Background

Surgical site infections (SSI) include superficial incisional infections, infections of the deep incision space and organ space infections.^1,2 A large body of evidence supports the premise that SSIs can be prevented through administration of appropriate prophylactic antibiotics. Two national organizations, the Federal Centers for Disease Control and Prevention (CDC) and the American Society for Health System Pharmacists (ASHP), have recently synthesized this vast literature to produce comprehensive guidelines regarding the administration of prophylactic antibiotics across a broad range of procedures.^3,4 Because of the breadth of this literature, we limited the focus of this review of strategies to prevent SSIs to adult surgery and procedures that typically occur in the operating room (as opposed to procedures such as endoscopy, interventional cardiology, or radiology procedures).

Practice Description

Antimicrobial prophylaxis refers to a brief course of an antimicrobial agent administered just before an operation begins in order to reduce intraoperative microbial contamination to a level that will not overwhelm host defenses and result in infection. ⁴ To maximize the benefits of antimicrobial prophylactic, the agent used should be safe, inexpensive, and bactericidal with an in vitro spectrum that covers the most probable contaminants for the operation. ⁴ Administration, usually by intravenous infusion, should be timed so that a bactericidal concentration is present in serum and tissues by the time the skin is incised. ⁵ This practice is now standard of care and recommended by professional societies. ⁶ Therapeutic levels in serum and tissues should be maintained until, at most, a few hours after the incision is closed in the operating room. ⁴

Prevalence and Severity of the Target Safety Problem

Surgical site infections are a common complication of care, occurring in 2-5% of patients after clean extra-abdominal surgeries (eg, thoracic and orthopedic surgery) and in up to 20% of patients undergoing intra-abdominal procedures.^7-12 Studies following patients into the post-discharge period have reported even higher rates of postoperative infection.^13-16 These complications increase morbidity for patients and consume substantial additional resources.^17-21

Opportunities for Impact

Approximately 80-90% of surgical patients receive some kind of antibiotic prophylaxis, though recent studies have shown that choice of regimen, timing of administration or duration of prophylaxis is inappropriate in approximately 25-50% of cases.^22-27

Study Designs and Outcomes

As previously noted, the literature on prophylactic antibiotics is extensive. Therefore, the review was limited to evidence from Level 1A study designs. We identified 9 relevant studies examining the use of prophylactic antibiotics to prevent surgical site infections: 7 meta-analyses and 2 systematic reviews.^28-36 (Tables -20.1.1 and -20.1.2) These reviews were of high quality and limited their source material to randomized controlled trials. Although additional randomized trials have been published since these reviews were performed, updating the results of each review was beyond the scope of this project. All studies examined measured rates of site infection directly (Level 1), using previously published definitions to allow comparability. In addition, the rates of sepsis, length of stay, and physiologic measures were reported. One meta-analysis ³¹ and one systematic review ³³ combined rates of several relevant infectious outcomes.

Table

Table 20.1.1. Meta-analyses examining antibiotic prophylaxis*.

Table

Table 20.1.2.Systematic reviews of antibiotic prophylaxis*.

Evidence for Effectiveness of the Practice

All studies showed a marked reduction in the odds or relative risk of SSI when antibiotic prophylaxis was employed. None of the meta-analyses reviewed explicitly examined the timing of prophylaxis, although many studies pooled data from investigations of antibiotic regimens administered in the immediate preoperative period, (ie, within minutes to an hour of initial incision). Two meta-analyses in our review^29,31 suggested a trend towards lower rates of infection with use of broader-spectrum antibiotic prophylaxis, such as third generation cephalosporins. When compared with single dose prophylaxis, multiple dose prophylaxis generally did not result in significant additional benefit.^29,30,35 In fact, Tanos et al found the odds of SSI were significantly less with single dose prophylaxis. ³¹ Gillespie et al reported a greater relative risk of infection with single dose prophylaxis with a short-acting antibiotic when compared with multiple dose prophylaxis. ³⁶ However, the risk of infection with single dose prophylaxis using long-acting antibiotics did not differ significantly from that seen with multiple-dose regimens.

Potential for Harm

None of the meta-analyses analyzed reported rates of adverse events (such as allergic reactions or nosocomial infections) associated with antibiotic prophylaxis of any type or duration. Both of the systematic reviews^33,36 noted a trend towards more frequent adverse events with the use of antibiotic prophylaxis. Authors of both systematic reviews observed that these events were reported rarely and that variation in the definition of "adverse events" across studies made pooling results difficult.

Infection with Clostridium difficile affects a large number of hospitalized patients and has significant clinical and economic implications. As many as 16% of C. difficile colitis cases in surgical patients can be attributed to prophylaxis alone, ³⁷ with higher risk for this complication among patients receiving broad-spectrum antibiotics or prolonged courses of therapy. Shortening the duration of antibiotic administration may reduce potential risks of prophylaxis (see Chapter 14). Emergence of other types of resistant pathogens is an additional theoretical concern of inappropriate antibiotic prophylaxis; our literature search found no data describing effect of antibiotic prophylaxis on population-level incidence of these pathogens.

Costs and Implementation

A number of studies have evaluated strategies for improving compliance with recommended practices for perioperative antibiotic prophylaxis. These include chart audit with feedback, ³⁸ computerized decision support,^{23, 39-42} dissemination of guidelines, ⁴³ total quality management (TQM) and continuous quality improvement (CQI) techniques,^44-47 provider education programs,^48,49 and comprehensive efforts by an infection control team. ⁵⁰ Another promising and easily implemented method is to delegate the administration of prophylactic antibiotics to the anesthesia team or the holding room nursing staff.^{22, 25, 48}

Costs for systems to increase appropriate use of antibiotics will likely be offset by savings due to prevented infections. However formal analyses of the cost-effectiveness of specific programs to improve prophylaxis have not been reported.

Comment

For many surgical procedures there is clear evidence supporting the use of antibiotic prophylaxis, administered in a timely manner, to prevent surgical site infections. The reviews suggest that broader spectrum antibiotics may be superior to limited-spectrum antibiotics for intra-abdominal or gynecologic surgeries. In addition, single-dose antibiotic prophylaxis appears to be at least as effective as multiple-dose regimens for a broad range of surgical procedures and may pose less risk to patients in terms of adverse events (eg, C. difficile colitis) and less risk to the population in terms of microbial resistance.

Future research will continue to address what prophylactic regimens are most effective for various surgical procedures. Investigation should also focus on methods to improve compliance. The optimal strategies for implementation will likely vary from institution to institution.

References

1.

Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR Guideline for the Prevention of Surgical Site Infection. Hospital Infection Program, Centers for Disease Control and Prevention. Available at: http://www​.cdc.gov/ncidod/hip/. Accessed April 29, 2001.

2.

Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol. . 1999;20:250–278. [PubMed: 10219875]

3.

American Society of Health-System Pharmacists. Am J Health Syst Pharm. . 1999;56:1839–1888. [PubMed: 10511234]

4.

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. [PubMed: 10196487]

5.

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;326:281–286. [PubMed: 1728731]

6.

Dellinger EP, Gross PA, Barrett TL, et al Quality standard for antimicrobial prophylaxis in surgical procedures. The Infectious Diseases Society of America. Infect Control Hosp Epidemiol. . 1994;15:182–188. [PubMed: 8207176]

7.

Delgado-Rodriguez M, Sillero-Arenas M, Medina-Cuadros M, Martinez-Gallego G Nosocomial infections in surgical patients: comparison of two measures of intrinsic patient risk. Infect Control Hosp Epidemiol. . 1997;18:19–23. [PubMed: 9013241]

8.

Horan TC, Culver DH, Gaynes RP, Jarvis WR, Edwards JR, Reid CR Nosocomial infections in surgical patients in the United States, January 1986-June 1992. National Nosocomial Infections Surveillance (NNIS) System. Infect Control Hosp Epidemiol. . 1993;14:73–80. [PubMed: 8440883]

9.

Horan TC, Gaynes RP, Martone WJ, Jarvis WR, Emori TG CDC definitions of nosocomial surgical site infections, 1992: a modification of CDC definitions of surgical wound infections. Infect Control Hosp Epidemiol. . 1992;13:606–608. [PubMed: 1334988]

10.

Horan TC, Emori TG Definitions of key terms used in the NNIS System. Am J Infect Control. . 1997;25:112–116. [PubMed: 9113287]

11.

Wallace WC, Cinat M, Gornick WB, Lekawa ME, Wilson SE Nosocomial infections in the surgical intensive care unit: a difference between trauma and surgical patients. Am Surg. . 1999;65:987–990. [PubMed: 10515549]

12.

Scheel O, Stormark M National prevalence survey on hospital infections in Norway. J Hosp Infect. . 1999;41:331–335. [PubMed: 10392340]

13.

Sands K, Vineyard G, Platt R Surgical site infections occurring after hospital discharge. J Infect Dis. . 1996;173:963–970. [PubMed: 8603978]

14.

Waddell TK, Rotstein OD Antimicrobial prophylaxis in surgery. Committee on Antimicrobial Agents, Canadian Infectious Disease Society. CMAJ. . 1994;151:925–931. [PMC free article: PMC1337278] [PubMed: 7922928]

15.

Medina-Cuadros M, Sillero-Arenas M, Martinez-Gallego G, Delgado-Rodriguez M Surgical wound infections diagnosed after discharge from hospital: epidemiologic differences with in-hospital infections. Am J Infect Control. . 1996;24:421–428. [PubMed: 8974167]

16.

Lynch W, Davey PG, Malek M, Byrne DJ, Napier A Cost-effectiveness analysis of the use of chlorhexidine detergent in preoperative whole-body disinfection in wound infection prophylaxis. J Hosp Infect. . 1992;21:179–191. [PubMed: 1353510]

17.

Vegas AA, Jodra VM, Garcia ML Nosocomial infection in surgery wards: a controlled study of increased duration of hospital stays and direct cost of hospitalization. Eur J Epidemiol. . 1993;9:504–510. [PubMed: 8307135]

18.

Kirkland KB, Briggs JP, Trivette SL, Wilkinson WE, Sexton DJ The impact of surgical-site infections in the 1990s: attributable mortality, excess length of hospitalization, and extra costs. Infect Control Hosp Epidemiol. . 1999;20:725–730. [PubMed: 10580621]

19.

Collins TC, Daley J, Henderson WH, Khuri SF Risk factors for prolonged length of stay after major elective surgery. Ann Surg. . 1999;230:251–259. [PMC free article: PMC1420868] [PubMed: 10450740]

20.

Asensio A, Torres J Quantifying excess length of postoperative stay attributable to infections: a comparison of methods. J Clin Epidemiol. . 1999;52:1249–1256. [PubMed: 10580789]

21.

Wong ES The price of a surgical-site infection: more than just excess length of stay. Infect Control Hosp Epidemiol. . 1999;20:722–724. [PubMed: 10580620]

22.

Silver A, Eichorn A, Kral J, et al Timeliness and use of antibiotic prophylaxis in selected inpatient surgical procedures. The Antibiotic Prophylaxis Study Group. Am J Surg. . 1996;171:548–552. [PubMed: 8678197]

23.

Larsen RA, Evans RS, Burke JP, Pestotnik SL, Gardner RM, Classen DC Improved perioperative antibiotic use and reduced surgical wound infections through use of computer decision analysis. Infect Control Hosp Epidemiol. . 1989;10:316–320. [PubMed: 2745959]

24.

Finkelstein R, Reinhertz G, Embom A Surveillance of the use of antibiotic prophylaxis in surgery. Isr J Med Sci. . 1996;32:1093–1097. [PubMed: 8960079]

25.

Matuschka PR, Cheadle WG, Burke JD, Garrison RN A new standard of care: administration of preoperative antibiotics in the operating room. Am Surg. . 1997;63:500–503. [PubMed: 9168761]

26.

Gorecki P, Schein M, Rucinski JC, Wise L Antibiotic administration in patients undergoing common surgical procedures in a community teaching hospital: the chaos continues. World J Surg. . 1999;23:429–432. [PubMed: 10085388]

27.

Zoutman D, Chau L, Watterson J, Mackenzie T, Djurfeldt M A Canadian survey of prophylactic antibiotic use among hip-fracture patients. Infect Control Hosp Epidemiol. . 1999;20:752–755. [PubMed: 10580626]

28.

Mittendorf R, Aronson MP, Berry RE, et al Avoiding serious infections associated with abdominal hysterectomy: a meta-analysis of antibiotic prophylaxis. Am J Obstet Gynecol. . 1993;169:1119–1124. [PubMed: 8238170]

29.

Meijer WS, Schmitz PI, Jeekel J Meta-analysis of randomized, controlled clinical trials of antibiotic prophylaxis in biliary tract surgery. Br J Surg. . 1990;77:283–290. [PubMed: 2138925]

30.

McDonald M, Grabsch E, Marshall C, Forbes A Single-versus multiple-dose antimicrobial prophylaxis for major surgery: a systematic review. Aust N Z J Surg. . 1998;68:388–396. [PubMed: 9623456]

31.

Tanos V, Rojansky N Prophylactic antibiotics in abdominal hysterectomy. J Am Coll Surg. . 1994;179:593–600. [PubMed: 7952465]

32.

Song F, Glenny AM Antimicrobial prophylaxis in colorectal surgery: a systematic review of randomized controlled trials. Published erratum appears in Br J Surg 1999;1286:1280. Br J Surg. . 1998;85:1232–1241. [PubMed: 9752867]

33.

Smaill F, Hofmeyr GJ Antibiotic prophylaxis for cesarean section. In: The Cochrane Library, Issue 2, 2000. Oxford: Update Software.

34.

Sharma VK, Howden CW Meta-analysis of randomized, controlled trials of antibiotic prophylaxis before percutaneous endoscopic gastrostomy. Am J Gastroenterol. . 2000;95:3133–3136. [PubMed: 11095330]

35.

Kreter B, Woods M Antibiotic prophylaxis for cardiothoracic operations. Meta-analysis of thirty years of clinical trials. J Thorac Cardiovasc Surg. . 1992;104:590–599. [PubMed: 1387437]

36.

Gillespie WJ, Walenkamp G Antibiotic prophylaxis for surgery for proximal femoral and other closed long bone fractures. In: The Cochrane Library, Issue 2, 2000. Oxford: Update Software; 2000. [PubMed: 10796333]

37.

Crabtree TD, Pelletier SJ, Gleason TG, Pruett TL, Sawyer RG Clinical characteristics and antibiotic utilization in surgical patients with Clostridium difficile-associated diarrhea. Am Surg. . 1999;65:507–511. [PubMed: 10366203]

38.

Zhanel GG, Gin AS, Przybylo A, Louie TJ, Otten NH Effect of interventions on prescribing of antimicrobials for prophylaxis in obstetric and gynecologic surgery. Am J Hosp Pharm. . 1989;46:2493–2496. [PubMed: 2603884]

39.

Pestotnik SL, Evans RS, Burke JP, Gardner RM, Classen DC Therapeutic antibiotic monitoring: surveillance using a computerized expert system. Am J Med. . 1990;88:43–48. [PubMed: 2294764]

40.

Pestotnik SL, Classen DC, Evans RS, Burke JP Implementing antibiotic practice guidelines through computer-assisted decision support: clinical and financial outcomes. Ann Intern Med. . 1996;124:884–890. [PubMed: 8610917]

41.

Evans RS, Pestotnik SL, Classen DC, et al A computer-assisted management program for antibiotics and other antiinfective agents. N Engl J Med. . 1998;338:232–238. [PubMed: 9435330]

42.

Evans RS, Pestotnik SL, Burke JP, Gardner RM, Larsen RA, Classen DC Reducing the duration of prophylactic antibiotic use through computer monitoring of surgical patients. DICP. . 1990;24:351–354. [PubMed: 2327113]

43.

Dobrzanski S, Lawley DI, McDermott I, Selby M, Ausobsky JR The impact of guidelines on peri-operative antibiotic administration. J Clin Pharm Ther. . 1991;16:19–24. [PubMed: 2026666]

44.

Koska MT Using CQI methods to lower postsurgical wound infection rate. Hospitals. . 1992;66:–. [PubMed: 1572629]

45.

Kroll DA, Brummitt CF, Berry BB A users group approach to quality improvement across an integrated healthcare delivery system. J Healthc Qual. . 2000;22:39–43. [PubMed: 10787787]

46.

Welch L, Teague AC, Knight BA, Kenney A, Hernandez JE A quality management approach to optimizing delivery and administration of preoperative antibiotics. Clin Perform Qual Health Care. . 1998;6:168–171. [PubMed: 10351283]

47.

Woster PS, Ryan ML, Ginsberg-Evans L, Olson J Use of total quality management techniques to improve compliance with a medication use indicator. Top Hosp Pharm Manage. . 1995;14:68–77. [PubMed: 10140429]

48.

Gyssens IC, Knape JT, Van Hal G, ver der Meer JW The anaesthetist as determinant factor of quality of surgical antimicrobial prophylaxis. A survey in a university hospital. Pharm World Sci. . 1997;19:89–92. [PubMed: 9151347]

49.

Everitt DE, Soumerai SB, Avorn J, Klapholz H, Wessels M Changing surgical antimicrobial prophylaxis practices through education targeted at senior department leaders. Infect Control Hosp Epidemiol. . 1990;11:578–583. [PubMed: 2124233]

50.

McConkey SJ, L'Ecuyer PB, Murphy DM, Leet TL, Sundt TM, Fraser VJ Results of a comprehensive infection control program for reducing surgical-site infections in coronary artery bypass surgery. Infect Control Hosp Epidemiol. . 1999;20:533–538. [PubMed: 10466552]

51.

Wilson AP, Shrimpton S, Jaderberg M A meta-analysis of the use of amoxycillin-clavulanic acid in surgical prophylaxis. J Hosp Infect. . 1992;22:9–21. [PubMed: 1362755]

Background

The body temperature of patients may fall by 1 to 1.5°C during the first hour of general anesthesia. ¹ Regional anesthesia also typically causes core hypothermia. ² Intraoperative hypothermia impairs immune function (especially oxidative killing by neutrophils) and results in dermal vasoconstriction and reduced blood flow to surgical sites, which further increases the risk of surgical site infection by lowering tissue oxygen tension. ³ Hypothermia also results in reduced platelet function, shivering associated with patient discomfort and activation of the sympathetic nervous system, and adverse cardiac events. ²

Practice Description

Normal core temperature can be maintained during surgery through use of active measures including warmed intravenous fluids and inspired gases, as well as forced air warming. The latter involves an air blanket placed over the patient that circulates air warmed to 40°C. Water blankets may also be used, but are not as effective in maintaining body temperature. ⁴ Patient temperature is monitored using conventional thermometer probes, with active measures adjusted to maintain core temperature near 36.5°C. Any method or combination of methods that maintains the target core temperature appears to have the same effect. ²

Prevalence and Severity of the Target Safety Problem

See Subchapter 20.1.

Opportunities for impact

Attention to patient temperature is standard of care in intraoperative anesthesia management.^* However, there are no data on the extent to which active warming measures are currently used perioperatively.

Study Designs and Outcomes

We identified one randomized controlled trial ³ and one retrospective cohort study ⁶ evaluating the effect of active warming interventions on the rate of wound infection (Level 1 outcome). (Table 20.2.1). Wound infection was either defined as "suppuration requiring removal of sutures" ³ or as in previously published definitions. ⁷

Table

Table 20.2.1. Summary of studies reporting effectiveness of perioperative normothermia*.

Evidence for Effectiveness of the Practice

Kurz et al performed a randomized controlled trial of active warming in the intraoperative care of patients undergoing elective colectomy. All patients received aggressive perioperative hydration and intravenous opioids for pain relief, in an effort to maximize wound perfusion. Patients in the normothermia arm experienced a 68% reduction in the rate of wound infection, lower wound infection scores (as defined by the elements of the acronym ASEPSIS: Additional treatment, Serous discharge, Erythema, Purulent exudate, Separation of deep tissues, Isolation of bacteria, and duration of inpatient Stay), and shorter length of hospitalization. ³ While the relatively high infection rate (19% of control group in this university-based population with a substantial degree of underlying disease) and suboptimal antibiotic prophylaxis (antibiotics continued for about 4 days postoperatively; see Subchapter 20.1) do not invalidate the study results, they do limit their generalizability.

In a retrospective cohort study based on chart reviews of 150 patients undergoing elective colectomy, Barone et al noted no independent association between intraoperative hypothermia (defined as temperature less than <34.3°C) and the incidence of wound infections, or the length of stay. Explanation for differences in the findings of the two studies may relate to confounding due to the retrospective design of the study by Barone, or in differences in defining wound infections by the authors (suppuration requiring removal of sutures). ⁸

Other potential benefits of maintaining perioperative normothermia have been reported in randomized controlled trials. Frank et al found the risk of morbid cardiac events (combined outcome of angina, myocardial ischemia or infarction, and ventricular arrhythmia) was significantly decreased among patients in the normothermia group (1% intervention vs. 6% control, p=0.02). ⁹ Maintaining normothermia has also been associated with decreased blood loss and transfusion requirements among patients undergoing elective colectomy ³ and hip arthroplasty.^10,11 Postoperative shivering, thermal discomfort, time to extubation, and duration of post-anesthesia recovery are all significantly reduced.^2,12

Potential for Harm

None of these studies reported an adverse effect directly related to these practices. Sigg et al observed a higher rate of wound bacterial colonization with the reuse of forced air coverlets. ¹³

Costs and Implementation

Equipment for monitoring temperature is readily available in operating rooms. Kruz et al estimated the direct cost of fluid and forced air warming at $30 per case. ⁹ Studies have not formally assessed all relevant costs, including additional physician time required. It is likely that added costs are largely offset by savings due to reduced surgical site infections and associated decreases in length of stay.

Comment

Given the evidence of effectiveness, the low potential for harm, and the simplicity of the intervention (including the ready availability of the equipment), maintenance of perioperative normothermia seems a promising practice to improve patient safety. The methodologically stronger of the 2 studies reviewed showed clear benefits. However, some of its benefits may not be generalizable to patient populations undergoing other procedures. For example, intraoperative hypothermia may have little impact on wound infections in patients undergoing cesarean section. ¹⁴ Thus, additional study of the practice is needed in other settings. Furthermore, for some procedures hypothermia is likely to protect patients. Core temperature is often intentionally reduced to protect the myocardium and central nervous system during certain cardiac and neurosurgical procedures.^2,12,15 In such cases the potential benefits of normothermia may not outweigh the associated risks.

References

1.

Matsukawa T, Sessler DI, Sessler AM, et al Heat flow and distribution during induction of general anesthesia. Anesthesiology. . 1995;82:662–673. [PubMed: 7879935]

2.

Sessler DI Mild perioperative hypothermia. N Engl J Med. . 1997;336:1730–1737. [PubMed: 9180091]

3.

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;334:1209–1215. [PubMed: 8606715]

4.

Kurz A, Kurz M, Poeschl G, Faryniak B, Redl G, Hackl W Forced-air warming maintains intraoperative normothermia better than circulating-water mattresses. Anesth Analg. . 1993;77:89–95. [PubMed: 8317754]

5.

Standards of the American Society of Anesthesiologists. Available at: http://www.asahq.org/Standards/02.html. Accessed June 6, 2001.

6.

Barone JE, Tucker JB, Cecere J, et al Hypothermia does not result in more complications after colon surgery. Am Surg. . 1999;65:356–359. [PubMed: 10190363]

7.

Wilson AP, Treasure T, Sturridge MF, Gruneberg RN A scoring method (ASEPSIS) for postoperative wound infections for use in clinical trials of antibiotic prophylaxis. Lancet. . 1986;1:311–313. [PubMed: 2868173]

8.

Sessler DI, Kurz A, Lenhardt R Re: Hypothermia reduces resistance to surgical wound infections. Am Surg. . 1999;65:1193–1196. [PubMed: 10597075]

9.

Frank SM, Fleisher LA, Breslow MJ, et al Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. A randomized clinical trial. JAMA. . 1997;277:1127–1134. [PubMed: 9087467]

10.

Schmied H, Kurz A, Sessler DI, Kozek S, Reiter A Mild hypothermia increases blood loss and transfusion requirements during total hip arthroplasty. Lancet. . 1996;347:289–292. [PubMed: 8569362]

11.

Winkler M, Akca O, Birkenberg B, et al Aggressive warming reduces blood loss during hip arthroplasty. Anesth Analg. . 2000;91:978–984. [PubMed: 11004060]

12.

Leslie K, Sessler DI The implications of hypothermia for early tracheal extubation following cardiac surgery. discussion 41-34. J Cardiothorac Vasc Anesth. . 1998;12:30–34. [PubMed: 9919465]

13.

Sigg DC, Houlton AJ, Iaizzo PA The potential for increased risk of infection due to the reuse of convective air-warming/cooling coverlets. Acta Anaesthesiol Scand. . 1999;43:173–176. [PubMed: 10027024]

14.

Munn MB, Rouse DJ, Owen J Intraoperative hypothermia and post-cesarean wound infection. Obstet Gynecol. . 1998;91:582–584. [PubMed: 9540945]

15.

Winfree CH, Baker KZ, Connollly ES Perioperative normothermia and surgical-wound infection. N Engl J Med. . 1996;335:–. [PubMed: 8786769]

Background

Low oxygen content in devitalized tissues predisposes them to bacterial colonization, which is thought to be a key pathophysiologic step in the initiation of surgical site infections. ¹ Administration of high concentrations of oxygen increases wound oxygen tension, allowing for more effective neutrophil function and the potential for reduced infection rates. ²

Practice Description

The practice of perioperative oxygen supplementation involves administration of 80% oxygen and 20% nitrogen by endotracheal tube intraoperatively and by sealed mask and manifold system or conventional non-rebreather mask for the first two hours of recovery. Oxygen is increased to 100% immediately before extubation, with the concentration returned to 80% as soon as deemed safe by the anesthesiologist. ³

Prevalence and Severity of the Target Safety Problem

See Subchapter 20.1.

Opportunities for Impact

Administration of oxygen is a routine part of perioperative care. However the frequency with which high oxygen concentrations (as described above) are administered is not known.

Study Designs and Outcomes

We identified one randomized controlled trial evaluating the effect of high concentration oxygen supplementation on surgical site infections (Table 20.3.1). ³ The primary outcome was incidence of wound infection within 15 days after surgery (Level 1). Wounds were considered infected when bacteria were cultured from pus expressed from the incision or aspirated from a loculated collection within the wound. ³

Table

Table 20.3.1. Randomized controlled trial of supplemental perioperative oxygen*.

Table

Table 20.4.1. Prospective, before-after study of aggressive perioperative glucose control*.

Evidence for Effectiveness of the Practice

The clinical characteristics of the intervention and control groups were similar at baseline, including risk of infection as assessed by a modified Study on the Efficacy of Nosocomial Infection Control (SENIC) score (p=0.8) and National Nosocomial Infection Surveillance System (NNISS) score (p=0.86). The incidence of wound infection was significantly less in the intervention group (13/250, 5%) than in the control group (28/250, 11%, p=0.014). The results remain statistically significant when the study definition of "infection" is broadened to include wounds with pus but no bacterial growth on culture (7% vs. 14%, p=0.012). Perioperative administration of high levels of oxygen was associated with a 54% relative risk reduction (95% CI: 12%-75%) of wound infection within 15 days of surgery. ASEPSIS (Additional treatment, Serous discharge, Erythema, Purulent exudate, Separation of deep tissues, Isolation of bacteria, and duration of inpatient Stay ⁴ ) scores were also significantly better with high levels of oxygen (3 vs. 5, p=0.01). Although longer follow-up might have identified additional wound infections, the authors argue that it was unlikely that these events would take place preferentially in one group as the proposed therapeutic effect of oxygen appears limited to the immediate perioperative period. ³ Admission to the intensive care unit and death were less frequent in the intervention group, but the difference failed to achieve statistical significance.

Two additional randomized controlled trials of perioperative supplemental oxygen were identified.^5,6 Both found a significant reduction in postoperative nausea and vomiting, but neither study evaluated the effect on wound infections.

Potential for Harm

The study by Greif et al reported no adverse affects related to the intervention. Several potential risks of high oxygen concentrations should be noted. High oxygen concentrations may present a fire hazard when heated surgical instruments (eg, lasers) are introduced into the airway.^7-11 Such concentrations can also induce lung injury in certain vulnerable patients ¹² or precipitate atelectasis in patients at risk.^3,13,14 Hyperoxic mixtures may increase oxidative myocardial injury in patients undergoing cardiopulmonary bypass. ¹⁵ Finally, patients who undergo resuscitation with 100% oxygen may have worsened neurologic outcomes, possibly also as a result of increased oxygen free-radical generation.^16,17

Costs and Implementation

The incremental direct costs associated with administering high oxygen concentrations are minimal, as oxygen delivery systems are elements of routine perioperative care and employ equipment readily available in operating rooms.

Comment

Administration of perioperative oxygen in high concentrations seems a promising adjunctive therapy: the practice is simple, the equipment needed is readily available, and a multicenter randomized trial has demonstrated its efficacy.

However, there are significant questions about the generalizability of the approach to expanded populations of surgical patients. All patients in the Grief et al study had core temperature maintained at 36°C, were aggressively hydrated, and had postoperative pain treated with opioids in order to maximize wound perfusion. To what degree the effectiveness of the practice is affected by changes in these "co-interventions" has not been assessed. There is reason for concern regarding use of high concentrations of oxygen in patients undergoing procedures associated with low blood flow (eg, cardiopulmonary bypass), or in whom local production of oxygen free radicals may cause further organ injury (eg, patients with head trauma).

Additionally, questions remain regarding whether modifications to the protocol used would impart similar or greater benefit. For example, would oxygen administration by nasal cannula at 10 LPM be as effective as oxygen delivered by a sealed mask? Would longer duration of therapy impart additional benefit? These questions should be answered in future trials.

References

1.

Hopf HW, Hunt TK, West JM, et al Wound tissue oxygen tension predicts the risk of wound infection in surgical patients. Arch Surg. . 1997;132:997–1004. [PubMed: 9301613]

2.

Hopf H, Sessler DI Routine postoperative oxygen supplementation. Anesth Analg. . 1994;79:615–616. [PubMed: 8067589]

3.

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;342:161–167. [PubMed: 10639541]

4.

Wilson AP, Treasure T, Sturridge MF, Gruneberg RN A scoring method (ASEPSIS) for postoperative wound infections for use in clinical trials of antibiotic prophylaxis. Lancet. . 1986;1:311–313. [PubMed: 2868173]

5.

Greif R, Laciny S, Rapf B, Hickle RS, Sessler DI Supplemental oxygen reduces the incidence of postoperative nausea and vomiting. Anesthesiology. . 1999;91:1246–1252. [PubMed: 10551573]

6.

Goll V, Akca O, Greif R, et al Ondansetron is no more effective than supplemental intraoperative oxygen for prevention of postoperative nausea and vomiting. Anesth Analg. . 2001;92:112–117. [PubMed: 11133611]

7.

Healy GB Complications of laser surgery. Otolaryngol Clin North Am. . 1983;16:815–820. [PubMed: 6422394]

8.

Hunsaker DH Anesthesia for microlaryngeal surgery: the case for subglottic jet ventilation. Laryngoscope. . 1994;104:1–30. [PubMed: 8052087]

9.

Aly A, McIlwain M, Duncavage JA Electrosurgery-induced endotracheal tube ignition during tracheotomy. Ann Otol Rhinol Laryngol. . 1991;100:31–33. [PubMed: 1985525]

10.

Barnes AM, Frantz RA Do oxygen-enriched atmospheres exist beneath surgical drapes and contribute to fire hazard potential in the operating room? Aana J. . 2000;68:153–161. [PubMed: 10876463]

11.

de Richemond AL, Bruley ME Use of supplemental oxygen during surgery is not risk free. Anesthesiology. . 2000;93:583–584. [PubMed: 10910516]

12.

Donat SM, Levy DA Bleomycin associated pulmonary toxicity: is perioperative oxygen restriction necessary? J Urol. . 1998;160:1347–1352. [PubMed: 9751352]

13.

Akca O, Podolsky A, Eisenhuber E, et al Comparable postoperative pulmonary atelectasis in patients given 30% or 80% oxygen during and 2 hours after colon resection. Anesthesiology. . 1999;91:991–998. [PubMed: 10519502]

14.

Lentschener C Prevention of atelectasis during general anaesthesia. Lancet. . 1995;346:514–515. [PubMed: 7637518]

15.

Ihnken K, Winkler A, Schlensak C, et al Normoxic cardiopulmonary bypass reduces oxidative myocardial damage and nitric oxide during cardiac operations in the adult. J Thorac Cardiovasc Surg. . 1998;116:327–334. [PubMed: 9699587]

16.

Zwemer CF, Whitesall SE, D'Alecy LG Cardiopulmonary-cerebral resuscitation with 100% oxygen exacerbates neurological dysfunction following nine minutes of normothermic cardiac arrest in dogs. Resuscitation. . 1994;27:159–170. [PubMed: 8086011]

17.

Rubertsson S, Karlsson T, Wiklund L Systemic oxygen uptake during experimental closed-chest cardiopulmonary resuscitation using air or pure oxygen ventilation. Acta Anaesthesiol Scand. . 1998;42:32–38. [PubMed: 9527741]

Background

Diabetesis a well-known risk factor for perioperative medical complications. Poor glucose control is an independent risk factor for surgical site infections^1-5 in a range of surgical procedures. Increased risk for infection is thought to result from a combination of clinically apparent effects of longstanding hyperglycemia (eg, macro- and microvascular occlusive disease) and subtle immunologic defects, most notably neutrophil dysfunction.^6-12 Hyperglycemia may also impair the function of complement and antibodies, reducing the opsonic potential of these factors and impairing phagocytosis, further reducing barriers to infection.^13,14 Although many of the clinically apparent manifestations of diabetes are not easily reversed in the perioperative period, there is a small literature that suggests that improving glucose control can improve immunologic function and reduce the incidence of surgical site infections (SSI).^6-8,12

Perioperative management of glucose for diabetic patients commonly includes withholding or administering a reduced dose of the patients' usual hypoglycemic agent(s) and commencing a low-rate intravenous glucose infusion while patients are NPO prior to surgery. The infusion is continued postoperatively until the patient is able to eat and resume outpatient diabetes therapy. Often a sliding scale insulin regimen, a schedule of subcutaneous regular insulin dosage contingent on capillary blood glucose measurements, is also continued through the perioperative period. However, use of a sliding scale may result in wide variations in serum glucose, ¹⁵ opening the rationale of this method to question.^16-18

Practice description

Aggressive glucose control in the perioperative period can be achieved using a continuous intravenous insulin infusion (CII). Nursing staff monitor fingerstick (or arterial line drop-of-blood sample) glucose measurements and adjust the infusion rate based on a protocol intended to maintain serum glucose within a certain range. For example, the target range for the original Portland Protocol was between 151 and 200 mg/dL.^16,19,20 In the most recent version, the range is between 125 and 175 mg/dL. ²¹

Prevalence and Severity of the Target Safety Problem

Little evidence exists to describe the practice of CII in prevention of surgical site infections in broad surgical practice. The small amount of evidence available describes its use in patients undergoing cardiac surgery, primarily coronary artery bypass grafting (CABG). Diabetes is a well-described risk factor for sternal wound infections, a catastrophic complication of median sternotomy.^19,22-25 Sternal wound infections occur in 0.8% to 2% of unselected patients undergoing median sternotomy and CABG.^20,22,23 Diabetic patients, who comprise between 17 and 20% of all patients undergoing CABG, have been reported to have an incidence of sternal wound infections as high as 5.6%. ²⁶ Such infections are associated with marked increases in morbidity and costs. Furnary et al reported that patients with sternal wound infections had an average increased length of stay of 16 days and a higher mortality rate (19% vs. 3.8% in patients without sternal wound infections). ²⁰ (See also Subchapter 20.1).

Opportunities for Impact

More than 700,000 Americans underwent open-heart surgery in 1998 alone. ²⁷ Up to 20% of these patients may be candidates for continuous insulin infusion. Although CII is included in the recent ACC/AHA Guidelines for CABG Surgery, ²⁸ there are no data on the extent to which the measure is currently used during cardiac or other surgical procedures.

Study Designs and Outcomes

We identified one prospective before-after study that compared rates of deep sternal wound infections (DSWI) in diabetic patients undergoing CABG before and after implementation of an aggressive CII protocol. ²⁰ DSWI included infections involving the sternum or mediastinal tissues, including mediastinitis. An older study from the same authors was not reviewed as it reported findings at an earlier point in the same trial. ¹⁹ Additional studies examined the use of CII in perioperative patients but did not report Level 1 clinical outcomes relevant to patient safety (eg, mortality, wound infection) and were also not reviewed. ²⁹

Evidence for Effectiveness of the Practice

Furnary et al found that aggressive glucose control with CII was associated with a reduction in deep sternal wound infections. ²⁰ The effect of the intervention remained statistically significant in a logistic regression model adjusting for multiple potential confounding variables. Furthermore, the demographic characteristics were generally biased against the CII group, which had a significantly higher percentage of patients with hypertension, renal insufficiency, and obesity but fewer patients with congestive heart failure. However, the authors did not adjust for long-term markers of glucose control such as glycosylated hemoglobin, nor did they describe other changes in patient care systems that resulted from changing patients to insulin infusions. Continuous insulin infusions require closer attention by nursing staff both for monitoring of infusion equipment and for frequent measurements of blood glucose. It is possible that the improved outcomes were due to closer overall attention to the patient. Although 74% of DSWI occurred after initial discharge (raising the concern that the shorter length of stay in the sliding scale insulin group may have resulted in some infection not being detected), the authors reported that they directly followed-up all diabetic patients for one year from the time of surgery. ³⁰ The personnel, equipment, surgical techniques, and use of prophylactic antibiotics were similar throughout the study period. ³¹ Nonetheless, it is likely that secular trends in the care of patients undergoing cardiac surgery account for some of the impact attributed to CII.

Potential for Harm

Hypoglycemic episodes are the most concerning adverse event associated with intensive glucose management with intravenous insulin. These episodes result in a range of medical complications, from delirium to myocardial infarction resulting from increased sympathetic activity. Furnary noted that, using the standardized protocol in their study, no cases of symptomatic hypoglycemia occurred in either group of patients. ³⁰ However, CII protocols intended to maintain normoglycemia in surgical patients have been associated with high rates (40%) of postoperative hypoglycemia requiring treatment (<60 mg/dL glucose). ³²

Costs and Implementation

The equipment and personnel required to administer intravenous insulin are readily available. Although a formal cost-effectiveness analysis of the practice has not yet been performed, limited data are available. Furnary et al estimate the additional expense of CII at $125-150 per patient. ³³ While this likely includes direct costs of CII such as infusion equipment and additional nursing care for more frequent monitoring of glucose and adjustment of insulin infusion rates, it may underestimate the true costs of the practice at other sites, particularly during early phases of implementation. Furnary reported that the practice required a significant period of time for staff to gain familiarity and expertise with CII, and that by the end of the study they had in place a system that required no significant changes in care patterns for CII to be administered. ³⁴ In early phases of implementation there may be additional costs related to excess time spent by patients in ICU or high-level care areas (ie, stepdown units) rather than regular wards. The start-up costs in terms of training and system changes, and whether the approach is easily adaptable to sites that lack the capability to administer CII in numerous inpatient settings, have yet to be determined.

It seems likely that savings from averted infections may substantially compensate for the incremental direct costs of CII. Based on Furnary's findings and cost assumptions, the average DSWI was associated with $26,000 in additional charges (not costs). Of 1499 patients in the intervention group, the number of DSWIs prevented was 10 (95% CI: 4-21) and the average cost to prevent one DSWI was approximately $21,000 (95% CI: $10,000-$52,500). Of course, these figures do not incorporate the potential effects of the intervention on other sites of infection, mortality, adverse events, and patients' preferences (utilities) for these possible health states.

Comment

An increasing body of evidence demonstrates that tight control of blood glucose improves overall outcomes of patients with diabetes.^35-37 Emerging data, coupled with an increasing appreciation of the deleterious effects of hyperglycemia on immune function, strongly support the supposition that aggressive control of perioperative glucose reduces the incidence of surgical site infections. Although the practice has been implemented at a number of institutions and is also being used in diabetic patients undergoing non-cardiac surgeries, ³⁴ studies of its effectiveness in these settings have not yet been published. Until additional evidence is available, preferably from blinded randomized controlled trials, the intervention can be considered promising but not yet proven to be causally associated with improved outcomes.

References

1.

Medina-Cuadros M, Sillero-Arenas M, Martinez-Gallego G, Delgado-Rodriguez M Surgical wound infections diagnosed after discharge from hospital: epidemiologic differences with in-hospital infections. Am J Infect Control . 1996;24:421–428. [PubMed: 8974167]

2.

Kanat A Risk factors for neurosurgical site infections after craniotomy: a prospective multicenter study of 2944 patients. Neurosurgery . 1998;43:189–190. [PubMed: 9657212]

3.

Moro ML, Carrieri MP, Tozzi AE, Lana S, Greco D Risk factors for surgical wound infections in clean surgery: a multicenter study. Italian PRINOS Study Group. Ann Ital Chir . 1996;67:13–19. [PubMed: 8712612]

4.

Barry B, Lucet JC, Kosmann MJ, Gehanno P Risk factors for surgical wound infections in patients undergoing head and neck oncologic surgery. Acta Otorhinolaryngol Belg . 1999;53:241–244. [PubMed: 10635401]

5.

Richet HM, Chidiac C, Prat A, Pol A, David M, Maccario M, et al Analysis of risk factors for surgical wound infections following vascular surgery. Am J Med . 1991;91:170S–72S. [PubMed: 1928160]

6.

Marhoffer W, Stein M, Schleinkofer L, Federlin K Monitoring of polymorphonuclear leukocyte functions in diabetes mellitus-a comparative study of conventional radiometric function tests and low-light imaging systems. J Biolumin Chemilumin . 1994;9:165–170. [PubMed: 7942121]

7.

Terranova A The effects of diabetes mellitus on wound healing. Plast Surg Nurs . 1991;11:20–25. [PubMed: 2034714]

8.

Allen DB, Maguire JJ, Mahdavian M, Wicke C, Marcocci L, Scheuenstuhl H, et al Wound hypoxia and acidosis limit neutrophil bacterial killing mechanisms. Arch Surg . 1997;132:991–996. [PubMed: 9301612]

9.

Nolan CM, Beaty HN, Bagdade JD Further characterization of the impaired bactericidal function of granulocytes in patients with poorly controlled diabetes. Diabetes . 1978;27:889–894. [PubMed: 689300]

10.

Bagdade JD, Walters E Impaired granulocyte adherence in mildly diabetic patients: effects of tolazamide treatment. Diabetes . 1980;29:309–311. [PubMed: 7358229]

11.

Mowat A, Baum J Chemotaxis of polymorphonuclear leukocytes from patients with diabetes mellitus. N Engl J Med . 1971;284:621–627. [PubMed: 5545603]

12.

MacRury SM, Gemmell CG, Paterson KR, MacCuish AC Changes in phagocytic function with glycaemic control in diabetic patients. J Clin Pathol . 1989;42:1143–1147. [PMC free article: PMC501970] [PubMed: 2584425]

13.

Hennessey PJ, Black CT, Andrassy RJ Nonenzymatic glycosylation of immunoglobulin G impairs complement fixation. JPEN J Parenter Enteral Nutr . 1991;15:60–64. [PubMed: 2008035]

14.

Black CT, Hennessey PJ, Andrassy RJ Short-term hyperglycemia depresses immunity through nonenzymatic glycosylation of circulating immunoglobulin. J Trauma . 1990;30:830–832. [PubMed: 2380999]

15.

Queale WS, Seidler AJ, Brancati FL Glycemic control and sliding scale insulin use in medical inpatients with diabetes mellitus. Arch Intern Med . 1997;157:545–552. [PubMed: 9066459]

16.

Zinman B Insulin regimens and strategies for IDDM. Diabetes Care . 1993;16(Suppl 3):24–28. [PubMed: 8299474]

17.

Kletter GG Sliding scale fallacy. Arch Intern Med . 1998;158:–. [PubMed: 9665363]

18.

Shagan B Does anyone here know how to make insulin work backwards? Why sliding scale insulin coverage doesn't work. Pract Diabetol . 1990;9:1–4.

19.

Zerr KJ, Furnary AP, Grunkemeier GL, Bookin S, Kanhere V, Starr A Glucose control lowers the risk of wound infection in diabetics after open heart operations. Ann Thorac Surg . 1997;63:356–361. [PubMed: 9033300]

20.

Furnary AP, Zerr KJ, Grunkemeier GL, Starr A Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg . 1999;67:352–360. [PubMed: 10197653]

21.

Starr Wood Research - Continuous Intravenous Insulin Infusion. Available at: http://www.starrwood.com/research/insulin.html. Accessed June 11, 2001.

22.

Borger MA, Rao V, Weisel RD, Ivanov J, Cohen G, Scully HE, et al Deep sternal wound infection: risk factors and outcomes. Ann Thorac Surg . 1998;65:1050–1056. [PubMed: 9564926]

23.

Trick WE, Scheckler WE, Tokars JI, Jones KC, Reppen ML, Smith EM, et al Modifiable risk factors associated with deep sternal site infection after coronary artery bypass grafting. J Thorac Cardiovasc Surg . 2000;119:108–114. [PubMed: 10612768]

24.

Zacharias A, Habib RH Factors predisposing to median sternotomy complications. Deep vs superficial infection. Chest . 1996;110:1173–1178. [PubMed: 8915216]

25.

Whang W, Bigger JT Diabetes and outcomes of coronary artery bypass graft surgery in patients with severe left ventricular dysfunction: results from The CABG Patch Trial database. The CABG Patch Trial Investigators and Coordinators. J Am Coll Cardiol . 2000;36:1166–1172. [PubMed: 11028466]

26.

Golden SH, Peart-Vigilance C, Kao WH, Brancati FL Perioperative glycemic control and the risk of infectious complications in a cohort of adults with diabetes. Diabetes Care . 1999;22:1408–1414. [PubMed: 10480501]

27.

2001 Heart and Stroke Statistical Update. Available at: http://www​.americanheart​.org/statistics/medical.html. Accessed June 11, 2001.

28.

Eagle KA, Guyton RA, Davidoff R, Ewy GA, Fonger J, Gardner TJ, et al ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery). American College of Cardiology/American Heart Association. J Am Coll Cardiol . 1999;34:1262–1347. [PubMed: 10520819]

29.

Lazar HL, Chipkin S, Philippides G, Bao Y, Apstein C Glucose-insulin-potassium solutions improve outcomes in diabetics who have coronary artery operations. Ann Thorac Surg . 2000;70:145–150. [PubMed: 10921699]

30.

Furnary AP Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures [discussion] Ann Thorac Surg . 1999;67:360–62. [PubMed: 10197653]

31.

Use of historical controls may weaken conclusions. Available at: Available at: http:www​.ctsnet.org/forum/78/0/2240. Accessed June 18, 2001.

32.

Chaney MA, Nikolov MP, Blakeman BP, Bakhos M Attempting to maintain normoglycemia during cardiopulmonary bypass with insulin may initiate postoperative hypoglycemia. Anesth Analg . 1999;89:1091–1095. [PubMed: 10553817]

33.

The Portland Insulin Protocol - Frequently Asked Questions Page 1. Available at: http://www.starrwood.com/research/Insulin_FAQ1.html. Accessed June 11, 2001.

34.

The Portland Insulin Protocol - Frequently Asked Questions Page 2. Available at: http://www.starrwood.com/research/Insulin_FAQ2.html. Accessed June 11, 2001.

35.

[No authors listed] The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med . 1993;329:977–986. [PubMed: 8366922]

36.

[No authors listed] The effect of intensive diabetes therapy on the development and progression of neuropathy. The Diabetes Control and Complications Trial Research Group. Ann Intern Med . 1995;122:561–568. [PubMed: 7887548]

37.

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med . 2000;342:381–389. [PMC free article: PMC2630213] [PubMed: 10666428]