Chapter 198 Prevention of Operative Infections
An Evidence-Based Approach
Surgical site infections (SSIs) are a known problem in spinal surgery. According to the National Nosocomial Infections Surveillance Survey (NNISS), they complicate up to 2.46% of laminectomies and 6.35% of fusion operations.1 These rates vary, depending on patient risk factors and hospital-related factors. They may even be higher in some circumstances. In general, an SSI is associated with a twofold increase in mortality rate, as well as an increase in the likelihood that a patient will require readmission to the hospital or treatment in the intensive care unit.2 The length and cost of the hospital stay are increased, as well.
Most SSIs are caused by the patient’s normal skin flora (Staphylococcus species being the most common). This is true for spinal surgery as well,3,4 and is an important concept in prevention of SSIs. The keys to prevention include reduction of the bacterial burden in the wound, minimization of patient-related factors that contribute to SSIs (e.g., hyperglycemia, hypothermia), and optimization of patient nutrition and baseline health status preoperatively.
Preoperative Factors
Nutrition
More has been reported about the relationship between infection and nutrition in the general surgery and critical care literature than the spine literature.5–9 Often such studies involve polytrauma and burn victims in severe catabolic states. However, the principles involved apply to elective spine surgery as well.
A study by Klein et al.10 followed three groups of patients and analyzed infections and other complications against markers of nutritional status. Patients were deemed nutritionally replete if they had a serum albumin of at least 3.5 g/dL and an absolute lymphocyte count (a stable immune marker) of at least 1500 cells/mm3. Patients falling below either or both of these cutoffs were considered malnourished.
Antiseptic Shower
The use of antiseptic showers, either with povidone-iodine (Betadine) or chlorhexidine gluconate (CHG), has been advocated by some. A study of 700 surgical patients demonstrated a reduction of bacterial skin colonization with either soap, by a factor of 1.3-fold with iodine and 9-fold with CHG.11 Similar results have been found elsewhere.12 Although evidence to support a clear reduction in SSIs is lacking,13 a bottle of CHG solution sufficient for two preoperative showers costs about $9 US at the time of this writing, and its use is likely of great enough benefit to offset that minor cost. Thus, the practice is recommended.
Mupirocin Nasal Ointment
Staphylococcus aureus is the leading cause of SSIs in clean surgical procedures, including spinal operations. An association has been noted between nasal carriage of S. aureus in patients and the occurrence of SSIs. Twenty-five percent to 30% of the U.S. population are nasal carriers of S. aureus at any given time.14 A short course of treatment with mupirocin (Bactroban) ointment has been shown to eliminate S. aureus in many of these carriers.
To date, two randomized, controlled trials (RCTs) have been conducted to evaluate the efficacy of preoperative mupirocin ointment usage in reducing SSI rates.14,15 Both studies showed a trend toward efficacy, but neither was significant. A later analysis showed that pooling of the results showed a nearly significant decrease in the infection rate.16 However, when all nosocomial S. aureus infections (not just SSIs) among patients with nasal S. aureus were considered, the study from Perl et al. did show a statistically significant decrease in incidence with the use of mupirocin ointment.14
At this point, it is difficult to advocate the widespread use of mupirocin ointment preoperatively, considering the lack of convincing evidence showing benefit, as well as the cost (about $40 US). However, a rapid screening test for S. aureus that uses polymerase chain reaction (PCR) technology has been developed17 and has shown excellent sensitivity and specificity. This has allowed treatment targeted only toward carriers, which shows promise.18 It is reasonable to expect that within the next several years this technology will be more widely accessible. If so, it could allow for the selective treatment of carriers, which would be expected to demonstrate a beneficial effect.
Hair Removal
Possibly one of the most ingrained practices in all of surgery is shaving the skin prior to an operation. Unfortunately, it is probably also detrimental. Removing hair by shaving with a razor has been compared with the use of electric clippers in three RCTs.19–21 These trials were similar in design and focused on clean operations (general and cardiac procedures), so their results were pooled in a recent Cochrane review.22 This yielded a total of 3193 patients, divided nearly evenly between shaving (1627) and clipping (1566). The infection rate was 2.8% for the former group, and 1.4% for the latter, yielding a relative risk (RR) of 2.02, which surpassed statistical significance.
In addition to this strong evidence against shaving, two other points can be made. First, there is no good evidence to show that hair removal lowers the infection rate. The step may be omitted entirely. Second, depilatory creams have been associated with a lower infection rate than shaving in several trials22; this provides another alternative to razors should complete hair removal be desired.
Skin Preparation
Commonly employed agents contain alcohol (isopropyl or ethyl), CHG, or iodine/iodophors. Alcohol has excellent activity against bacteria and good activity against mycobacteria, fungi, and viruses.23 However, it cannot be used alone because it has essentially no residual activity once allowed to evaporate. Prior to evaporation it is flammable, which makes it incompatible with electrocautery.
CHG has good to excellent activity against bacteria and viruses. It is fair at eliminating fungi and has little activity against mycobacteria.23 Its residual activity is excellent; however, it can cause keratitis and ototoxicity with serious consequences.
Nevertheless, in a large RCT, CHG has been shown to reduce the line infection rate when compared with iodophor prep in the placement of central venous catheters.24 A similar level of evidence does not yet exist for CHG as a surgical skin prep, but it is logical to expect that the superiority of CHG would hold true here as well. Thus, favoring CHG as a skin prep is advisable, provided that there is no risk of the solution entering the eyes or ears.
Handwashing
Several options exist here as well. Iodophor and CHG solutions are available and are commonly used with scrub brushes for a specified period of time. Ten minutes has been traditional, but there is no evidence to support this ritual; the U.S. Centers for Disease Control and Prevention (CDC) recommends a duration of 2 to 5 minutes.23
Another category of hand cleaners includes water-aided, brushless formulations. Triseptin (Healthpoint Ltd., Fort Worth, TX) is one of these. It also contains ethyl alcohol 61% w/w, as well as a proprietary formulation of conditioners and fragrances. A large RCT has demonstrated equivalence of an aqueous alcohol-based hand rub with traditional handwashing techniques25; the results of this trial can safely be extrapolated to the products available on the U.S. market.
Because most SSIs arise from the patient’s skin flora, the use of one type of hand cleanser over another is largely left to individual preference. If there is a difference amongst the different agents available, it is likely quite small and has yet to be proven. Guidelines from the CDC regarding this are available.23
First, artificial nails should be avoided. They can harbor micro-organisms and predispose gloves to tearing. A series of Serratia marcescens wound infections have been traced to a surgical team member with artificial nails.26 Second, fingernails should be kept short and neat. Third, cleaning under the nails is recommended, as is removal of jewelry on the hands and arms, but the scientific support for this is overshadowed by the clear theoretical basis on which these recommendations are founded.
Surgical Gowns
The U.S. Occupational Safety and Health Administration (OSHA) requires that gowns have a minimum level of strikethrough resistance. All of the commercially available, disposable surgical gowns in the United States meet this standard. Porous cloth gowns have generally been eliminated because they do not offer this protection to the patient or to the surgeon.
Some have recommended that gowns and gloves be changed every 1.5 to 2 hours during lengthy cases.27 Although this recommendation is sensible, the cost of this practice must also be considered.
Double-Gloving
The practice of double-gloving has been advocated as a protection to both the medical staff and the patient. For the staff, the risk of transmission of a communicable disease, such as HIV or hepatitis, is likely reduced, as is the risk of gross contamination through a compromised glove. Not only is perforation of two gloves more difficult than one, but in the event of a needlestick, the “squeegee effect” of the second glove has been shown as well.28
Double-gloving may reduce the risk of SSI as well. Perforation rates of greater than 20% have been reported for the primary operator.29,30 This puts the surgeon’s skin in direct contact with the surgical bed, increasing the chance of bacterial contamination for the patient and creating a hazardous exposure for the surgeon.
Although the superiority of double-gloving in prevention of SSI has not been shown, a perusal of a recent Cochrane review reinforces the theoretical benefit of double-gloving to the patient.31 When studying the risk of perforation of the inner glove (which is the only glove for single-gloved surgeons, and the inner for those double-gloving), there is a clear trend across the 18 studies reviewed toward a lower likelihood of perforation for those who were double-gloved.31
Intraoperative Factors
Antimicrobial Adhesive Drapes
Antimicrobial adhesive drapes, such as Ioban (3M), are commonly used. These consist of an adhesive-backed plastic film that is impregnated with an iodine-containing compound. They have been shown to reduce bacterial contamination of wounds32 but have not reduced SSI rates in a prospective trial.33 However, because of their insignificant cost (about $7 US), their use remains at the discretion of the surgeon.
Antibiotic Prophylaxis
Timing and route of administration should follow the tenet of providing a tissue concentration of antibiotic that is greater than the minimum bactericidal concentration (MBC) of the organisms most likely to cause infection (i.e., Staphylococcus spp.) at the time of incision and maintaining same until the skin is closed. A first-generation cephalosporin (usually cefazolin) is most often given. Peak serum concentration of cefazolin, when given intravenously, is achieved within 5 minutes. The half-life is 1.5 to 2.5 hours; however, with doses commonly given (1 g), the MBC is generally maintained for 4 hours or more. Based on this, redosing cefazolin every 4 hours during the operation is indicated. This regimen also provides for adequate concentrations of cefazolin in clotted blood that remains in the surgical bed postoperatively. Patients allergic to penicillins may require vancomycin or clindamycin for prophylaxis. Vancomycin is also recommended by the CDC if a cluster of infections due to methicillin-resistant organisms is detected; however, no scientific cutoff has been determined for this, and its routine use as prophylaxis is discouraged.23
Antibiotic prophylaxis, according to the guidelines of the CDC and others,23,34 should be continued throughout the operation, but should be terminated not more than 24 hours postoperatively. It is important to remember that the use of prophylactic antibiotics can be associated with infectious complications and Clostridium difficile colitis.35,36 There is no good evidence to support the practice of “drain prophylaxis” or the continuation of antibiotics until surgical drains have been removed.
Core Body Temperature
Hypothermia can cause impaired immune function, including reduced antibody production, decreased chemotaxis, and phagocytosis. Kurz et al. conducted an RCT of 200 patients undergoing major colon surgery.37 Core body temperature was allowed to trend downward in the control group (n = 96; mean, 34.7°C) and maintained with warmed fluids and forced warm air heating blankets in the experimental group (n = 104; mean, 36.6°C). The infection rate in the former was 18.8% compared with 5.8% in the latter, a significant difference. Additionally, the normothermic patients tolerated solid food sooner, were discharged earlier, and had greater collagen deposition in the wound. Several other studies were not nearly as well-designed but showed similar results.38,39
It is incumbent on the surgical team to assist the anesthesiologist in maintenance of normothermia throughout the case. Anecdotally, it seems easier to maintain temperature than it is to warm up an anesthetized patient who has been allowed to become hypothermic. This can generally be accomplished by keeping the patient covered until skin prep and the operating room warm until the drapes and warm air blankets are applied.
Intraoperative Hyperoxygenation
In experimental studies the role of operative hyperoxia has proven uncertain. Greif et al. studied 500 patients undergoing major colorectal procedures.40 Oxygen was administered at the fraction of inspired oxygen, Fio2 = 0.3 (control) or 0.8 (experimental). This was continued throughout the procedure and for 2 hours postoperatively. The infection rate in the hyperoxic group was 5.2%, compared with 11.2% in the control group.
These results have yet to be repeated in a study of similar size and design. In another study of 160 patients, Pryor et al. found the infection rate of the hyperoxic group to be 25%, compared with 11% in the control group.41 This is the opposite of what the earlier study showed, and what would be predicted theoretically. However, this study’s design has been criticized on several grounds, including the small sample size and some significant differences between the control and experimental groups. Finally, Belda et al., in a study of 300 patients, found results similar to those of Greif et al.42
Surgical Drains
At all events, no convincing evidence proves that drains alter the infection rate, one way or the other, in spinal surgery. There is some argument from other disciplines that drains can increase the infection rate, at least drains of the open (i.e., Penrose) variety.27,43–45 However, this must be taken with a grain of salt, as direct interdisciplinary comparisons cannot necessarily be made.
Because of the inherently low infection rate in spinal surgery, and the likely minimal impact of drains on the infection rate, the number of patients needed for an RCT are substantial. Illustrative of this point is an article by Brown and Brookfield.46 Eighty-three patients were enrolled and underwent lumbar procedures “larger than single-level unilateral decompressions.” Drain placement was randomized. However, there were no infections. In fact, the only significant result was a higher temperature on postoperative day 1 in the drained group. The significance of this is unclear. In their discussion, the investigators eloquently summarized the reason definitive evidence for or against the use of drains in spinal surgery is unlikely: “We used data on rates of infection from previously published drain studies to estimate the sample size necessary to achieve a power of 0.80. Based on these numbers, it was determined that 9,539 patients would have to be randomized into two groups to determine a true statistically significant difference. We discontinued the study after enrolling a more realistic sample size of 83 patients.”
In a meta-analysis of RCTs in the orthopaedic literature, 3689 wounds were studied in 3495 patients.47 All patients underwent total hip or knee arthroplasty, and the groups were evenly divided with regard to drain placement. Although there was a trend toward lower infection rates in the group with drains, it was not significant. What was significant, however, was an increased transfusion requirement in the drained patients.
Operating Room Hygiene
Traffic should be kept to a minimum during a procedure. Although the surgeons are generally present in a case for the duration, this is not true of the others in the room. Allowing breaks for the scrub and circulating nurses and the anesthetist is a matter of established routine, but it still increases traffic flow into and out of the operating room. To be avoided is the practice of a person entering the room to ask if breaks are desired. This can be accomplished by use of the telephone. Certainly the restocking of surgical and anesthetic supplies should not take place during a case.
The Association of periOperative Registered Nurses (AORN) maintains a list of operating room standards and recommendations.48 This set of clear, straightforward guidelines should be familiar to all practicing surgeons. Among other things, they advise against covering sterile fields. This is because the cover can create air currents during removal, which could carry bacteria or contaminants onto the field and also because nonsterile parts of the cover may brush against the field during removal.
Postoperative Factors
Glucose Control
In a landmark study, 1548 ICU patients (mostly postsurgical) were randomized to one of two regimens of glucose control.49 In the control group, patients were started on an insulin drip if the serum glucose measured 215 mg/dL or higher, and the same was adjusted to maintain serum glucose of 180 to 200 mg/dL. The study group was started on an insulin drip for any reading greater than 110 mg/dL and titrated to maintain 80 to 110 mg/dL.
A dose-response–type relationship between postoperative blood glucose levels and deep sternal wound infections has been reported in several studies of cardiac surgery patients.50,51 These levels seem to be most important in the first 48 hours postoperatively.
Klein J.D., Hey L.A., Yu C.S., et al. Perioperative nutrition and postoperative complications in patients undergoing spinal surgery. Spine (Phila Pa 1976). 1996;21(22):2676-2682.
Kurz A., Sessler D.I., 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;334(19):1209-1215.
Maki D.G., Ringer M., Alvarado C.J. Prospective randomised trial of povidone-iodine, alcohol, and chlorhexidine for prevention of infection associated with central venous and arterial catheters. Lancet. 1991;338(8763):339-343.
National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control. 2004;32(8):470-485.
Tanner J., Woodings D., Moncaster K. Preoperative hair removal to reduce surgical site infection. Cochrane Database Syst Rev. 2006;3:CD004122.
van den Berghe G., Wouters P., Weekers F., et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345(19):1359-1367.
1. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control. 2004;32(8):470-485.
2. Kirkland K.B., Briggs J.P., Trivette S.L., et al. The impact of surgical–site infections in the 1990s: attributable mortality, excess length of hospitalization, and extra costs. Infect Control Hosp Epidemiol. 1999;20(11):725-730.
3. Weinstein M.A., McCabe J.P., Cammisa F.P.Jr. Postoperative spinal wound infection: a review of 2,391 consecutive index procedures. J Spinal Disord. 2000;13(5):422-426.
4. Olsen M.A., Mayfield J., Lauryssen C., et al. Risk factors for surgical site infection in spinal surgery. J Neurosurg. 2003;98(Suppl 2):149-155.
5. Demling R.H. The incidence and impact of pre-existing protein energy malnutrition on outcome in the elderly burn patient population. J Burn Care Rehabil. 2005;26(1):94-100.
6. Malone D.L., Genuit T., Tracy J.K., et al. Surgical site infections: reanalysis of risk factors. J Surg Res. 2002;103(1):89-95.
7. Shaw J.H., Wolfe R.R. An integrated analysis of glucose, fat, and protein metabolism in severely traumatized patients. Studies in the basal state and the response to total parenteral nutrition. Ann Surg. 1989;209(1):63-72.
8. McPhee I.B., Williams R.P., Swanson C.E. Factors influencing wound healing after surgery for metastatic disease of the spine. Spine (Phila Pa 1976). 1998;23(6):726-732. discussion 732–733
9. Engelman D.T., Adams D.H., Byrne J.G., et al. Impact of body mass index and albumin on morbidity and mortality after cardiac surgery. J Thorac Cardiovasc Surg. 1999;118(5):866-873.
10. Klein J.D., Hey L.A., Yu C.S., et al. Perioperative nutrition and postoperative complications in patients undergoing spinal surgery. Spine (Phila Pa 1976). 1996;21(22):2676-2682.
11. Garibaldi R.A. Prevention of intraoperative wound contamination with chlorhexidine shower and scrub. J Hosp Infect. 1988;11(Suppl B):5-9.
12. Paulson D.S. Efficacy evaluation of a 4% chlorhexidine gluconate as a full-body shower wash. Am J Infect Control. 1993;21(4):205-209.
13. Hayek L.J., Emerson J.M., Gardner A.M. A placebo-controlled trial of the effect of two preoperative baths or showers with chlorhexidine detergent on postoperative wound infection rates. J Hosp Infect. 1987;10(2):165-172.
14. Perl T.M., Cullen J.J., Wenzel R.P., et al. Intranasal mupirocin to prevent postoperative Staphylococcus aureus infections. N Engl J Med. 2002;346(24):1871-1877.
15. Kalmeijer M.D., Coertjens H., van Nieuwland-Bollen P.M., et al. Surgical site infections in orthopedic surgery: the effect of mupirocin nasal ointment in a double-blind, randomized, placebo-controlled study. Clin Infect Dis. 2002;35(4):353-358.
16. Kluytmans J.A., Wertheim H.F. Nasal carriage of Staphylococcus aureus and prevention of nosocomial infections. Infection. 2005;33(1):3-8.
17. Shrestha N.K., Shermock K.M., Gordon S.M., et al. Predictive value and cost-effectiveness analysis of a rapid polymerase chain reaction for preoperative detection of nasal carriage of Staphylococcus aureus. Infect Control Hosp Epidemiol. 2003;24(5):327-333.
18. Shrestha N.K., Banbury M.K., Weber M., et al. Safety of targeted perioperative mupirocin treatment for preventing infections after cardiac surgery. Ann Thorac Surg. 2006;81(6):2183-2188.
19. Alexander J.W., Fischer J.E., Boyajian M., et al. The influence of hair-removal methods on wound infections. Arch Surg. 1983;118(3):347-352.
20. Balthazar E.R., Colt J.D., Nichols R.L. Preoperative hair removal: a random prospective study of shaving versus clipping. South Med J. 1982;75(7):799-801.
21. Ko W., Lazenby W.D., Zelano J.A., et al. Effects of shaving methods and intraoperative irrigation on suppurative mediastinitis after bypass operations. Ann Thorac Surg. 1992;53(2):301-305.
22. Tanner J., Woodings D., Moncaster K. Preoperative hair removal to reduce surgical site infection. Cochrane Database Syst Rev. 2006;3:CD004122.
23. Mangram A.J., Horan T.C., Pearson M.L., et al. 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(2):97-132. quiz 133–134; discussion 96
24. Maki D.G., Ringer M., Alvarado C.J. Prospective randomised trial of povidone-iodine, alcohol, and chlorhexidine for prevention of infection associated with central venous and arterial catheters. Lancet. 1991;338(8763):339-343.
25. Parienti J.J., Thibon P., Heller R., et al. Hand-rubbing with an aqueous alcoholic solution vs traditional surgical hand-scrubbing and 30-day surgical site infection rates: a randomized equivalence study. JAMA. 2002;288(6):722-727.
26. Passaro D.J., Waring L., Armstrong R., et al. Postoperative Serratia marcescens wound infections traced to an out-of-hospital source. J Infect Dis. 175(4), 1997. 992–925
27. Barie P.S., Eachempati S.R. Surgical site infections. Surg Clin North Am. 2005;85(6):1115-1135. viii–ix
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29. Driever R., Beie M., Schmitz E., et al. Surgical glove perforation in cardiac surgery. Thorac Cardiovasc Surg. 2001;49(6):328-330.
30. Berguer R., Heller P.J. Strategies for preventing sharps injuries in the operating room. Surg Clin North Am. 2005;85(6):1299-1305. xiii
31. Tanner J., Parkinson H. Double gloving to reduce surgical cross-infection. Cochrane Database Syst Rev. 2006;3:CD003087.
32. Fairclough J.A., Johnson D., Mackie I. The prevention of wound contamination by skin organisms by the pre-operative application of an iodophor impregnated plastic adhesive drape. J Int Med Res. 1986;14(2):105-109.
33. Dewan P.A., Van Rij A.M., Robinson R.G., et al. The use of an iodophor-impregnated plastic incise drape in abdominal surgery––a controlled clinical trial. Aust N Z J Surg. 1987;57(11):859-863.
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35. Namias N., Harvill S., Ball S., et al. Cost and morbidity associated with antibiotic prophylaxis in the ICU. J Am Coll Surg. 1999;188(3):225-230.
36. Morris A.M., Jobe B.A., Stoney M., et al. Clostridium difficile colitis: an increasingly aggressive iatrogenic disease? Arch Surg. 2002;137(10):1096-1100.
37. Kurz A., Sessler D.I., 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;334(19):1209-1215.
38. Melling A.C., Ali B., Scott E.M., Leaper D.J. Effects of preoperative warming on the incidence of wound infection after clean surgery: a randomised controlled trial. Lancet. 2001;358(9285):876-880.
39. Flores-Maldonado A., Medina-Escobedo C.E., Rios-Rodriguez H.M., et al. Mild perioperative hypothermia and the risk of wound infection. Arch Med Res. 2001;32(3):227-231.
40. Greif R., Akca O., Horn E.P., et al. Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection. Outcomes Research Group. N Engl J Med. 2000;342(3):161-167.
41. Pryor K.O., Fahey T.J.3rd, Lien C.A., Goldstein P.A. Surgical site infection and the routine use of perioperative hyperoxia in a general surgical population: a randomized controlled trial. JAMA. 2004;291(1):79-87.
42. Belda F.J., Aguilera L., Garcia de la Asuncion J., et al. Supplemental perioperative oxygen and the risk of surgical wound infection: a randomized controlled trial. JAMA. 2005;294(16):2035-2042.
43. Sarr M.G., Parikh K.J., Minken S.L., et al. Closed-suction versus Penrose drainage after cholecystectomy. A prospective, randomized evaluation. Am J Surg. 1987;153(4):394-398.
44. Vilar-Compte D., Mohar A., Sandoval S., et al. Surgical site infections at the National Cancer Institute in Mexico: a case–control study. Am J Infect Control. 2000;28(1):14-20.
45. Fong Y., Brennan M.F., Brown K., et al. Drainage is unnecessary after elective liver resection. Am J Surg. 1996;171(1):158-162.
46. Brown M.D., Brookfield K.F. A randomized study of closed wound suction drainage for extensive lumbar spine surgery. Spine (Phila Pa 1976). 2004;29(10):1066-1068.
47. Parker M.J., Roberts C.P., Hay D. Closed suction drainage for hip and knee arthroplasty. A meta–analysis. J Bone Joint Surg [Am]. 2004;86(6):1146-1152.
48. Recommended practices for maintaining a sterile field. AORN J. 2006;83(2):402-404. 407–410, 413–416
49. van den Berghe G., Wouters P., Weekers F., et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345(19):1359-1367.
50. Latham R., Lancaster A.D., Covington J.F., et al. The association of diabetes and glucose control with surgical-site infections among cardiothoracic surgery patients. Infect Control Hosp Epidemiol. 2001;22(10):607-612.
51. Zerr K.J., Furnary A.P., Grunkemeier G.L., et al. Glucose control lowers the risk of wound infection in diabetics after open heart operations. Ann Thorac Surg. 1997;63(2):356-361.