- Email: [email protected]
Impact of preoperative anxiolytic on surgical site infection in patients undergoing abdominal hysterectomy
Impact of preoperative anxiolytic on surgical site infection in patients undergoing abdominal hysterectomy Rosa Levandovski, MSH,a Maria Beatriz Cardoso Ferreira, MD, PhD,a,b Maria Paz Loayza Hidalgo, MD, PhD,a,c Ca´ssio Alves Konrath, MD,d Daniel Lemons da Silva, MD,d and Wolnei Caumo, MD, PhDa,b,d Porto Alegre, Brazil
Background: An increased anxiety may be associated with a higher risk of surgical site infection (SSI), but there is little objective data on the effect of preoperative anxiolytic interventions on SSI. To address this issue, we evaluated the effects of preoperative diazepam on postoperative SSI following abdominal hysterectomy. Methods: This randomized, double-blinded, placebo-controlled study included 130 patients, American Society of Anesthesiologist physical status 1 or 2. Patients were randomly assigned to receive either oral diazepam 10 mg (n 5 65) or placebo (n 565) the night before and 1 hour prior to surgery. The assessment instruments were the Visual Analogue Scale and the State-Trait Anxiety Inventory. SSI was diagnosed according to the criteria of the Centers for Disease Control and Prevention with standard follow-up of 30 days. Results: The relative risk (RR) was 1.79 (95% confidence interval [CI]: 1.31-2.43), and the number of patients that needed to be treated was 5.2 (95% CI: 2.74-50.76) to prevent 1 additional SSI. The RR for SSI in placebo-treated patients with high postoperative anxiety was 1.65 (95% CI: 1.07-2.56). Conclusion: Diazepam-treated patients showed lower postoperative anxiety and lower incidence of SSI up to 30 days after surgery compared with placebo in patients undergoing abdominal hysterectomy. (Am J Infect Control 2008;36:718-26.)
Wound infections are among the most common serious complications of anesthesia and surgery.1 Surgical wound infections can prolong hospitalization2 and substantially increase the cost of care.1,3 The first few hours after tissue is contaminated by bacteria constitute a critical period during which wound infection is established,4 but infections are typically not detected until some days after surgery. The factors that influence the incidence of surgical wound infection include site and complexity of surgery,3 patient’s underlying illness, smoking, obesity,5,6 blood transfusion, hyperglycemia,7 presence or absence of hypovolemia,8 patient’s temperature during surgery,2 use or not of From the Postgraduate Program in Medical Sciences,a School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS); Pharmacology Department,b Instituto de Cieˆncias Ba´sicas da Sau´de of UFRGS; Department of Psychiatry,c School of Medicine, UFRGS; and Anesthesia Service and Perioperative Medicine,d Hospital de Clı´nicas de Porto Alegre (HCPA)/Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. Address correspondence to Wolnei Caumo, MD, PhD, Coronel Corte Real, 295 Bairro Petropolis CEP: 90630-008, Porto Alegre, RS, Brazil. E-mail: [email protected].
Supported by The Postgraduate Research Group (GPPG) at Hospital de Clı´nicas de Porto Alegre.
prophylactic antibiotics,9 and degree to which pain and anxiety are controlled.10 Studies published in the health-psychology literature suggest that increased preoperative anxiety is associated with poor postoperative behavioral and clinical recovery.11,12 Furthermore, numerous reports indicate that preoperative psychologic interventions aimed at reducing preoperative anxiety may also result in improved postoperative behavioral and clinical recovery.12-14 Additionally, several reports indicate that increased perioperative anxiety and uncontrolled postoperative pain may increase the perioperative neuroendocrine stress response.14,15 Thus, a possible hypothesis is that factors such as anxiety and pain can stimulate sympathetic vasoconstriction16,17 and thereby increase the risk of postoperative infection.18 Accordingly, one can hypothesize that the use of preoperative benzodiazepine can reduce postoperative anxiety and enhance the postoperative clinical recovery process involved in warding off infection. To test this hypothesis, we conducted a randomized, double-blind, placebo-controlled trial to evaluate the effect of preoperative diazepam on the postoperative incidence of surgical site infection (SSI) during the first 30 days following abdominal hysterectomy.
Conflicts of interest: There were no financial relationshipa between any of the authors or any commercial interest in the outcome of this study.
MATERIALS AND METHODS
0196-6553/$34.00
Study population
Copyright ª 2008 by the Association for Professionals in Infection Control and Epidemiology, Inc. doi:10.1016/j.ajic.2007.12.010
718
Following ethics committee approval and written informed consent, 130 patients, American Society of Anesthesiologist classification 1 or 2, aged 19 to 60 years,
Levandovski et al
scheduled to undergo total abdominal hysterectomy, were enrolled in the randomized, double-blind, placebo-controlled study. The patients were undergoing elective abdominal hysterectomy for myomatosis in the Gynecology Service, and all operations were performed by a third-year resident supervised by one of the attending gynecologists. All patients were admitted to the hospital 1 day before surgery, and those patients who did not develop complications were discharged on day 3 postsurgery, on any day of the week. Patients with contraindications to regional anesthesia; mental impairment; chronic pain; or a history of congestive heart failure, valvular heart disease, renal or hepatic disease, psychotropic drug use, and language or communication difficulties were excluded. In addition, patients with a body mass index (BMI) higher than 35 kg/m2 and those with a history of psychiatric disorder and/or positive screening for minor psychiatric disorders (scores, $8) on the World Health Organization’s (WHO) Self-Reporting Questionnaire (SRQ-20) were excluded.19 The SRQ-20 measures somatic symptoms, depressive mood, depressive thoughts, and decreased energy.
Randomization and interventions The treatment allocation method used was advanced simple randomization without blocking or stratification. Before the recruitment phase of the study, 160 envelopes containing all protocol materials were prepared and numbered sequentially. A random number was used to assign each consecutively numbered envelope to receive either 10 mg oral diazepam or placebo the night before (10 PM) and 1 hour prior to surgery, and the envelopes were grouped so that each had an independent 50% probability of being included in either group. A sheet indicating the allocated treatment was then placed in the envelope, and the envelopes were sealed. Throughout the course of the study, the sealed envelopes were removed and opened sequentially by a pharmacy technician, who delivered the tablets of diazepam 10 mg or placebo only after prospective patients had been screened and had consented to participation. No other preoperative medication was given. During the entire protocol time line, blinding and randomization were undertaken by 2 investigators who were not involved in the patient’s evaluation. Other individuals involved in the patient’s care were unaware of the treatment group to which the patient belonged.
Outcome measures Our major outcome (SSI) was either of 2 distinct criteria for diagnosis. The first criterion, as in previous studies,2,20 was that wounds were considered likely to be infected when pus could be expressed from the
December 2008
719
incision or aspirated from a loculated mass within the wound. The second criterion was based on the Centers for Disease Control and Prevention (CDC)’s National Nosocomial Infections Surveillance (NNIS) system, modified in 1999,5 in which SSI is classified as being either incisional (superficial or deep) or organ space with a diagnostic period up to 30 days. At all times, the gynecologist examiner was blinded to the aim of the study, preoperative interventions, and all other measures.
Instruments and assessment The data were collected in the following multiple standardized phases: (1) during the period of preoperative evaluation, a structured questionnaire was used to collect information concerning demographic characteristics, clinical state, and anxiety level; (2) the surgical procedures were assessed using the anesthesiologist’s records; (3) during the patients’ stay at the hospital, the gynecologists examined the surgical wound daily for the presence of SSI; (4) after discharge, all patients were examined 2 times, at 1 and 4 weeks of followup, carried out by a gynecologist in the same hospital, in the outpatient service. Data regarding drug records, medical and diagnostic examinations, reinterventions, other medical procedures, and hospital readmission for treatment of surgical complications were all collected from the patient’s records. Two independent, trained data collectors followed a standard method by which they reviewed all clinical and laboratory information available in the hospital. Urinary and respiratory infections were defined by clinical and laboratory criteria. The gynecologist in charge of discharge was blinded to the aim of the study and all other measures. The length of hospital stay was defined as the number of days spent in the hospital.
Assessment of pain and psychologic state The day prior to surgery, the same anesthesiologist, who provided patients with information on the perioperative course and instructed them regarding the use of the patient-controlled analgesia pump, saw all patients. Moreover, each patient underwent psychologic testing and pain evaluation. The pain was measured by a 100-mm Visual Analog Scale (VAS), by which scores ranged from no pain (zero) to worst possible pain (100 mm).21 Incisional pain at rest was defined as the average of pain ratings obtained at 6 and 24 hours following surgery. A 30-mm cut-off point was used to classify the patients into 2 groups: (1) absence of pain or mild pain (scores equal to or less than 30 mm); and (2) moderate, intense, or worst possible pain (scores greater than 30 mm).21 Incisional pain on coughing, deep breathing, or movement assessed using yes or no type questions and the patient’s
720
Levandovski et al
Vol. 36 No. 10
desire for additional analgesic were assessed at 6 and 24 hours after surgery. The presence of incisional pain during coughing or movement and the desire for additional analgesic in any assessment were the criteria used to classify the patients as presenting or not with pain on coughing or movement and desiring or not additional analgesia. Sedation was assessed by the following criteria: zero, completely alert; 1, dozes now and then but answers immediately; 2, often asleep but arousable; 3, asleep and not arousable. A sedation level equal to or higher than 2 in any assessment was used as the cutoff point to classify patients as follows: (1) mild sedation level (,2) or (2) moderate to intense sedation level ($2). To measure pre- and postoperative anxiety, we used the State-Trait Anxiety Inventory (STAI)22 validated for the Brazilian population: state-anxiety (transitory anxiety that varies according to the situation) and trait-anxiety (stable personality disposition reflecting general level of fearfulness). The postoperative anxiety was defined as the average of the scores obtained at 2 time points: 6 and 24 hours following surgery.13 The cut-off point to classify high anxiety or low anxiety was the highest quartile so that individuals with a score above the highest quartile were classified as highly anxious and those with a score equal to or below the highest quartile as mildly anxious. The highest quartile for postoperative state-anxiety was 45.5. The stratification procedure was based on Spielberger and DiazGuerrero’s manual.22 To ensure that the evaluators were blinded to preoperative psychologic state, the physicians involved in the preoperative evaluation did not perform the postoperative assessment.
Anesthesia technique All patients had standard monitoring prior to epidural anesthesia. An isotonic saline solution (10 mL kg-1), cefazolin (2 g), and intravenous (IV) fentanyl (100 mg) were administered. Afterward, all patients had an extradural catheter inserted at lumbar segments L2/ L3 or L3/L4. An injection of 15 to 20 mL ropivacaine (10 mg mL-1) was given epidurally. If there were signs of inadequate analgesia, additional 5-mL doses were used. During surgery, all patients received propofol continuously to maintain sedation and supplementary oxygen by an intranasal catheter. A vesicourethral catheter was routinely maintained until the first postoperative day. In the operating room, the patient’s skin was disinfected with alcoholic chlorhexidine. At the end of surgery, sedation was stopped, and the extradural catheter was removed.
Postoperative analgesia The PCA device (APM; Abbott, Chicago, IL) was available as soon as the patient arrived in the postanesthesia
care unit. The PCA was programmed to deliver a 2-mg morphine bolus with a lockout period of 10 minutes. The maximum dose that could be requested during a 4-hour period was 30 mg. If the pain was not relieved, an additional dose of 20 mg/day of tenoxicam was administered intravenously. The patients were connected to PCA for the entire period of 72 hours after surgery. Analgesia in all patients at 72 hours after surgery was maintained with codeine 30 mg plus acetaminophen 500 mg every 6 hours and 75 mg sodium diclofenac three times per day. If pain was still not relieved, 1000 mg dipyrone was given every 6 hours.
Statistical analysis For the initial power analysis, the number of subjects in each study group was determined based on previous studies involving the incidence of SSI according to the American NISS risk index23 and the effect of interventions to attenuate the preoperative stress response on postoperative outcomes.14 To determine the power analysis, an infection rate of 2.5% was expected in the diazepam-treated patients, which corresponds to a prorating incidence of SSI reported in a large cohort study in patients having undergone abdominal hysterectomy.23 However, the rate used in the placebo group was the incidence of postoperative infection reported in placebo-treated patients in an earlier study that assessed the effect of interventions to attenuate the preoperative stress response on postoperative outcomes, which was 16%.14 The analysis indicated that a study of 130 subjects (65 per group) was required to detect a 15% difference between groups with a power of 80% and a set at 0.05.24 Considering that the sample size calculation is just an estimation, we thus decided to calculate the power of this analysis based on the incidence of SSI that we found in this study, that is, 25.8% in the placebo-treated and 6.6% in the diazepam-treated patients, which resulted in a power of 89.72% (with a 2-tailed a level of 0.05). The differences between groups for continuing data were examined by the t test for independent samples, and categorical data were examined by x2 or Fisher exact tests. Multivariate logistic regression was used following the stepwise forward procedure to minimize the effect of the differences between groups of other factors showing significant imbalance in the univariate analysis, except for preoperative anxiolytic intervention.25 The variables related to pain were included without considering the statistical significance of univariate analysis because a previous study suggested that postoperative pain10 could be linked to SSI.14 To analyze the effect of morphine doses used in the first 24 hours after surgery, the cut-off points were established using the mean (60 mg kg-1). For all analyses, statistical
Levandovski et al
Fig 1. Flow diagram of study, including number of patients at each point. significance was set at P , .05, 2-tailed. Data were analyzed using SPSS version 11.0 (SPSS, Inc, Chicago, IL). The magnitude of the effect of preoperative diazepam was demonstrated by the number of patients who needed to be treated (NNT) to avoid 1 additional SSI.
RESULTS Figure 1 is a flow diagram of the 130 women eligible to participate in the trial. Patients’ characteristics and perioperative variables are summarized in Tables 1 to 3. Demographic and morphometric characteristics were similar in patients assigned to diazepam and placebo. However, the diazepam-treated patients demonstrated a level of anxiety significantly lower than that of placebo-treated patients throughout the first 24 hours after surgery (Table 3). In the placebo group, 59.7% (40/62) showed high state-anxiety postoperatively, compared with 21.4% (27/61) in the diazepam group. In the placebo group, the relative risk (RR) was 1.52 (95% confidence interval [CI]: 1.04-2.22) and the NNT 5.15 (95% CI: 2.74-42.55) to observe 1 additional patient with high anxiety in the postoperative period. The overall incidence of SSI was 15.20% (95% CI: 10.23-21.75), in which 6.1% had the diagnosis before discharge and 9.1% had the diagnosis after discharge. The superficial SSI rate was 8.6% (95% CI: 4.8914.10), the deep incision infection rate was 4.2% (95% CI: 1.87-8.89), and the organ/cavity infection frequency was 2.4% (95% CI: 0.78-6.48). The placebotreated group showed an SSI incidence of 25.8% (16/ 62), compared with 6.6% (4/61) in the diazepam group. In the placebo-treated patients, the RR to SSI was 1.79 (95% CI: 1.31-2.43) and the NNT 5.2 (95% CI: 2.7450.76). Subgroup analysis demonstrated that the incidence of SSI in highly anxious placebo-treated women was 47.6% and 10% in diazepam treated and that the RR to SSI in placebo treated was 1.65 (95% CI: 1.07-2.56). The incidence of SSI in mildly anxious placebo-treated patients was 14.6% and 3% in diazepam-treated patients, and the RR to SSI in placebo-
December 2008
721
treated patients was 1.58 (95% CI: 0.93-2.67). There was no case of mortality, sepsis, or major cardiovascular complications in either group. The length of hospital stay was significantly longer in placebo-treated compared with diazepam-treated patients (Table 3), and this difference was even larger when comparing those patients who developed a SSI compared with patients without SSI (7.25 6 2.73 days vs 4.66 6 0.9 days; t 5 4.19, P 5 .00, respectively). The multivariate analysis summarized in Table 4 confirmed the effect of preoperative anxiolytic intervention on SSI infection after controlling for dose of local anesthetic used during the surgery, morphine consumption during the first 24 hours after surgery, type of surgical incision, and postoperative incisional pain at rest and during coughing or movement (Table 4).
DISCUSSION Patients treated with diazepam preoperatively had a lower risk of high state-anxiety postoperatively and lower incidence of SSI. Furthermore, it was demonstrated that patients who were highly anxious postoperatively had a higher incidence of SSI up to 30 days after surgery. These findings are supported by a previous study in patients undergoing minor outpatient surgery, in which midazolam-treated patients showed lower rates of postoperative infection compared with placebo-treated patients.14 Additionally, the present findings may be supported by the immunologic results of a previous randomized clinical trial, in which placebo-treated patients exhibited a greater postoperative B-cell response compared with midazolam-treated patients, suggesting that anxiety may influence the function of circulating immune cells in the immediate postoperative period.26 In addition, we can hypothesize that diazepam used preoperatively itself could reduce the risk of infection. This hypothesis may be supported by evidence from studies in animals, possibly by diverse mechanisms such as an interaction of benzodiazepine with the benzodiazepine receptors (both central and peripheral) that form part of a molecular network that mediates the effects of stress and anxiety on immune function. The pathways by which endogenous and exogenous ligands of benzodiazepine receptors may modulate the immune system involve the attenuation of behavioral stress responses induced by corticotrophin releasing hormone (CRH), responsible for immune suppression.27 Additionally, diazepam may decrease the release of tumor necrosis factor-a, interleukin-1, and interleukin-6 by macrophages.28 In addition, its action on peripheral receptors inhibits apoptosis of neutrophils, which is essential for maintaining immune homeostasis and limiting host tissue damage by promoting resolution of the inflammatory
722
Levandovski et al
Vol. 36 No. 10
Table 1. Characteristics of the study sample Group Characteristic Formal education, yr* Age, yr* Weight, kg* Body mass index* Smoking status, yes/noy Diabetes, yes/noy Alcohol consumption, yes/noy ASA status, 1/2y Hemoglobin preoperative, mg Number of previous surgeries* Preoperative pain reported on Visual Analogue Scale* Trait-anxiety* Preoperative state-anxiety*
Placebo (n 5 62)
Diazepam (n 5 61)
P value
6.19 6 3.77 45.29 6 5.87 67.66 6 11.79 26.45 6 3.95 15/47 5/57 4/58 24/38 11.17 6 2.59 1.58 6.1.54 0.96 6 1.80 40.95 6 11.13 40.05 6 10.10
6.54 6 3.38 44.54 6 7.18 69.44 6 10.19 27.43 6 4.55 10/51 4/57 6/55 27/34 11.8161.70 1.59 6 1.27 1.42 6 2.11 40.84 6 8.73 39.98 6 8.92
.59 .52 .37 .21 .20 .51 .36 .33 .14 .97 .20 .83 .88
Placebo (n 5 62)
Diazepam (n 5 61)
P value
25/37
28/33
.33
33/29 625.85 6 535.84 8 (531.75 6 150.73) 154.27 6 39.69 158.83 6 32.86 2.23 6 2.12 0/62
25/35 551.84 6 449.35 10 (488.60 6 194.22) 149.05 6 37.84 136.74 6 35.08 2.39 6 1.82 0/61
.14 .40 .48 .20 .00z .65 —
NOTE. Values are means (SD) or frequencies (n 5 123). *Unpaired t test to compare means 6 standard deviation. y Fisher exact test or x2 test to compare frequencies.
Table 2. Clinical variables measured during intraoperative periods Group Characteristic Type of abdominal hysterectomy* Hysterectomy/ Hysterectomy plus ophoorectomy Type of incision* Vertical/ pfannenstiel Bleeding, mLy Red cell transfusion, No. of patients (mean 6 SD)y Duration of surgery, miny Dose of ropivacaine (mg kg-1)y Intraoperative fentanyl dose (mg kg-1)y Anesthetic or surgical complications, yes/no* NOTE. Values are means (SD) or frequencies (n 5 123). *Fisher exact test or x2 test to compare frequencies. y Unpaired t test to compare means 6 standard deviation. z P , .05.
response.29 Thus, these effects may influence the inflammatory response to surgery and explain the effect shown in diazepam-treated patients. Although we did observe this clinical phenomenon, our data only permit us to hypothesize this cause-effect relationship because the diazepam effect on apoptosis was not directly assessed. In addition, if we consider that perioperative stress is determined by pre- and postoperative anxiety, it is possible that placebo-treated patients had higher rates of postoperative infection because of increased anxiety levels throughout the postoperative period, whereas the prolonged anxiolytic effect of diazepam attenuated the anxiety in those who received the benzodiazepine.30 This hypothesis can explain the contrast between our findings and the previous investigation that assessed the effects of preoperative midazolam on postoperative anxiety in patients undergoing abdominal
hysterectomy,14 in which midazolam had a minimal impact on the clinical recovery process.26 Possibly, this discrepancy may be attributed to a short midazolam half-life, leaving the patients without the benefits of anxiolysis during most of the postoperative period. Therefore, because the anxiety level is related to the type and the extension of surgery and because the purpose of this investigation was to determine whether preoperative anxiolytic could reduce the incidence of SSI in patients after abdominal hysterectomy, we chose diazepam, which could extend its effect throughout the postoperative period. However, further studies are needed to elucidate the possible mechanism implicated in this response and to clarify the issue about the impact of different pharmacologic and nonpharmacologic anxiolytic interventions on postoperative SSI. In addition, there may be additional mechanisms to explain our SSI findings. First, one mechanism may be
Levandovski et al
December 2008
723
Table 3. Clinical variables measured during the postoperative period Group Characteristic Hemoglobin postoperative, mg Oxygen in the Postoperative Care Unit, yes/no* Time of urinary catheterization after surgery, days Urinary infection, yes/no* Pulmonary infection, yes/no* Postoperative time to eliminate first flatus, daysy Sedation level in any assessment in the first 24 h after surgery, $2/,2 Mean of postoperative state-anxiety Incisional pain on VAS 6 h after surgeryy Incisional pain on VAS 24 h after surgeryy Incisional pain on coughing or deep breathing 6 h after surgery, yes/no* Incisional pain on coughing or deep breathing 24 h after surgery, yes/no* Some incisional pain at rest but no desire for additional analgesic, yes/no* Time to delivery of the first dose of morphine after surgery, miny Morphine consumption during the first 24 h after surgery, mgy Morphine consumption during the first 24 h after surgery, .60/#60 mg Morphine consumption during the first 72 h after surgery, mg Number of antiinflammatory doses used during the first 72 h after surgeryy Surgical site infection up to 30 days after surgery, yes/no Length of hospital stay, daysy
Placebo (n 5 62)
Diazepam (n 5 61)
P value
9.69 6 2.17 60/02 1.16 6 0.79 12/50 02/60 1.27 6 0.51 16/46 41.91 6 8.88 4.83 6 3.07 1.73 6 1.68 34/28 39/23 17/45 69.77 6 88.39 66.39 6 23.98 41/21 87.62 6 34.16 5.08 6 3.68 16/46 5.61 6 1.84
9.94 6 1.95 59/02 1.31 6 0.88 10/51 01/60 1.36 6 0.60 17/44 38.13 6 6.94 5.13 6 2.74 2.17 6 1.82 29/32 38/23 21/40 58.97 6 82.71 57.65 6 23.92 21/40 83.48 6 35.48 5.66 6 3.93 4/57 4.54 6 1.24
.67 .68 .34 .42 .50 .39 .48 .01z .20 .16 .27 .54 .26 .48 .04z .00z .51 .41 .00z .00z
NOTE. Values are means (SD) or frequencies (n 5 123). *Fisher exact test or x2 test to compare frequencies. y Unpaired t test to compare means 6 standard deviation. z P , .05.
Table 4. Results of stepwise forward logistic regression analysis of the adjusted effect of preoperative anxiolytic intervention on SSI
Preoperative placebo use Incisional pain on coughing or movement Morphine consumption .60 mg during the first 24 h after surgery
Beta
SE
P value
OR*
95% CI
1.38 1.347 1.165
0.622 0.583 0.591
.03 .02 .04
3.99 3.84 3.20
(1.18-13.53) (1.22-12.06) (1.01-10.21)
NOTE. N 5 123. *Adjusted by type of surgical incision, postoperative incisional pain at rest, and local anesthetic dose.
similar to that responsible for the finding reported in studies involving preoperative psychologic interventions.31 Given that preoperative anxiety is associated with a surge of stress hormones,31 if we are able to prevent or decrease this surge, we may in fact change the onset of the entire perioperative neuroendocrinologic stress response. This in turn could result in an overall decrease in the global hormonal stress response. Second, previous reports indicate that multiple perioperative factors, including anxiety, hypovolemia, pain, and cold, all stimulate sympathetic vasoconstriction16,17 and, therefore, probably increase the risk of infection.18 Of interest in this regard are the multiple studies in the psychosomatic field that have reported an increased incidence of various infectious processes in patients who were more anxious and felt more stress.32 Finally, even though the mechanism involved in this response is not clear, the magnitude of clinical effect
of diazepam in the incidence of SSI is undoubtedly important because the NNT relative to placebo for 1 additional patient to show SSI was 5.15, and, to the best of our knowledge, this is the first clinical trial specifically designed to assess the effect of preoperative anxiolytic medication on the incidence of SSI, which extends some literature data. In addition, in the present study, patients with incisional pain during coughing or movement had a higher incidence of SSI, even though they did not wish additional analgesic (Table 3). This suggests that pain control was satisfactory because some pain level during coughing or movement is expected with opioid-based analgesia,33 even though the patient’s pain at rest was controlled. In the preset study, those patients who acquired SSI had higher morphine consumption during the first 24 hours following surgery, but this difference is not statically significant when
724
Vol. 36 No. 10
we consider drug consumption for the entire period of the first 72 hours after surgery. Although the reason for this finding is not clear, one hypothetic explanation is that SSI may stimulate a heightened pain response and thereby contribute to the continuity of the cycle of pain-morphine consumption and a greater requirement for opioid analgesic. Alternatively, according to earlier reports, the immunosuppressive effects of moderate to large morphine doses administered intravenously could explain the present finding.34 Finally, it is possible that the higher incidence of SSI in the placebo group indicates a requirement for more morphine to control pain because of increased anxiety levels. Further investigations are needed to clarify this issue. Possibly, the higher doses of ropivacaine used in the placebo-treated patients was also determined by the patient’s anxiety level because no patients needed to switch from epidural to general anesthesia because of insufficient anesthesia. Thus, as the duration of surgery was similar between treatment groups, one hypothesis to explain this finding was that placebo-treated patients were more anxious during surgery, which induced the anesthetist to use higher doses of local anesthetic according to previous studies.35 This hypothesis is supported by previous studies that showed that the patient’s anxiety was the strongest trigger for provider-directed medication.35 Although a widely used and validated scoring system36 was employed by examiners to establish the diagnosis of SSI directly, there were limitations in confirming SSI using culture because the gynecologist sometimes had difficulty in collecting the sample adequately in detriment of the small quantity of purulent exudate and because in other cases the drainage of the purulent exudate occurred only at 1 or 2 points. To standardize the clinical criteria to define the diagnosis of SSI, in addition to using the CDC criteria, the examiners could rely on at least 1 of the following criteria: drainage of pus or purulent exudates at least at 1 point, separation of deep tissues with purulent exudates, and drainage of pus during local anesthesia or in the debridement of the wound during general anesthesia. A global incidence of SSI of 15.2% was found, which is equivalent to the highest incidence of SSI observed in contaminated surgery in our institution in the last 5 years. This rate is more than 4 times the rate observed in potentially contaminated surgery in the same institution in the last 5 years, which oscillated between 1.99 and 4.38. Still, this rate is within the limits of studies published in the last decade for patients undergoing abdominal hysterectomy (0%-27%).37,38 However, the incidence of SSI observed in the diazepam-treated patients is in agreement with the incidence of infection in abdominal hysterectomy reported by the Nosocomial Infection National Surveillance Service for British
Levandovski et al
hospitals, which included more than 60,000 surgical procedures.23 On the other hand, the incidence of SSI in placebo-treated patients was excessively high, even though the groups were closely matched for psychologic and clinical characteristics and despite that all patients received standardized perioperative care (antibiotic prophylaxis and anesthetic and analgesic procedures). This discrepancy may be explained by several reasons. First, because the groups were homogenous on baseline and they received the same perioperative management, except for preoperative medication, it is unlikely that factors other than the use of diazepam accounted for the decreased rate of SSI in diazepamtreated patients. Second, the absence of any anxiolytic medication prior to and during the surgery in placebotreated individuals makes management of this group different from that of other patients treated in our institution because all patients undergo an anesthesiologist’s assessment and they routinely receive benzodiazepine preoperatively. Furthermore, most of the patients undergoing surgery in our hospital receive benzodiazepine during the surgery. Thus, these differences do not permit us to compare the incidence of SSI in placebo-treated patients with the incidence observed in the same hospital prior to this protocol. Additionally, because this study is a clinical trial that was specifically designed to assess the effect of preoperative medication on SSI, it does allow us to standardize the perioperative management, the diagnosis protocol of SSI, and the follow-up period. Thus, this may increase the possibility of detecting SSI compared with previous observational studies. Furthermore, we assessed the incidence of SSI diagnosed during the hospitalization period up to the first 30 days after surgery. This may explain in part the higher incidence of SSI detected in the present investigation. However, even after conducting this protocol carefully and adjusting our estimates as much as possible for the confounding effect of changes in patients and procedure-related characteristics over time, some unmeasured, confounding residual effects may persist, but it is unlikely that it would change the direction of the conclusion. Furthermore, it was noted that hospitalization was prolonged (by approximately 1 day) in the placebotreated patients (Table 3). Although the difference in hospital stay between the treatment groups was only 1 day, this difference was more than 3 days when we compared the length of hospitalization of patients with SSI patients with that of patients without SSI, thus indicating that most infections were substantial. This is an expected finding and similar to the prolongation of hospitalization previously reported in infected patients.2,23 Finally, we must also emphasize that we excluded from this investigation patients with American Society of Anesthesiologists status higher than 2,
Levandovski et al
patients with a history of affective disorders or positive screening for minor psychiatric disorders, and patients taking any psychotropic medication. It is important to point out that, although the homogenous population of this study is methodologically advantageous, the issue of external validity arises. That is, hysterectomy may be associated with a specific psychologic and behavioral state that is not common in other surgical populations. In addition, it is important to emphasize that, although diazepam was effective in attenuating anxiety and the risk of postoperative SSI with the anesthesia and analgesia used in this investigation, these findings cannot be generalized to patients undergoing general anesthesia or some other form of sedation, as well as other types of postoperative analgesia. Thus, the conclusion of this study may be limited in its generalization to this surgical population alone. In conclusion, diazepam-treated patients showed lower postoperative anxiety and lower incidence of SSI up to 30 days after surgery compared with placebo in patients undergoing abdominal hysterectomy. Although the clinical effect of diazepam is undoubtedly important, further studies are needed to elucidate the mechanism underlying this response. The authors thank Dr. A. Leyva for the English editing of the manuscript.
References 1. Bremmelgaard A, Raahave D, Beier-Holgersen R, Pedersen JV, Andersen S, Sorensen AI. Computer-aided surveillance of surgical infections and identification of risk factors. J Hosp Infect 1989;13:1-18. 2. Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group. N Engl J Med 1996;9(334):1209-15. 3. Haley RW, Culver DH, Morgan WM, White JW, Emori TG, Hooton TM. Identifying patients at high risk of surgical wound infection: a simple multivariate index of patient susceptibility and wound contamination. Am J Epidemiol 1985;121:206-15. 4. Miles AA, Miles EM, Burke J. The value and duration of defence reactions of the skin to the primary lodgement of bacteria. Br J Exp Pathol 1957;38:79-96. 5. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for Prevention of Surgical Site Infection 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control 1999;27:97-132. 6. Hughes JM. Study on the efficacy of nosocomial infection control (SENIC Project): results and implications for the future. Chemotherapy 1988;34:553-61. 7. Cheadle WG. Risk factors for surgical site infection. Surg Infect 2006; (Suppl 1)7:7–11. 8. Hartmann M, Jonsson K, Zederfeldt B. Effect of tissue perfusion and oxygenation on accumulation of collagen in healing wounds: randomized study in patients after major abdominal operations. Eur J Surg 1992;158:521-6. 9. Classen DC, Evans RS, Pestotnik SL, Horn SD, Menlove RL, Burke JP. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med 1992;326:281-6.
December 2008
725
10. Akc xa O, Melischek M, Scheck T, Hellwagner K, Arkilic CF, Kurz A, et al. Postoperative pain and subcutaneous oxygen tension. Lancet 1999;354:41-2. 11. Wallace LM. Trait anxiety as a predictor of adjustment to and recovery from surgery. Br. J Clin Psychol 1987;26:73-4. 12. Kiecolt-Glaser JK, Page GG, Marucha PT, MacCallum RC, Glaser R. Psychological influences on surgical recovery: perspectives from psychoneuroimmunology. Am Psychol 1998;53:1209-18. 13. Johnston M, Vogele C. Benefits of psychological preparation for surgery: a meta-analysis. Ann Behav Med 1993;15:245-56. 14. Kain ZN, Sevarino F, Pincus S, Alexander GM, Wang SM, Ayoub C, et al. Attenuation of the preoperative stress response with midazolam: effects on postoperative outcomes. Anesthesiology 2000;93: 141-7. 15. Zhou D, Kusnecov AW, Shurin MR, DePaoli M, Rabin BS. Exposure to physical and psychological stressors elevates plasma interleukin 6: relationship to the activation of hypothalamic-pituitary-adrenal axis. Endocrinology 1993;133:2523-30. 16. Derbyshire D, Smith G. Sympathoadrenal responses to anaesthesia and surgery. Br J Anaesth 1984;56:725-39. 17. Halter J, Pflug A, Porte D. Mechanism of plasma catecholamine increases during surgical stress in man. J Clin Endocrinol Metab 1977; 45:936-44. 18. Hopf HW, Hunt TK, West JM, Blomquist P, Goodson WH III, Jensen JA, et al. Wound tissue oxygen tension predicts the risk of wound infection in surgical patients. Arch Surg 1997;132:997-1004. 19. Mari JJ, Williams P. A validity study of a psychiatric screening questionnaire (SRQ-20) in primary care in the city of Sao Paulo. Br J Psychiatry 1986;148:23-6. 20. Greif R, Akca O, Horn EP, Kurz A, Sessler DI. Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection. Outcomes Research Group. N Engl J Med 2000;342:161-7. 21. Collins SL, Moore RA, McQuay HJ. The visual analogue pain intensity scale: what is moderate pain in millimeters? Pain 1997;72:95-7. 22. Biaggio AMB. A decade of research on State-Trait Anxiety in Brazil. In: Spielberger CD, Diaz-Guerrero R, editors. Cross-cultural anxiety. New York: Hemisphere; 1990. p. 157-67. 23. Coello R, Charlett A, Wilson J, Ward V, Pearson A, Borriello P. Adverse impact of surgical site infections in English hospitals. J Hosp Infect 2005;60:93-103. 24. Browner WS, Black D, Newman TB, Hulley SB. Estimating sample size and power. In: Hulley SB, Cummings SR, editors. Designing clinical research. Baltimore: Lippincott Williams & Wilkins; 1988. p. 139-58. 25. Hosmer DW Jr, Lemeshow SM. Applied logistic regression. 2nd ed. New York: John Wiley & Sons, Inc.; 1989. 26. Kain ZN, Sevarino FB, Rinder C, Pincus S, Alexander GM, Ivy M, et al. Preoperative anxiolysis and postoperative recovery in women undergoing abdominal hysterectomy. Anesthesiology 2001;94:415-22. 27. Irwin M, Hauger R, Brown M. Central corticotropin-releasing hormone activates the sympathetic nervous system and reduces immune function: increased responsivity of the aged rat. Endocrinology 1992; 131:1047-53. 28. Zavala F, Taupin V, Descamps-Latscha B. In vivo treatment with benzodiazepines inhibits murine phagocyte oxidative metabolism and production of interleukin 1, tumor necrosis factor and interleukin-6. J Pharmacol Exp Ther 1990;255:442-50. 29. Goto Y, O’Malley C, Fanning NF, Wang J, Redmond HP, Shorten GD. Benzodiazepines inhibit the rate of neutrophil apoptosis. Ir J Med Sci 2003;172:191-4. 30. Stoelting RK. Benzodiazepines. In: Stoelting RK, editor. Pharmacology & physiology in anaesthetic practice. Philadelphia: Lipincott-Raven; 1999. p. 126-39. 31. Williams JG, Jones JR, Workhoven MN, Williams B. The psychological control of preoperative anxiety. Psychophysiology 1975;12:50-4.
726
Vol. 36 No. 10
32. Biondi M, Zannino LG. Psychological stress, neuroimmunomodulation, and susceptibility to infectious diseases in animals and man: a review. Psychother Psychosom 1997;66:3-26. 33. Carr DB, Cousins MJ. Spinal route of analgesia opioids and future potions. In: Cousins MJ, Bridenbaugh PO, editors. Neural blockade in clinical anesthesia and management of pain. Philadelphia: Lippincott-Raven; 1998. p. 915-83. 34. Beilin B, Shavit Y, Hart J, Mordashov B, Cohn S, Notti I, et al. Effects of anesthesia based on large versus small doses of fentanyl on natural killer cell cytotoxicity in the perioperative period. Anesth Analg 1996;82:492-7. 35. Schupp CJ, Berbaum K, Berbaum M, Lang EV. Pain and anxiety during interventional radiologic procedures: effect of patients’ state anxiety at
Levandovski et al baseline and modulation by nonpharmacologic analgesia adjuncts. J Vasc Interv Radiol 2005;16:1585-92. 36. Gaynes RP, Culver DH, Horan TC, Edwards JR, Richards C, Tolson JS. Surgical site infection (SSI) rates in the United States, 1992-1998: the National Nosocomial Infections Surveillance System basic SSI risk index. Clin Infect Dis 2001;33:S69-77. 37. Kandula PK, Wenzel RP. Postoperative wound infection after total adominal hysterectomy: a controlled study of the increased duration of hospital stay and trends in postoperative wound infection. Am J Infect Control 1993;21:201-4. 38. Costa RJ, Krauss-Silva L. Systematic review and meta-analysis of antibiotic prophylaxis in abdominal Hysterectomy. Cad Saude Publica 2004;20:S175-89.
Background: An increased anxiety may be associated with a higher risk of surgical site infection (SSI), but there is little objective data on the effect of preoperative anxiolytic interventions on SSI. To address this issue, we evaluated the effects of preoperative diazepam on postoperative SSI following abdominal hysterectomy. Methods: This randomized, double-blinded, placebo-controlled study included 130 patients, American Society of Anesthesiologist physical status 1 or 2. Patients were randomly assigned to receive either oral diazepam 10 mg (n 5 65) or placebo (n 565) the night before and 1 hour prior to surgery. The assessment instruments were the Visual Analogue Scale and the State-Trait Anxiety Inventory. SSI was diagnosed according to the criteria of the Centers for Disease Control and Prevention with standard follow-up of 30 days. Results: The relative risk (RR) was 1.79 (95% confidence interval [CI]: 1.31-2.43), and the number of patients that needed to be treated was 5.2 (95% CI: 2.74-50.76) to prevent 1 additional SSI. The RR for SSI in placebo-treated patients with high postoperative anxiety was 1.65 (95% CI: 1.07-2.56). Conclusion: Diazepam-treated patients showed lower postoperative anxiety and lower incidence of SSI up to 30 days after surgery compared with placebo in patients undergoing abdominal hysterectomy. (Am J Infect Control 2008;36:718-26.)
Wound infections are among the most common serious complications of anesthesia and surgery.1 Surgical wound infections can prolong hospitalization2 and substantially increase the cost of care.1,3 The first few hours after tissue is contaminated by bacteria constitute a critical period during which wound infection is established,4 but infections are typically not detected until some days after surgery. The factors that influence the incidence of surgical wound infection include site and complexity of surgery,3 patient’s underlying illness, smoking, obesity,5,6 blood transfusion, hyperglycemia,7 presence or absence of hypovolemia,8 patient’s temperature during surgery,2 use or not of From the Postgraduate Program in Medical Sciences,a School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS); Pharmacology Department,b Instituto de Cieˆncias Ba´sicas da Sau´de of UFRGS; Department of Psychiatry,c School of Medicine, UFRGS; and Anesthesia Service and Perioperative Medicine,d Hospital de Clı´nicas de Porto Alegre (HCPA)/Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. Address correspondence to Wolnei Caumo, MD, PhD, Coronel Corte Real, 295 Bairro Petropolis CEP: 90630-008, Porto Alegre, RS, Brazil. E-mail: [email protected].
Supported by The Postgraduate Research Group (GPPG) at Hospital de Clı´nicas de Porto Alegre.
prophylactic antibiotics,9 and degree to which pain and anxiety are controlled.10 Studies published in the health-psychology literature suggest that increased preoperative anxiety is associated with poor postoperative behavioral and clinical recovery.11,12 Furthermore, numerous reports indicate that preoperative psychologic interventions aimed at reducing preoperative anxiety may also result in improved postoperative behavioral and clinical recovery.12-14 Additionally, several reports indicate that increased perioperative anxiety and uncontrolled postoperative pain may increase the perioperative neuroendocrine stress response.14,15 Thus, a possible hypothesis is that factors such as anxiety and pain can stimulate sympathetic vasoconstriction16,17 and thereby increase the risk of postoperative infection.18 Accordingly, one can hypothesize that the use of preoperative benzodiazepine can reduce postoperative anxiety and enhance the postoperative clinical recovery process involved in warding off infection. To test this hypothesis, we conducted a randomized, double-blind, placebo-controlled trial to evaluate the effect of preoperative diazepam on the postoperative incidence of surgical site infection (SSI) during the first 30 days following abdominal hysterectomy.
Conflicts of interest: There were no financial relationshipa between any of the authors or any commercial interest in the outcome of this study.
MATERIALS AND METHODS
0196-6553/$34.00
Study population
Copyright ª 2008 by the Association for Professionals in Infection Control and Epidemiology, Inc. doi:10.1016/j.ajic.2007.12.010
718
Following ethics committee approval and written informed consent, 130 patients, American Society of Anesthesiologist classification 1 or 2, aged 19 to 60 years,
Levandovski et al
scheduled to undergo total abdominal hysterectomy, were enrolled in the randomized, double-blind, placebo-controlled study. The patients were undergoing elective abdominal hysterectomy for myomatosis in the Gynecology Service, and all operations were performed by a third-year resident supervised by one of the attending gynecologists. All patients were admitted to the hospital 1 day before surgery, and those patients who did not develop complications were discharged on day 3 postsurgery, on any day of the week. Patients with contraindications to regional anesthesia; mental impairment; chronic pain; or a history of congestive heart failure, valvular heart disease, renal or hepatic disease, psychotropic drug use, and language or communication difficulties were excluded. In addition, patients with a body mass index (BMI) higher than 35 kg/m2 and those with a history of psychiatric disorder and/or positive screening for minor psychiatric disorders (scores, $8) on the World Health Organization’s (WHO) Self-Reporting Questionnaire (SRQ-20) were excluded.19 The SRQ-20 measures somatic symptoms, depressive mood, depressive thoughts, and decreased energy.
Randomization and interventions The treatment allocation method used was advanced simple randomization without blocking or stratification. Before the recruitment phase of the study, 160 envelopes containing all protocol materials were prepared and numbered sequentially. A random number was used to assign each consecutively numbered envelope to receive either 10 mg oral diazepam or placebo the night before (10 PM) and 1 hour prior to surgery, and the envelopes were grouped so that each had an independent 50% probability of being included in either group. A sheet indicating the allocated treatment was then placed in the envelope, and the envelopes were sealed. Throughout the course of the study, the sealed envelopes were removed and opened sequentially by a pharmacy technician, who delivered the tablets of diazepam 10 mg or placebo only after prospective patients had been screened and had consented to participation. No other preoperative medication was given. During the entire protocol time line, blinding and randomization were undertaken by 2 investigators who were not involved in the patient’s evaluation. Other individuals involved in the patient’s care were unaware of the treatment group to which the patient belonged.
Outcome measures Our major outcome (SSI) was either of 2 distinct criteria for diagnosis. The first criterion, as in previous studies,2,20 was that wounds were considered likely to be infected when pus could be expressed from the
December 2008
719
incision or aspirated from a loculated mass within the wound. The second criterion was based on the Centers for Disease Control and Prevention (CDC)’s National Nosocomial Infections Surveillance (NNIS) system, modified in 1999,5 in which SSI is classified as being either incisional (superficial or deep) or organ space with a diagnostic period up to 30 days. At all times, the gynecologist examiner was blinded to the aim of the study, preoperative interventions, and all other measures.
Instruments and assessment The data were collected in the following multiple standardized phases: (1) during the period of preoperative evaluation, a structured questionnaire was used to collect information concerning demographic characteristics, clinical state, and anxiety level; (2) the surgical procedures were assessed using the anesthesiologist’s records; (3) during the patients’ stay at the hospital, the gynecologists examined the surgical wound daily for the presence of SSI; (4) after discharge, all patients were examined 2 times, at 1 and 4 weeks of followup, carried out by a gynecologist in the same hospital, in the outpatient service. Data regarding drug records, medical and diagnostic examinations, reinterventions, other medical procedures, and hospital readmission for treatment of surgical complications were all collected from the patient’s records. Two independent, trained data collectors followed a standard method by which they reviewed all clinical and laboratory information available in the hospital. Urinary and respiratory infections were defined by clinical and laboratory criteria. The gynecologist in charge of discharge was blinded to the aim of the study and all other measures. The length of hospital stay was defined as the number of days spent in the hospital.
Assessment of pain and psychologic state The day prior to surgery, the same anesthesiologist, who provided patients with information on the perioperative course and instructed them regarding the use of the patient-controlled analgesia pump, saw all patients. Moreover, each patient underwent psychologic testing and pain evaluation. The pain was measured by a 100-mm Visual Analog Scale (VAS), by which scores ranged from no pain (zero) to worst possible pain (100 mm).21 Incisional pain at rest was defined as the average of pain ratings obtained at 6 and 24 hours following surgery. A 30-mm cut-off point was used to classify the patients into 2 groups: (1) absence of pain or mild pain (scores equal to or less than 30 mm); and (2) moderate, intense, or worst possible pain (scores greater than 30 mm).21 Incisional pain on coughing, deep breathing, or movement assessed using yes or no type questions and the patient’s
720
Levandovski et al
Vol. 36 No. 10
desire for additional analgesic were assessed at 6 and 24 hours after surgery. The presence of incisional pain during coughing or movement and the desire for additional analgesic in any assessment were the criteria used to classify the patients as presenting or not with pain on coughing or movement and desiring or not additional analgesia. Sedation was assessed by the following criteria: zero, completely alert; 1, dozes now and then but answers immediately; 2, often asleep but arousable; 3, asleep and not arousable. A sedation level equal to or higher than 2 in any assessment was used as the cutoff point to classify patients as follows: (1) mild sedation level (,2) or (2) moderate to intense sedation level ($2). To measure pre- and postoperative anxiety, we used the State-Trait Anxiety Inventory (STAI)22 validated for the Brazilian population: state-anxiety (transitory anxiety that varies according to the situation) and trait-anxiety (stable personality disposition reflecting general level of fearfulness). The postoperative anxiety was defined as the average of the scores obtained at 2 time points: 6 and 24 hours following surgery.13 The cut-off point to classify high anxiety or low anxiety was the highest quartile so that individuals with a score above the highest quartile were classified as highly anxious and those with a score equal to or below the highest quartile as mildly anxious. The highest quartile for postoperative state-anxiety was 45.5. The stratification procedure was based on Spielberger and DiazGuerrero’s manual.22 To ensure that the evaluators were blinded to preoperative psychologic state, the physicians involved in the preoperative evaluation did not perform the postoperative assessment.
Anesthesia technique All patients had standard monitoring prior to epidural anesthesia. An isotonic saline solution (10 mL kg-1), cefazolin (2 g), and intravenous (IV) fentanyl (100 mg) were administered. Afterward, all patients had an extradural catheter inserted at lumbar segments L2/ L3 or L3/L4. An injection of 15 to 20 mL ropivacaine (10 mg mL-1) was given epidurally. If there were signs of inadequate analgesia, additional 5-mL doses were used. During surgery, all patients received propofol continuously to maintain sedation and supplementary oxygen by an intranasal catheter. A vesicourethral catheter was routinely maintained until the first postoperative day. In the operating room, the patient’s skin was disinfected with alcoholic chlorhexidine. At the end of surgery, sedation was stopped, and the extradural catheter was removed.
Postoperative analgesia The PCA device (APM; Abbott, Chicago, IL) was available as soon as the patient arrived in the postanesthesia
care unit. The PCA was programmed to deliver a 2-mg morphine bolus with a lockout period of 10 minutes. The maximum dose that could be requested during a 4-hour period was 30 mg. If the pain was not relieved, an additional dose of 20 mg/day of tenoxicam was administered intravenously. The patients were connected to PCA for the entire period of 72 hours after surgery. Analgesia in all patients at 72 hours after surgery was maintained with codeine 30 mg plus acetaminophen 500 mg every 6 hours and 75 mg sodium diclofenac three times per day. If pain was still not relieved, 1000 mg dipyrone was given every 6 hours.
Statistical analysis For the initial power analysis, the number of subjects in each study group was determined based on previous studies involving the incidence of SSI according to the American NISS risk index23 and the effect of interventions to attenuate the preoperative stress response on postoperative outcomes.14 To determine the power analysis, an infection rate of 2.5% was expected in the diazepam-treated patients, which corresponds to a prorating incidence of SSI reported in a large cohort study in patients having undergone abdominal hysterectomy.23 However, the rate used in the placebo group was the incidence of postoperative infection reported in placebo-treated patients in an earlier study that assessed the effect of interventions to attenuate the preoperative stress response on postoperative outcomes, which was 16%.14 The analysis indicated that a study of 130 subjects (65 per group) was required to detect a 15% difference between groups with a power of 80% and a set at 0.05.24 Considering that the sample size calculation is just an estimation, we thus decided to calculate the power of this analysis based on the incidence of SSI that we found in this study, that is, 25.8% in the placebo-treated and 6.6% in the diazepam-treated patients, which resulted in a power of 89.72% (with a 2-tailed a level of 0.05). The differences between groups for continuing data were examined by the t test for independent samples, and categorical data were examined by x2 or Fisher exact tests. Multivariate logistic regression was used following the stepwise forward procedure to minimize the effect of the differences between groups of other factors showing significant imbalance in the univariate analysis, except for preoperative anxiolytic intervention.25 The variables related to pain were included without considering the statistical significance of univariate analysis because a previous study suggested that postoperative pain10 could be linked to SSI.14 To analyze the effect of morphine doses used in the first 24 hours after surgery, the cut-off points were established using the mean (60 mg kg-1). For all analyses, statistical
Levandovski et al
Fig 1. Flow diagram of study, including number of patients at each point. significance was set at P , .05, 2-tailed. Data were analyzed using SPSS version 11.0 (SPSS, Inc, Chicago, IL). The magnitude of the effect of preoperative diazepam was demonstrated by the number of patients who needed to be treated (NNT) to avoid 1 additional SSI.
RESULTS Figure 1 is a flow diagram of the 130 women eligible to participate in the trial. Patients’ characteristics and perioperative variables are summarized in Tables 1 to 3. Demographic and morphometric characteristics were similar in patients assigned to diazepam and placebo. However, the diazepam-treated patients demonstrated a level of anxiety significantly lower than that of placebo-treated patients throughout the first 24 hours after surgery (Table 3). In the placebo group, 59.7% (40/62) showed high state-anxiety postoperatively, compared with 21.4% (27/61) in the diazepam group. In the placebo group, the relative risk (RR) was 1.52 (95% confidence interval [CI]: 1.04-2.22) and the NNT 5.15 (95% CI: 2.74-42.55) to observe 1 additional patient with high anxiety in the postoperative period. The overall incidence of SSI was 15.20% (95% CI: 10.23-21.75), in which 6.1% had the diagnosis before discharge and 9.1% had the diagnosis after discharge. The superficial SSI rate was 8.6% (95% CI: 4.8914.10), the deep incision infection rate was 4.2% (95% CI: 1.87-8.89), and the organ/cavity infection frequency was 2.4% (95% CI: 0.78-6.48). The placebotreated group showed an SSI incidence of 25.8% (16/ 62), compared with 6.6% (4/61) in the diazepam group. In the placebo-treated patients, the RR to SSI was 1.79 (95% CI: 1.31-2.43) and the NNT 5.2 (95% CI: 2.7450.76). Subgroup analysis demonstrated that the incidence of SSI in highly anxious placebo-treated women was 47.6% and 10% in diazepam treated and that the RR to SSI in placebo treated was 1.65 (95% CI: 1.07-2.56). The incidence of SSI in mildly anxious placebo-treated patients was 14.6% and 3% in diazepam-treated patients, and the RR to SSI in placebo-
December 2008
721
treated patients was 1.58 (95% CI: 0.93-2.67). There was no case of mortality, sepsis, or major cardiovascular complications in either group. The length of hospital stay was significantly longer in placebo-treated compared with diazepam-treated patients (Table 3), and this difference was even larger when comparing those patients who developed a SSI compared with patients without SSI (7.25 6 2.73 days vs 4.66 6 0.9 days; t 5 4.19, P 5 .00, respectively). The multivariate analysis summarized in Table 4 confirmed the effect of preoperative anxiolytic intervention on SSI infection after controlling for dose of local anesthetic used during the surgery, morphine consumption during the first 24 hours after surgery, type of surgical incision, and postoperative incisional pain at rest and during coughing or movement (Table 4).
DISCUSSION Patients treated with diazepam preoperatively had a lower risk of high state-anxiety postoperatively and lower incidence of SSI. Furthermore, it was demonstrated that patients who were highly anxious postoperatively had a higher incidence of SSI up to 30 days after surgery. These findings are supported by a previous study in patients undergoing minor outpatient surgery, in which midazolam-treated patients showed lower rates of postoperative infection compared with placebo-treated patients.14 Additionally, the present findings may be supported by the immunologic results of a previous randomized clinical trial, in which placebo-treated patients exhibited a greater postoperative B-cell response compared with midazolam-treated patients, suggesting that anxiety may influence the function of circulating immune cells in the immediate postoperative period.26 In addition, we can hypothesize that diazepam used preoperatively itself could reduce the risk of infection. This hypothesis may be supported by evidence from studies in animals, possibly by diverse mechanisms such as an interaction of benzodiazepine with the benzodiazepine receptors (both central and peripheral) that form part of a molecular network that mediates the effects of stress and anxiety on immune function. The pathways by which endogenous and exogenous ligands of benzodiazepine receptors may modulate the immune system involve the attenuation of behavioral stress responses induced by corticotrophin releasing hormone (CRH), responsible for immune suppression.27 Additionally, diazepam may decrease the release of tumor necrosis factor-a, interleukin-1, and interleukin-6 by macrophages.28 In addition, its action on peripheral receptors inhibits apoptosis of neutrophils, which is essential for maintaining immune homeostasis and limiting host tissue damage by promoting resolution of the inflammatory
722
Levandovski et al
Vol. 36 No. 10
Table 1. Characteristics of the study sample Group Characteristic Formal education, yr* Age, yr* Weight, kg* Body mass index* Smoking status, yes/noy Diabetes, yes/noy Alcohol consumption, yes/noy ASA status, 1/2y Hemoglobin preoperative, mg Number of previous surgeries* Preoperative pain reported on Visual Analogue Scale* Trait-anxiety* Preoperative state-anxiety*
Placebo (n 5 62)
Diazepam (n 5 61)
P value
6.19 6 3.77 45.29 6 5.87 67.66 6 11.79 26.45 6 3.95 15/47 5/57 4/58 24/38 11.17 6 2.59 1.58 6.1.54 0.96 6 1.80 40.95 6 11.13 40.05 6 10.10
6.54 6 3.38 44.54 6 7.18 69.44 6 10.19 27.43 6 4.55 10/51 4/57 6/55 27/34 11.8161.70 1.59 6 1.27 1.42 6 2.11 40.84 6 8.73 39.98 6 8.92
.59 .52 .37 .21 .20 .51 .36 .33 .14 .97 .20 .83 .88
Placebo (n 5 62)
Diazepam (n 5 61)
P value
25/37
28/33
.33
33/29 625.85 6 535.84 8 (531.75 6 150.73) 154.27 6 39.69 158.83 6 32.86 2.23 6 2.12 0/62
25/35 551.84 6 449.35 10 (488.60 6 194.22) 149.05 6 37.84 136.74 6 35.08 2.39 6 1.82 0/61
.14 .40 .48 .20 .00z .65 —
NOTE. Values are means (SD) or frequencies (n 5 123). *Unpaired t test to compare means 6 standard deviation. y Fisher exact test or x2 test to compare frequencies.
Table 2. Clinical variables measured during intraoperative periods Group Characteristic Type of abdominal hysterectomy* Hysterectomy/ Hysterectomy plus ophoorectomy Type of incision* Vertical/ pfannenstiel Bleeding, mLy Red cell transfusion, No. of patients (mean 6 SD)y Duration of surgery, miny Dose of ropivacaine (mg kg-1)y Intraoperative fentanyl dose (mg kg-1)y Anesthetic or surgical complications, yes/no* NOTE. Values are means (SD) or frequencies (n 5 123). *Fisher exact test or x2 test to compare frequencies. y Unpaired t test to compare means 6 standard deviation. z P , .05.
response.29 Thus, these effects may influence the inflammatory response to surgery and explain the effect shown in diazepam-treated patients. Although we did observe this clinical phenomenon, our data only permit us to hypothesize this cause-effect relationship because the diazepam effect on apoptosis was not directly assessed. In addition, if we consider that perioperative stress is determined by pre- and postoperative anxiety, it is possible that placebo-treated patients had higher rates of postoperative infection because of increased anxiety levels throughout the postoperative period, whereas the prolonged anxiolytic effect of diazepam attenuated the anxiety in those who received the benzodiazepine.30 This hypothesis can explain the contrast between our findings and the previous investigation that assessed the effects of preoperative midazolam on postoperative anxiety in patients undergoing abdominal
hysterectomy,14 in which midazolam had a minimal impact on the clinical recovery process.26 Possibly, this discrepancy may be attributed to a short midazolam half-life, leaving the patients without the benefits of anxiolysis during most of the postoperative period. Therefore, because the anxiety level is related to the type and the extension of surgery and because the purpose of this investigation was to determine whether preoperative anxiolytic could reduce the incidence of SSI in patients after abdominal hysterectomy, we chose diazepam, which could extend its effect throughout the postoperative period. However, further studies are needed to elucidate the possible mechanism implicated in this response and to clarify the issue about the impact of different pharmacologic and nonpharmacologic anxiolytic interventions on postoperative SSI. In addition, there may be additional mechanisms to explain our SSI findings. First, one mechanism may be
Levandovski et al
December 2008
723
Table 3. Clinical variables measured during the postoperative period Group Characteristic Hemoglobin postoperative, mg Oxygen in the Postoperative Care Unit, yes/no* Time of urinary catheterization after surgery, days Urinary infection, yes/no* Pulmonary infection, yes/no* Postoperative time to eliminate first flatus, daysy Sedation level in any assessment in the first 24 h after surgery, $2/,2 Mean of postoperative state-anxiety Incisional pain on VAS 6 h after surgeryy Incisional pain on VAS 24 h after surgeryy Incisional pain on coughing or deep breathing 6 h after surgery, yes/no* Incisional pain on coughing or deep breathing 24 h after surgery, yes/no* Some incisional pain at rest but no desire for additional analgesic, yes/no* Time to delivery of the first dose of morphine after surgery, miny Morphine consumption during the first 24 h after surgery, mgy Morphine consumption during the first 24 h after surgery, .60/#60 mg Morphine consumption during the first 72 h after surgery, mg Number of antiinflammatory doses used during the first 72 h after surgeryy Surgical site infection up to 30 days after surgery, yes/no Length of hospital stay, daysy
Placebo (n 5 62)
Diazepam (n 5 61)
P value
9.69 6 2.17 60/02 1.16 6 0.79 12/50 02/60 1.27 6 0.51 16/46 41.91 6 8.88 4.83 6 3.07 1.73 6 1.68 34/28 39/23 17/45 69.77 6 88.39 66.39 6 23.98 41/21 87.62 6 34.16 5.08 6 3.68 16/46 5.61 6 1.84
9.94 6 1.95 59/02 1.31 6 0.88 10/51 01/60 1.36 6 0.60 17/44 38.13 6 6.94 5.13 6 2.74 2.17 6 1.82 29/32 38/23 21/40 58.97 6 82.71 57.65 6 23.92 21/40 83.48 6 35.48 5.66 6 3.93 4/57 4.54 6 1.24
.67 .68 .34 .42 .50 .39 .48 .01z .20 .16 .27 .54 .26 .48 .04z .00z .51 .41 .00z .00z
NOTE. Values are means (SD) or frequencies (n 5 123). *Fisher exact test or x2 test to compare frequencies. y Unpaired t test to compare means 6 standard deviation. z P , .05.
Table 4. Results of stepwise forward logistic regression analysis of the adjusted effect of preoperative anxiolytic intervention on SSI
Preoperative placebo use Incisional pain on coughing or movement Morphine consumption .60 mg during the first 24 h after surgery
Beta
SE
P value
OR*
95% CI
1.38 1.347 1.165
0.622 0.583 0.591
.03 .02 .04
3.99 3.84 3.20
(1.18-13.53) (1.22-12.06) (1.01-10.21)
NOTE. N 5 123. *Adjusted by type of surgical incision, postoperative incisional pain at rest, and local anesthetic dose.
similar to that responsible for the finding reported in studies involving preoperative psychologic interventions.31 Given that preoperative anxiety is associated with a surge of stress hormones,31 if we are able to prevent or decrease this surge, we may in fact change the onset of the entire perioperative neuroendocrinologic stress response. This in turn could result in an overall decrease in the global hormonal stress response. Second, previous reports indicate that multiple perioperative factors, including anxiety, hypovolemia, pain, and cold, all stimulate sympathetic vasoconstriction16,17 and, therefore, probably increase the risk of infection.18 Of interest in this regard are the multiple studies in the psychosomatic field that have reported an increased incidence of various infectious processes in patients who were more anxious and felt more stress.32 Finally, even though the mechanism involved in this response is not clear, the magnitude of clinical effect
of diazepam in the incidence of SSI is undoubtedly important because the NNT relative to placebo for 1 additional patient to show SSI was 5.15, and, to the best of our knowledge, this is the first clinical trial specifically designed to assess the effect of preoperative anxiolytic medication on the incidence of SSI, which extends some literature data. In addition, in the present study, patients with incisional pain during coughing or movement had a higher incidence of SSI, even though they did not wish additional analgesic (Table 3). This suggests that pain control was satisfactory because some pain level during coughing or movement is expected with opioid-based analgesia,33 even though the patient’s pain at rest was controlled. In the preset study, those patients who acquired SSI had higher morphine consumption during the first 24 hours following surgery, but this difference is not statically significant when
724
Vol. 36 No. 10
we consider drug consumption for the entire period of the first 72 hours after surgery. Although the reason for this finding is not clear, one hypothetic explanation is that SSI may stimulate a heightened pain response and thereby contribute to the continuity of the cycle of pain-morphine consumption and a greater requirement for opioid analgesic. Alternatively, according to earlier reports, the immunosuppressive effects of moderate to large morphine doses administered intravenously could explain the present finding.34 Finally, it is possible that the higher incidence of SSI in the placebo group indicates a requirement for more morphine to control pain because of increased anxiety levels. Further investigations are needed to clarify this issue. Possibly, the higher doses of ropivacaine used in the placebo-treated patients was also determined by the patient’s anxiety level because no patients needed to switch from epidural to general anesthesia because of insufficient anesthesia. Thus, as the duration of surgery was similar between treatment groups, one hypothesis to explain this finding was that placebo-treated patients were more anxious during surgery, which induced the anesthetist to use higher doses of local anesthetic according to previous studies.35 This hypothesis is supported by previous studies that showed that the patient’s anxiety was the strongest trigger for provider-directed medication.35 Although a widely used and validated scoring system36 was employed by examiners to establish the diagnosis of SSI directly, there were limitations in confirming SSI using culture because the gynecologist sometimes had difficulty in collecting the sample adequately in detriment of the small quantity of purulent exudate and because in other cases the drainage of the purulent exudate occurred only at 1 or 2 points. To standardize the clinical criteria to define the diagnosis of SSI, in addition to using the CDC criteria, the examiners could rely on at least 1 of the following criteria: drainage of pus or purulent exudates at least at 1 point, separation of deep tissues with purulent exudates, and drainage of pus during local anesthesia or in the debridement of the wound during general anesthesia. A global incidence of SSI of 15.2% was found, which is equivalent to the highest incidence of SSI observed in contaminated surgery in our institution in the last 5 years. This rate is more than 4 times the rate observed in potentially contaminated surgery in the same institution in the last 5 years, which oscillated between 1.99 and 4.38. Still, this rate is within the limits of studies published in the last decade for patients undergoing abdominal hysterectomy (0%-27%).37,38 However, the incidence of SSI observed in the diazepam-treated patients is in agreement with the incidence of infection in abdominal hysterectomy reported by the Nosocomial Infection National Surveillance Service for British
Levandovski et al
hospitals, which included more than 60,000 surgical procedures.23 On the other hand, the incidence of SSI in placebo-treated patients was excessively high, even though the groups were closely matched for psychologic and clinical characteristics and despite that all patients received standardized perioperative care (antibiotic prophylaxis and anesthetic and analgesic procedures). This discrepancy may be explained by several reasons. First, because the groups were homogenous on baseline and they received the same perioperative management, except for preoperative medication, it is unlikely that factors other than the use of diazepam accounted for the decreased rate of SSI in diazepamtreated patients. Second, the absence of any anxiolytic medication prior to and during the surgery in placebotreated individuals makes management of this group different from that of other patients treated in our institution because all patients undergo an anesthesiologist’s assessment and they routinely receive benzodiazepine preoperatively. Furthermore, most of the patients undergoing surgery in our hospital receive benzodiazepine during the surgery. Thus, these differences do not permit us to compare the incidence of SSI in placebo-treated patients with the incidence observed in the same hospital prior to this protocol. Additionally, because this study is a clinical trial that was specifically designed to assess the effect of preoperative medication on SSI, it does allow us to standardize the perioperative management, the diagnosis protocol of SSI, and the follow-up period. Thus, this may increase the possibility of detecting SSI compared with previous observational studies. Furthermore, we assessed the incidence of SSI diagnosed during the hospitalization period up to the first 30 days after surgery. This may explain in part the higher incidence of SSI detected in the present investigation. However, even after conducting this protocol carefully and adjusting our estimates as much as possible for the confounding effect of changes in patients and procedure-related characteristics over time, some unmeasured, confounding residual effects may persist, but it is unlikely that it would change the direction of the conclusion. Furthermore, it was noted that hospitalization was prolonged (by approximately 1 day) in the placebotreated patients (Table 3). Although the difference in hospital stay between the treatment groups was only 1 day, this difference was more than 3 days when we compared the length of hospitalization of patients with SSI patients with that of patients without SSI, thus indicating that most infections were substantial. This is an expected finding and similar to the prolongation of hospitalization previously reported in infected patients.2,23 Finally, we must also emphasize that we excluded from this investigation patients with American Society of Anesthesiologists status higher than 2,
Levandovski et al
patients with a history of affective disorders or positive screening for minor psychiatric disorders, and patients taking any psychotropic medication. It is important to point out that, although the homogenous population of this study is methodologically advantageous, the issue of external validity arises. That is, hysterectomy may be associated with a specific psychologic and behavioral state that is not common in other surgical populations. In addition, it is important to emphasize that, although diazepam was effective in attenuating anxiety and the risk of postoperative SSI with the anesthesia and analgesia used in this investigation, these findings cannot be generalized to patients undergoing general anesthesia or some other form of sedation, as well as other types of postoperative analgesia. Thus, the conclusion of this study may be limited in its generalization to this surgical population alone. In conclusion, diazepam-treated patients showed lower postoperative anxiety and lower incidence of SSI up to 30 days after surgery compared with placebo in patients undergoing abdominal hysterectomy. Although the clinical effect of diazepam is undoubtedly important, further studies are needed to elucidate the mechanism underlying this response. The authors thank Dr. A. Leyva for the English editing of the manuscript.
References 1. Bremmelgaard A, Raahave D, Beier-Holgersen R, Pedersen JV, Andersen S, Sorensen AI. Computer-aided surveillance of surgical infections and identification of risk factors. J Hosp Infect 1989;13:1-18. 2. Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group. N Engl J Med 1996;9(334):1209-15. 3. Haley RW, Culver DH, Morgan WM, White JW, Emori TG, Hooton TM. Identifying patients at high risk of surgical wound infection: a simple multivariate index of patient susceptibility and wound contamination. Am J Epidemiol 1985;121:206-15. 4. Miles AA, Miles EM, Burke J. The value and duration of defence reactions of the skin to the primary lodgement of bacteria. Br J Exp Pathol 1957;38:79-96. 5. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for Prevention of Surgical Site Infection 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control 1999;27:97-132. 6. Hughes JM. Study on the efficacy of nosocomial infection control (SENIC Project): results and implications for the future. Chemotherapy 1988;34:553-61. 7. Cheadle WG. Risk factors for surgical site infection. Surg Infect 2006; (Suppl 1)7:7–11. 8. Hartmann M, Jonsson K, Zederfeldt B. Effect of tissue perfusion and oxygenation on accumulation of collagen in healing wounds: randomized study in patients after major abdominal operations. Eur J Surg 1992;158:521-6. 9. Classen DC, Evans RS, Pestotnik SL, Horn SD, Menlove RL, Burke JP. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med 1992;326:281-6.
December 2008
725
10. Akc xa O, Melischek M, Scheck T, Hellwagner K, Arkilic CF, Kurz A, et al. Postoperative pain and subcutaneous oxygen tension. Lancet 1999;354:41-2. 11. Wallace LM. Trait anxiety as a predictor of adjustment to and recovery from surgery. Br. J Clin Psychol 1987;26:73-4. 12. Kiecolt-Glaser JK, Page GG, Marucha PT, MacCallum RC, Glaser R. Psychological influences on surgical recovery: perspectives from psychoneuroimmunology. Am Psychol 1998;53:1209-18. 13. Johnston M, Vogele C. Benefits of psychological preparation for surgery: a meta-analysis. Ann Behav Med 1993;15:245-56. 14. Kain ZN, Sevarino F, Pincus S, Alexander GM, Wang SM, Ayoub C, et al. Attenuation of the preoperative stress response with midazolam: effects on postoperative outcomes. Anesthesiology 2000;93: 141-7. 15. Zhou D, Kusnecov AW, Shurin MR, DePaoli M, Rabin BS. Exposure to physical and psychological stressors elevates plasma interleukin 6: relationship to the activation of hypothalamic-pituitary-adrenal axis. Endocrinology 1993;133:2523-30. 16. Derbyshire D, Smith G. Sympathoadrenal responses to anaesthesia and surgery. Br J Anaesth 1984;56:725-39. 17. Halter J, Pflug A, Porte D. Mechanism of plasma catecholamine increases during surgical stress in man. J Clin Endocrinol Metab 1977; 45:936-44. 18. Hopf HW, Hunt TK, West JM, Blomquist P, Goodson WH III, Jensen JA, et al. Wound tissue oxygen tension predicts the risk of wound infection in surgical patients. Arch Surg 1997;132:997-1004. 19. Mari JJ, Williams P. A validity study of a psychiatric screening questionnaire (SRQ-20) in primary care in the city of Sao Paulo. Br J Psychiatry 1986;148:23-6. 20. Greif R, Akca O, Horn EP, Kurz A, Sessler DI. Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection. Outcomes Research Group. N Engl J Med 2000;342:161-7. 21. Collins SL, Moore RA, McQuay HJ. The visual analogue pain intensity scale: what is moderate pain in millimeters? Pain 1997;72:95-7. 22. Biaggio AMB. A decade of research on State-Trait Anxiety in Brazil. In: Spielberger CD, Diaz-Guerrero R, editors. Cross-cultural anxiety. New York: Hemisphere; 1990. p. 157-67. 23. Coello R, Charlett A, Wilson J, Ward V, Pearson A, Borriello P. Adverse impact of surgical site infections in English hospitals. J Hosp Infect 2005;60:93-103. 24. Browner WS, Black D, Newman TB, Hulley SB. Estimating sample size and power. In: Hulley SB, Cummings SR, editors. Designing clinical research. Baltimore: Lippincott Williams & Wilkins; 1988. p. 139-58. 25. Hosmer DW Jr, Lemeshow SM. Applied logistic regression. 2nd ed. New York: John Wiley & Sons, Inc.; 1989. 26. Kain ZN, Sevarino FB, Rinder C, Pincus S, Alexander GM, Ivy M, et al. Preoperative anxiolysis and postoperative recovery in women undergoing abdominal hysterectomy. Anesthesiology 2001;94:415-22. 27. Irwin M, Hauger R, Brown M. Central corticotropin-releasing hormone activates the sympathetic nervous system and reduces immune function: increased responsivity of the aged rat. Endocrinology 1992; 131:1047-53. 28. Zavala F, Taupin V, Descamps-Latscha B. In vivo treatment with benzodiazepines inhibits murine phagocyte oxidative metabolism and production of interleukin 1, tumor necrosis factor and interleukin-6. J Pharmacol Exp Ther 1990;255:442-50. 29. Goto Y, O’Malley C, Fanning NF, Wang J, Redmond HP, Shorten GD. Benzodiazepines inhibit the rate of neutrophil apoptosis. Ir J Med Sci 2003;172:191-4. 30. Stoelting RK. Benzodiazepines. In: Stoelting RK, editor. Pharmacology & physiology in anaesthetic practice. Philadelphia: Lipincott-Raven; 1999. p. 126-39. 31. Williams JG, Jones JR, Workhoven MN, Williams B. The psychological control of preoperative anxiety. Psychophysiology 1975;12:50-4.
726
Vol. 36 No. 10
32. Biondi M, Zannino LG. Psychological stress, neuroimmunomodulation, and susceptibility to infectious diseases in animals and man: a review. Psychother Psychosom 1997;66:3-26. 33. Carr DB, Cousins MJ. Spinal route of analgesia opioids and future potions. In: Cousins MJ, Bridenbaugh PO, editors. Neural blockade in clinical anesthesia and management of pain. Philadelphia: Lippincott-Raven; 1998. p. 915-83. 34. Beilin B, Shavit Y, Hart J, Mordashov B, Cohn S, Notti I, et al. Effects of anesthesia based on large versus small doses of fentanyl on natural killer cell cytotoxicity in the perioperative period. Anesth Analg 1996;82:492-7. 35. Schupp CJ, Berbaum K, Berbaum M, Lang EV. Pain and anxiety during interventional radiologic procedures: effect of patients’ state anxiety at
Levandovski et al baseline and modulation by nonpharmacologic analgesia adjuncts. J Vasc Interv Radiol 2005;16:1585-92. 36. Gaynes RP, Culver DH, Horan TC, Edwards JR, Richards C, Tolson JS. Surgical site infection (SSI) rates in the United States, 1992-1998: the National Nosocomial Infections Surveillance System basic SSI risk index. Clin Infect Dis 2001;33:S69-77. 37. Kandula PK, Wenzel RP. Postoperative wound infection after total adominal hysterectomy: a controlled study of the increased duration of hospital stay and trends in postoperative wound infection. Am J Infect Control 1993;21:201-4. 38. Costa RJ, Krauss-Silva L. Systematic review and meta-analysis of antibiotic prophylaxis in abdominal Hysterectomy. Cad Saude Publica 2004;20:S175-89.