showed preserved T-cell-mediated immunity. Placebo-treated patients had an increased postoperative infection rate, especially nosocomial pneumonia, followed by prolonged ICU stay. Long-term alcoholic patients who were randomized to perioperative intervention with ethanol and morphine did not develop AWS.
The role of perioperative treatment with ethanol remains controversial, however. A large part of the problem with using ethanol in a clinical setting is that its therapeutic index is very narrow and monitoring is not straightforward.47 Our study, however, illustrates that low-dose treatment in patients with long-term alcohol problems may be of considerable clinical benefit.
Another approach may be preoperative stimulation of the immune system via vaccination. Vaccination stimulates HLA-DR expression; however, only limited data are available regarding the clinical utility of vaccination in the setting of alcohol misuse.
Long-term alcoholic patients have an increased risk of postoperative infections due to immune suppression. This immune suppression occurs both before surgery (decreased Th1/Th2 ratio) and during surgery (decreased Tc1/Tc2 ratio and pathological perturbations of the inflammatory response after whole blood LPS stimulation) (Table 1).
There are considerable benefits to be accrued from early preoperative identification of AUDs followed by appropriate measures to prevent or treat the attendant alterations of the hypothalamic-pituitary-adrenal axis, hypercortisolism, and perturbations in T-cell-mediated immunity. Perioperative intervention at the level of the hypothalamus (via ethanol therapy), the pituitary (via morphine therapy), or the adrenals (via ketoconazole therapy) may prevent postoperative infections, such as nosocomial pneumonia, and should be considered before major surgery when abstinence cannot be achieved.
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